Author Report for: Markowitz JSNo contact information in database for Markowitz JS
Melchert PW, Zhang Q, Mukhopadhyay S, Kanumuri SRR, McCurdy CR, Markowitz JS Ref: Chemico-Biological Interactions, :110715, 2023 : PubMed ESTHER: Melchert_2023_Chem.Biol.Interact__110715 PubMedSearch: Melchert 2023 Chem.Biol.Interact 110715 PubMedID: 37716419 Abstract Kratom, (Mitragyna Speciosa Korth.) is a plant indigenous to Southeast Asia whose leaves are cultivated for a variety of medicinal purposes and mostly consumed as powders or tea in the United States. Kratom use has surged in popularity with the lay public and is currently being investigated for possible therapeutic benefits including as a treatment for opioid withdrawal due to the pharmacologic effects of its indole alkaloids. A wide array of psychoactive compounds are found in kratom, with mitragynine being the most abundant alkaloid. The drug-drug interaction (DDI) potential of mitragynine and related alkaloids have been evaluated for effects on the major cytochrome P450s (CYPs) via in vitro assays and limited clinical investigations. However, no thorough assessment of their potential to inhibit the major hepatic hydrolase, carboxylesterase 1 (CES1), exists. The purpose of this study was to evaluate the in vitro inhibitory potential of kratom extracts and its individual major alkaloids using an established CES1 assay and incubation system. Three separate kratom extracts and the major kratom alkaloids mitragynine, speciogynine, speciociliatine, paynantheine, and corynantheidine displayed a concentration-dependent reversible inhibition of CES1. The experimental K(i) values were determined as follows for mitragynine, speciociliatine, paynantheine, and corynantheidine: 20.6, 8.6, 26.1, and 12.5 microM respectively. Speciociliatine, paynantheine, and corynantheidine were all determined to be mixed-type reversible inhibitors of CES1, while mitragynine was a purely competitive inhibitor. Based on available pharmacokinetic data, determined Ki values, and a physiologically based inhibition screen mimicking alkaloid exposures in humans, a DDI mediated via CES1 inhibition appears unlikely across a spectrum of doses (i.e., 2-20g per dose). However, further clinical studies need to be conducted to exclude the possibility of a DDI at higher and extreme doses of kratom and those who are chronic users. Title: The Influence of Cannabidiol on the Pharmacokinetics of Methylphenidate in Healthy Subjects Markowitz JS, De Faria L, Zhang Q, Melchert PW, Frye RF, Klee BO, Qian Y Ref: Med Cannabis Cannabinoids, 5:199, 2022 : PubMed ESTHER: Markowitz_2022_Med.Cannabis.Cannabinoids_5_199 PubMedSearch: Markowitz 2022 Med.Cannabis.Cannabinoids 5 199 PubMedID: 36467779 Abstract INTRODUCTION: Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as an over-the-counter supplement, a component of medical cannabis, and a prescriptive treatment of childhood epilepsies. In vitro studies suggest CBD may inhibit a number of drug-metabolizing enzymes, including carboxylesterase 1 (CES1). The aim of this study was to evaluate effect of CBD on the disposition of the CES1 substrate methylphenidate (MPH). METHODS: In a randomized, placebo-controlled, crossover study, 12 subjects ingested 750 mg of CBD solution, or alternatively, a placebo solution twice daily for a 3-day run-in period followed by an additional CBD dose (or placebo) and a single 10 mg dose of MPH and completed serial blood sampling for pharmacokinetic analysis. MPH and CBD concentrations were measured by liquid chromatography with tandem mass spectrometry. RESULTS: The C(max) (mean +/- CV) for the CBD group and placebo group was 13.5 +/- 43.7% ng/mL and 12.2 +/- 36.4% ng/mL, respectively. AUC(inf) (ng/mL*h) for the CBD group and placebo group was 70.7 +/- 32.5% and 63.6 +/- 25.4%, respectively. The CBD AUC(0-8h) (mean +/- CV) was 1,542.2 +/- 32% ng/mL*h, and C(max) was 389.2 +/- 39% ng/mL. When compared to MPH only, the geometric mean ratio (CBD/control, 90% CI) for AUC(inf) and C(max) with CBD co-administration was 1.09 (0.89, 1.32) and 1.08 (0.85, 1.37), respectively. DISCUSSION/CONCLUSION: Although the upper bound of bioequivalence was not met, the mean estimates of AUC and C(max) ratios were generally small and unlikely to be of clinical significance. Title: In vitro inhibition of carboxylesterase 1 by Kava (Piper methysticum) Kavalactones Melchert PW, Qian Y, Zhang Q, Klee BO, Xing C, Markowitz JS Ref: Chemico-Biological Interactions, :109883, 2022 : PubMed ESTHER: Melchert_2022_Chem.Biol.Interact__109883 PubMedSearch: Melchert 2022 Chem.Biol.Interact 109883 PubMedID: 35278473 Abstract Kava refers to the extracts from the rhizome of the plant Piper methysticum which is of particular significance to various indigenous cultures in the South Pacific region. Kavalactones are the active constituents of kava products and are associated with sedative and anxiolytic effects. Kavalactones have been evaluated in vitro for their potential to alter the activity of various CYP450 enzymes but have undergone little systematic investigation as to their potential influence on esterases. This study investigated the inhibition effects of kava and its kavalactones on carboxylesterase 1 (CES1) in an in vitro system and established associated kinetic parameters. Kava and its kavalactones were found to produce reversible inhibition of CES1 to varying degrees. Kavain, dihydrokavain, and desmethoxyyangonin displayed competitive type inhibition, while methysticin, dihydromethysticin, and yangonin displayed a mixed competitive-noncompetitive type inhibition. The inhibition constants (K(i)) values for each of the kavalactones were as follows: methysticin (35.2 microM), dihydromethysticin (68.2 microM), kavain (81.6 microM), dihydrokavain (105.3 microM), yangonin (24.9 microM), and desmethoxyyangonin (25.2 microM). With consideration to the in vitro K(i) for each evaluated kavalactone as well as available clinical kavalactone concentrations in blood circulation, co-administration of CES1 substrate medications and kava products at the recommended daily dose is generally free of drug interaction concerns. However, uncertainty around kavalactone exposure in humans has been noted and a clinically relevant CES1 inhibition by kavain, dihydrokavain, and dihydromethysticin is indeed possible if the kavalactone consumption is higher than 1000 mg in the context of over-the-counter usage. Further clinical studies would be required to assess the possibility of clinically significant kava drug-drug interactions with CES1 substrate medications. Title: Prediction of Carboxylesterase 1 (CES1)-mediated In Vivo Drug Interaction between Methylphenidate and Cannabinoids using Static and Physiologically Based Pharmacokinetic Models Qian Y, Markowitz JS Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, :, 2022 : PubMed ESTHER: Qian_2022_Drug.Metab.Dispos__ PubMedSearch: Qian 2022 Drug.Metab.Dispos PubMedID: 35512806 Abstract The use of cannabis products has increased substantially. Cannabis products have been perceived and investigated as potential treatments for attention-deficit/hyperactivity disorder (ADHD). Accordingly, co-administration of cannabis products and methylphenidate (MPH), a first-line medication for ADHD, is possible. Oral MPH undergoes extensive pre-systemic metabolism by carboxylesterase 1 (CES1), a hepatic enzyme which can be inhibited by two prominent cannabinoids, delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). This prompts further investigation into the likelihood of clinical interactions between MPH and these two cannabinoids through CES1 inhibition. In the present study, inhibition parameters were obtained from a human liver S9 system and then incorporated into static and physiologically-based pharmacokinetic (PBPK) models for prediction of potential clinical significance. The inhibition of MPH hydrolysis by THC and CBD was reversible, with estimated unbound inhibition constants (K(i,u)) of 0.031 and 0.091 microM, respectively. The static model predicted a mild increase in MPH exposure by concurrent THC (34%) and CBD (94%) from smoking a cannabis cigarette and ingestion of prescriptive CBD, respectively. PBPK models suggested no significant interactions between single doses of MPH and CBD (2.5 - 10 mg/kg) when administered simultaneously, while a mild interaction (AUC increased by up to 55% and C(max) by up to 45%) is likely if multiple doses of CBD (10 mg/kg twice daily) are administered. In conclusion, the pharmacokinetic disposition of MPH can be potentially influenced by THC and CBD under certain clinical scenarios. Whether the magnitude of predicted interactions translates into clinically relevant outcomes requires verification in an appropriately designed clinical study. Significance Statement This work demonstrated a potential mechanism of drug-drug interactions between methylphenidate (MPH) and two major cannabinoids (delta(9)-tetrahydrocannabinol [THC] and cannabidiol [CBD]) not previously reported. We predicted a mild interaction between MPH and THC when the cannabinoid exposure occurred via cannabis smoking. Mild interactions between MPH and CBD were predicted with multiple oral administrations of CBD. Title: Involvement of esterases in the pulmonary metabolism of beclomethasone dipropionate and the potential influence of cannabis use Qian Y, Melchert PW, Markowitz JS Ref: Chemico-Biological Interactions, :110228, 2022 : PubMed ESTHER: Qian_2022_Chem.Biol.Interact__110228 PubMedSearch: Qian 2022 Chem.Biol.Interact 110228 PubMedID: 36283465 Abstract Beclomethasone dipropionate (BDP) is an inhaled glucocorticoid used for maintenance treatment of asthma in adults and children. BDP is a prodrug activated in lung when hydrolyzed to its major active metabolite beclomethasone-17-monopropionate (17-BMP), which can be further deactivated to beclomethasone (BOH). The specific hydrolases contributing to these processes have not been identified which warrants an investigation to enable a better assessment of the drug-drug interaction (DDI) liability and a better management of drug efficacy and systemic toxicity. In the present study, the pulmonary metabolism of BDP was investigated using both human lung S9 (HLuS9) and recombinant carboxylesterase 1 (CES1) S9. By employing the relative activity approach, we tested the hypothesis of CES1 being the major enzyme involved. Assessment of other hydrolases were conducted in an assay with selective esterase inhibitors. In addition, the DDI potentials between BDP and delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) were evaluated due to the increasing use of inhaled cannabis both recreationally and medically. The mechanism of DDI was conducted in an in vitro time-dependent inhibition assay, and further interpreted utilizing a proposed model. In HLuS9, BDP was efficiently metabolized almost completely to 17-BMP, which was then converted to BOH at a much lower rate. CES1 was found as a minor contributor accounting for only 1.4% of BDP metabolism in HLuS9, while arylacetamide deacetylase might be the main enzyme involved. Both THC and CBD inhibited the HLuS9 mediated BDP hydrolysis in a reversible manner, with reported IC(50) values estimated as 8.98 and 36.8 microM, respectively. Our proposed model suggested a moderately decreased 17-BMP exposure in lung by concomitant THC from a cannabis cigarette, while the effects from orally taken CBD was expected to be of no clinical relevance. Title: In vitro evaluation of the impact of Covid-19 therapeutic agents on the hydrolysis of the antiviral prodrug remdesivir Zhang Q, Melchert PW, Markowitz JS Ref: Chemico-Biological Interactions, 365:110097, 2022 : PubMed ESTHER: Zhang_2022_Chem.Biol.Interact_365_110097 PubMedSearch: Zhang 2022 Chem.Biol.Interact 365 110097 PubMedID: 35964681 Inhibitor(s) related to this paper: Remdesivir Abstract Remdesivir (RDV, Veklury(a)) is an FDA-approved prodrug for the treatment of hospitalized patients with COVID-19. Recent in vitro studies have indicated that human carboxylesterase 1 (CES1) is the major metabolic enzyme catalyzing RDV activation. COVID-19 treatment for hospitalized patients typically also involves a number of antibiotics and anti-inflammatory drugs. Further, individuals who are carriers of a CES1 variant (polymorphism in exon 4 codon 143 [G143E]) may experience impairment in their ability to metabolize therapeutic agents which are CES1 substrates. The present study assessed the potential influence of nine therapeutic agents (hydroxychloroquine, ivermectin, erythromycin, clarithromycin, roxithromycin, trimethoprim, ciprofloxacin, vancomycin, and dexamethasone) commonly used in treating COVID-19 and 5 known CES1 inhibitors on the metabolism of RDV. Additionally, we further analyzed the mechanism of inhibition of cannabidiol (CBD), as well as the impact of the G143E polymorphism on RDV metabolism. An in vitro S9 fraction incubation method and in vitro to in vivo pharmacokinetic scaling were utilized. None of the nine therapeutic agents evaluated produced significant inhibition of RDV hydrolysis; CBD was found to inhibit RDV hydrolysis by a mixed type of competitive and noncompetitive partial inhibition mechanism. In vitro to in vivo modeling suggested a possible reduction of RDV clearance and increase of AUC when coadministration with CBD. The same scaling method also suggested a potentially lower clearance and higher AUC in the presence of the G143E variant. In conclusion, a potential CES1-mediated DDI between RDV and the nine assessed medications appears unlikely. However, a potential CES1-mediated DDI between RDV and CBD may be possible with sufficient exposure to the cannabinoid. Patients carrying the CES1 G143E variant may exhibit a slower biotransformation and clearance of RDV. Further clinical studies would be required to evaluate and characterize the clinical significance of a CBD-RDV interaction. Title: Plasma carboxylesterase 1 predicts methylphenidate exposure: a proof-of-concept study using plasma protein biomarker for hepatic drug metabolism Shi J, Xiao J, Wang X, Jung SM, Bleske BE, Markowitz JS, Patrick KS, Zhu HJ Ref: Clinical Pharmacology & Therapeutics, :, 2021 : PubMed ESTHER: Shi_2021_Clin.Pharmacol.Ther__ PubMedSearch: Shi 2021 Clin.Pharmacol.Ther PubMedID: 34743324 Abstract Hepatic drug-metabolizing enzymes (DMEs) play critical roles in determining the pharmacokinetics and pharmacodynamics of numerous therapeutic agents. As such, noninvasive biomarkers capable of predicting DME expression in the liver have the potential to be used to personalize pharmacotherapy and improve drug treatment outcomes. In the present study, we quantified carboxylesterase 1 (CES1) protein concentrations in plasma samples collected during a methylphenidate (MPH) PK study. CES1 is a prominent hepatic enzyme responsible for the metabolism of many medications containing small ester moieties, including MPH. The results revealed a significant inverse correlation between plasma CES1 protein concentrations and the area under the concentration-time curves (AUCs) of plasma d-MPH (p = 0.014, r = -0.617). In addition, when plasma CES1 protein levels were normalized to the plasma concentrations of 24 liver-enriched proteins to account for potential interindividual differences in hepatic protein release rate, the correlation was further improved (p = 0.003, r = -0.703), suggesting that plasma CES1 protein could explain approximately 50% of the variability in d-MPH AUCs in the study participants. A physiologically based pharmacokinetic (PBPK) modeling simulation revealed that the CES1-based individualized dosing strategy might significantly reduce d-MPH exposure variability in pediatric patients relative to conventional fixed dosing trial and error regimens. This proof-of-concept study indicates that the plasma protein of a hepatic DME may serve as a biomarker for predicting its metabolic function and the pharmacokinetics of its substrate drugs. Title: Natural Products as Modulators of CES1 Activity Qian Y, Markowitz JS Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, 48:993, 2020 : PubMed ESTHER: Qian_2020_Drug.Metab.Dispos_48_993 PubMedSearch: Qian 2020 Drug.Metab.Dispos 48 993 PubMedID: 32591414 Abstract Carboxylesterase (CES) 1 is the predominant esterase expressed in the human liver and is capable of catalyzing the hydrolysis of a wide range of therapeutic agents, toxins, and endogenous compounds. Accumulating studies have demonstrated associations between the expression and activity of CES1 and the pharmacokinetics and/or pharmacodynamics of CES1 substrate medications (e.g., methylphenidate, clopidogrel, oseltamivir). Therefore, any perturbation of CES1 by coingested xenobiotics could potentially compromise treatment. Natural products are known to alter drug disposition by modulating cytochrome P450 and UDP-glucuronosyltransferase enzymes, but this issue is less thoroughly explored with CES1. We report the results of a systematic literature search and discuss natural products as potential modulators of CES1 activity. The majority of research reports reviewed were in vitro investigations that require further confirmation through clinical study. Cannabis products (delta (9)-tetrahydrocannabinol, cannabidiol, cannabinol); supplements from various plant sources containing naringenin, quercetin, luteolin, oleanolic acid, and asiatic acid; and certain traditional medicines (danshen and zhizhuwan) appear to pose the highest inhibition potential. In addition, ursolic acid, gambogic acid, and glycyrrhetic acid, if delivered intravenously, may attain high enough systemic concentrations to significantly inhibit CES1. The provision of a translational interpretation of in vitro assessments of natural product actions and interactions is limited by the dearth of basic pharmacokinetic data of the natural compounds exhibiting potent in vitro influences on CES1 activity. This is a major impediment to assigning even potential clinical significance. The modulatory effects on CES1 expression after chronic exposure to natural products warrants further investigation. SIGNIFICANCE STATEMENT: Modulation of CES1 activity by natural products may alter the course of treatment and clinical outcome. In this review, we have summarized the natural products that can potentially interact with CES1 substrate medications. We have also noted the limitations of existing reports and outlined challenges and future directions in this field. Title: The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications Qian Y, Gurley BJ, Markowitz JS Ref: J Clin Psychopharmacol, 39:462, 2019 : PubMed ESTHER: Qian_2019_J.Clin.Psychopharmacol_39_462 PubMedSearch: Qian 2019 J.Clin.Psychopharmacol 39 462 PubMedID: 31433338 Abstract PURPOSE: Increased cannabis use and recent drug approvals pose new challenges for avoiding drug interactions between cannabis products and conventional medications. This review aims to identify drug-metabolizing enzymes and drug transporters that are affected by concurrent cannabis use and, conversely, those co-prescribed medications that may alter the exposure to one or more cannabinoids. METHODS: A systematic literature search was conducted utilizing the Google Scholar search engine and MEDLINE (PubMed) database through March 2019. All articles describing in vitro or clinical studies of cannabis drug interaction potential were retrieved for review. Additional articles of interest were obtained through cross-referencing of published bibliographies. FINDINGS: After comparing the in vitro inhibition parameters to physiologically achievable cannabinoid concentrations, it was concluded that CYP2C9, CYP1A1/2, and CYP1B1 are likely to be inhibited by all 3 major cannabinoids Delta-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). The isoforms CYP2D6, CYP2C19, CYP2B6, and CYP2J2 are inhibited by THC and CBD. CYP3A4/5/7 is potentially inhibited by CBD. Delta-Tetrahydrocannabinol also activates CYP2C9 and induces CYP1A1. For non-CYP drug-metabolizing enzymes, UGT1A9 is inhibited by CBD and CBN, whereas UGT2B7 is inhibited by CBD but activated by CBN. Carboxylesterase 1 (CES1) is potentially inhibited by THC and CBD. Clinical studies suggest inhibition of CYP2C19 by CBD, inhibition of CYP2C9 by various cannabis products, and induction of CYP1A2 through cannabis smoking. Evidence of CBD inhibition of UGTs and CES1 has been shown in some studies, but the data are limited at present. We did not identify any clinical studies suggesting an influence of cannabinoids on drug transporters, and in vitro results suggest that a clinical interaction is unlikely. CONCLUSIONS: Medications that are prominent substrates for CYP2C19, CYP2C9, and CYP1A2 may be particularly at risk of altered disposition by concomitant use of cannabis or 1 or more of its constituents. Caution should also be given when coadministered drugs are metabolized by UGT or CES1, on which subject the information remains limited and further investigation is warranted. Conversely, conventional drugs with strong inhibitory or inductive effects on CYP3A4 are expected to affect CBD disposition. Title: In Vitro Inhibition of Carboxylesterase 1 by Major Cannabinoids and Selected Metabolites Qian Y, Wang X, Markowitz JS Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, 47:465, 2019 : PubMed ESTHER: Qian_2019_Drug.Metab.Dispos_47_465 PubMedSearch: Qian 2019 Drug.Metab.Dispos 47 465 PubMedID: 30833288 Gene_locus related to this paper: human-CES1 Abstract The escalating use of medical cannabis and significant recreational use of cannabis in recent years has led to a higher potential for metabolic interactions between cannabis or one or more of its components and concurrently used medications. Although there have been a significant number of in vitro and in vivo assessments of the effects of cannabis on cytochrome P450 and UDP-glucuronosyltransferase enzyme systems, there is limited information regarding the effects of cannabis on the major hepatic esterase, carboxylesterase 1 (CES1). In this study, we investigated the in vitro inhibitory effects of the individual major cannabinoids and metabolites 9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabinol (CBN), 11-nor-THC-carboxylic acid, and 11-hydroxy-THC on CES1 activity. S9 fractions from human embryonic kidney 293 cells stably expressing CES1 were used in the assessment of cannabinoid inhibitory effects. THC, CBD, and CBN each exhibited substantial inhibitory potency, and were further studied to determine their mechanism of inhibition and kinetic parameters. The inhibition of CES1 by THC, CBD, and CBN was reversible and appears to proceed through a mixed competitive-noncompetitive mechanism. The inhibition constant (K i) values for THC, CBD, and CBN inhibition were 0.541, 0.974, and 0.263 microM (0.170, 0.306, and 0.0817 microg/ml), respectively. Inhibition potency was increased when THC, CBD, and CBN were combined. Compared with the potential unbound plasma concentrations attainable clinically, the K i values suggest a potential for clinically significant inhibition of CES1 by THC and CBD. CBN, however, is expected to have a limited impact on CES1. Carefully designed clinical studies are warranted to establish the clinical significance of these in vitro findings. Title: The influence of carboxylesterase 1 polymorphism and cannabidiol on the hepatic metabolism of heroin Qian Y, Gilliland TK, Markowitz JS Ref: Chemico-Biological Interactions, :108914, 2019 : PubMed ESTHER: Qian_2019_Chem.Biol.Interact__108914 PubMedSearch: Qian 2019 Chem.Biol.Interact 108914 PubMedID: 31837295 Abstract Heroin (diamorphine) is a highly addictive opioid drug synthesized from morphine. The use of heroin and incidence of heroin associated overdose death has increased sharply in the US. Heroin is primarily metabolized via deacetylation (hydrolysis) forming the active metabolites 6-monoacetylmorphine (6-MAM) and morphine. A diminution in heroin hydrolysis is likely to cause higher drug effects and toxicities. In this study, we sought to determine the contribution of the major hepatic hydrolase carboxylesterase 1 (CES1) to heroin metabolism in the liver as well as the potential influence of one of its known genetic variants, G143E (rs71647871). Furthermore, given the potential therapeutic application of cannabidiol (CBD) for heroin addiction and the frequent co-abuse of cannabis and heroin, we also assessed the effects of CBD on heroin metabolism. In vitro systems containing human liver, wild-type CES1, and G143E CES1 S9 fractions were utilized in the assessment. The contribution of CES1 to the hydrolysis of heroin to 6-MAM was determined as 3.66%, and CES1 was unable to further catalyze 6-MAM under our assay conditions. The G143E variant showed a 3.2-fold lower intrinsic clearance of heroin as compared to the WT. CBD inhibited heroin and 6-MAM hydrolysis in a reversible manner, with IC50s of 14.7 and 12.1muM, respectively. Our study results suggested only minor involvement of CES1 in heroin hydrolysis in the liver. Therefore, the G143E variant is unlikely to cause significant impact despite a much lower hydrolytic activity. CBD exhibited potent in vitro inhibition toward both heroin and 6-MAM hydrolysis, which may be of potential clinical relevance. Title: Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers Zhu HJ, Patrick KS, Straughn AB, Reeves OT, 3rd, Bernstein H, Shi J, Johnson HJ, Knight JM, Smith AT and Markowitz JS <1 more author(s)> Zhu HJ, Patrick KS, Straughn AB, Reeves OT, 3rd, Bernstein H, Shi J, Johnson HJ, Knight JM, Smith AT, Malcolm RJ, Markowitz JS (- 1) Ref: J Clin Psychopharmacol, 37:419, 2017 : PubMed ESTHER: Zhu_2017_J.Clin.Psychopharmacol_37_419 PubMedSearch: Zhu 2017 J.Clin.Psychopharmacol 37 419 PubMedID: 28590363 Abstract BACKGROUND/PURPOSE: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH. Title: CES1P1 variant -816A>C is not associated with hepatic carboxylesterase 1 expression and activity or antihypertensive effect of trandolapril Zhu HJ, Langaee TY, Gong Y, Wang X, Pepine CJ, Cooper-DeHoff RM, Johnson JA, Markowitz JS Ref: European Journal of Clinical Pharmacology, 72:681, 2016 : PubMed ESTHER: Zhu_2016_Eur.J.Clin.Pharmacol_72_681 PubMedSearch: Zhu 2016 Eur.J.Clin.Pharmacol 72 681 PubMedID: 26915813 Gene_locus related to this paper: human-CES1 Abstract PURPOSE: The majority of angiotensin-converting enzyme inhibitors (ACEIs) are synthesized as ester prodrugs that must be converted to their active forms in vivo in order to exert therapeutic effects. Hepatic carboxylesterase 1 (CES1) is the primary enzyme responsible for the bioactivation of ACEI prodrugs in humans. The genetic variant -816A>C (rs3785161) is a common variant located in the promoter region of the CES1P1 gene. Previous studies report conflicting results with regard to the association of this variant and therapeutic outcomes of CES1 substrate drugs. The purpose of this study was to determine the effect of the variant -816A>C on the activation of the ACEI prodrug trandolapril in human livers and the blood pressure (BP)-lowering effect of trandolapril in hypertensive patients. Title: Carboxylesterase 1-Mediated Drug-Drug Interactions between Clopidogrel and Simvastatin Wang X, Zhu HJ, Markowitz JS Ref: Biol Pharm Bull, 38:292, 2015 : PubMed ESTHER: Wang_2015_Biol.Pharm.Bull_38_292 PubMedSearch: Wang 2015 Biol.Pharm.Bull 38 292 PubMedID: 25747989 Abstract Patients with coronary artery disease often receive concurrent treatment with clopidogrel and a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor medication. Accordingly, potential drug-drug interactions associated with the concomitant use of these agents present an area of concern. Both CYP enzymes and carboxylesterase 1 (CES1) are involved in the metabolism of clopidogrel, while CES1 is believed to be the enzyme responsible for the activation of simvastatin. Some in vitro studies have suggested that simvastatin could attenuate clopidogrel activation via inhibiting CYP3A activity. However, these findings have not found support in several recently published clinical investigations. The present study addresses these inconsistencies by exploring the potential role of CES1 in the metabolism of clopidogrel and simvastatin. Our in vitro human liver s9 fraction incubation study demonstrated that simvastatin significantly enhanced the formation of the intermediate metabolite 2-oxo-clopidogrel, and inhibited the CES1-mediated hydrolysis of clopidogrel, 2-oxo-clopidogrel, and the active metabolite. However, the production of the active metabolite remained unchanged. Conversely, clopidogrel was not found to influence the CES1 mediated hydrolysis (activation) of simvastatin. Moreover, we provided evidence that CES1 is not an efficient enzyme for catalyzing simvastatin activation. In summary, the inhibitory effect of simvastatin on the hydrolysis of clopidogrel and its principal metabolites may have offset the influence of simvastatin-mediated inhibition of CYP3A, and permitted the unaltered formation of the clopidogrel active metabolite. These data help explain the conflicting accounts in previous reports regarding clopidogrel and simvastatin interactions by taking into consideration CES1; they suggest that the interactions are unlikely to significantly influence clinical outcomes. Title: Clopidogrel Bioactivation and Risk of Bleeding in Patients Cotreated With Angiotensin-Converting Enzyme Inhibitors After Myocardial Infarction: A Proof-of-Concept Study Kristensen KE, Zhu HJ, Wang X, Gislason GH, Torp-Pedersen C, Rasmussen HB, Markowitz JS, Hansen PR Ref: Clinical Pharmacology & Therapeutics, 96:713, 2014 : PubMed ESTHER: Kristensen_2014_Clin.Pharmacol.Ther_96_713 PubMedSearch: Kristensen 2014 Clin.Pharmacol.Ther 96 713 PubMedID: 25222620 Abstract Clopidogrel is an oral antiplatelet prodrug, the majority of which is hydrolyzed to an inactive metabolite by hepatic carboxylesterase 1 (CES1). Most angiotensin-converting enzyme inhibitors (ACEIs) are also metabolized by this enzyme. We examined the effects of ACEIs on clopidogrel bioactivation in vitro and linked the results with a pharmacoepidemiological study. In vitro, ACEIs inhibited CES1-mediated hydrolysis of a model substrate, and trandolapril and enalapril increased formation of clopidogrel active metabolite. In 70,934 patients with myocardial infarction, hazard ratios for clinically significant bleeding in ACEI-treated patients cotreated with or without clopidogrel were 1.10 (95% confidence interval (CI): 0.97-1.25, P = 0.124) and 0.90 (95% CI: 0.81-0.99, P = 0.025), respectively, as compared with patients who did not receive ACEIs. This difference was statistically significant (P = 0.002). We conclude that cotreatment with selected ACEIs and clopidogrel may increase the risk of bleeding. Combination of in vitro and pharmacoepidemiological studies may be a useful paradigm for assessment of drug-drug interactions. Title: Isopropylphenidate: an ester homolog of methylphenidate with sustained and selective dopaminergic activity and reduced drug interaction liability Markowitz JS, Zhu HJ, Patrick KS Ref: J Child Adolesc Psychopharmacol, 23:648, 2013 : PubMed ESTHER: Markowitz_2013_J.Child.Adolesc.Psychopharmacol_23_648 PubMedSearch: Markowitz 2013 J.Child.Adolesc.Psychopharmacol 23 648 PubMedID: 24261661 Abstract Abstract Objective: The most widely utilized pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD) is the psychostimulant methylphenidate (MPH). Most MPH formulations consist of the racemic mixture of d-threo-(R, R)-MPH and l-threo-(S, S)-MPH isomers. MPH is characterized by its low bioavailability and short half-life (2-3 hours). Additionally, significant inter-individual variability in MPH pharmacokinetics has been consistently documented. Accordingly, efforts have been directed at developing alternatives to MPH as therapeutic agents. A wide range of MPH analogues (dl-alpha-[2-piperidyl]-phenylacetic acid esters) have been synthesized with the dopamine transporter (DAT) and norepinephrine transporter (NET) as principle neuropharmacological targets. The present study investigated the metabolic profiles and pharmacological activity of the isopropyl ester derivative of MPH, dl-isopropylphenidate (IPH), both in vitro and in vivo. Methods: The synthesis, monoaminergic transporter binding, cellular uptake profiles, and assessment of metabolic hydrolysis and transesterification in the presence of ethanol are described using MPH as a comparator. Additionally, an in vivo assessment of IPH stimulant effects (vs. saline) in rats was performed with locomotor activity as a pharmacodynamic outcome. Results: IPH displayed unique pharmacological characteristics including greater DAT than NET binding and cellular uptake activity, and greater resistance to hydrolysis and transesterification via carboxylesterase 1 relative to MPH. Further, sustained psychostimulant properties offer the prospect of an enhanced duration of action. Conclusions: Our findings are consistent with IPH exhibiting attributes distinguishing it from MPH and warranting further study and development of IPH as a novel psychotherapeutic agent. Title: Carboxylesterase 1 (CES1) genetic polymorphisms and oseltamivir activation Zhu HJ, Markowitz JS Ref: European Journal of Clinical Pharmacology, 69:733, 2013 : PubMed ESTHER: Zhu_2013_Eur.J.Clin.Pharmacol_69_733 PubMedSearch: Zhu 2013 Eur.J.Clin.Pharmacol 69 733 PubMedID: 22847618 Title: Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation Zhu HJ, Wang X, Gawronski BE, Brinda BJ, Angiolillo DJ, Markowitz JS Ref: Journal of Pharmacology & Experimental Therapeutics, 344:665, 2013 : PubMed ESTHER: Zhu_2013_J.Pharmacol.Exp.Ther_344_665 PubMedSearch: Zhu 2013 J.Pharmacol.Exp.Ther 344 665 PubMedID: 23275066 Gene_locus related to this paper: human-CES1 Abstract Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognized substrate of hepatic carboxylesterase 1 (CES1), undergoes extensive hydrolytic metabolism in the liver. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. We determined whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter the formation of the active metabolite. Coincubation of clopidogrel with the CES1 inhibitor bis(4-nitrophenyl) phosphate in human liver s9 fractions significantly increased the concentrations of clopidogrel, 2-oxo-clopidogrel, and clopidogrel active metabolite, while the concentrations of all formed carboxylate metabolites were significantly decreased. As anticipated, clopidogrel and 2-oxo-clopidogrel were efficiently hydrolyzed by the cell s9 fractions prepared from wild-type CES1 transfected cells. The enzymatic activity of the CES1 variants G143E and D260fs were completely impaired in terms of catalyzing the hydrolysis of clopidogrel and 2-oxo-clopidogrel. However, the natural variants G18V, S82L, and A269S failed to produce any significant effect on CES1-mediated hydrolysis of clopidogrel or 2-oxo-clopidogrel. In summary, deficient CES1 catalytic activity resulting from CES1 inhibition or CES1 genetic variation may be associated with higher plasma concentrations of clopidogrel-active metabolite, and hence may enhance antiplatelet activity. Additionally, CES1 genetic variants have the potential to serve as a biomarker to predict clopidogrel response and individualize clopidogrel dosing regimens in clinical practice. Title: Prediction and in vitro evaluation of selected protease inhibitor antiviral drugs as inhibitors of carboxylesterase 1: a potential source of drug-drug interactions Rhoades JA, Peterson YK, Zhu HJ, Appel DI, Peloquin CA, Markowitz JS Ref: Pharm Res, 29:972, 2012 : PubMed ESTHER: Rhoades_2012_Pharm.Res_29_972 PubMedSearch: Rhoades 2012 Pharm.Res 29 972 PubMedID: 22161308 Abstract PURPOSE: To predict and determine whether the protease inhibitors (PIs) nelfinavir, amprenavir, atazanavir, ritonavir, and saquinavir could serve as metabolic inhibitors of the human CES1 (hCES1) using both molecular modeling techniques and in vitro inhibition assays. METHODS: Initially, a molecular modeling approach was utilized to predict whether the selected PIs could serve as hCES1 inhibitors. The inhibitory effects of these PIs on hCES1 activity were then further evaluated utilizing previously established in vitro assay. RESULTS: Pharmacophore and 2D-QSAR modeling predicted that nelfinavir would serve as a potent hCES1 inhibitor. This hypothesis was validated by in vitro hCES1 inhibition studies. Other PIs (amprenavir, atazanavir, ritonavir, saquinavir) were evaluated and also shown to be hCES1 inhibitors in vitro, although substantially less potent relative to nelfinavir. CONCLUSION: Computational molecular modeling is a valid approach to identify potential hCES1 inhibitors as candidates for further assessment using validated in vitro techniques. DDIs could occur when nelfinavir is co-administered with drugs metabolized by hCES1. Title: A discriminative analytical method for detection of CES1A1 and CES1A2/CES1A3 genetic variants Zhu HJ, Brinda B, Froehlich TE, Markowitz JS Ref: Pharmacogenet Genomics, 22:215, 2012 : PubMed ESTHER: Zhu_2012_Pharmacogenet.Genomics_22_215 PubMedSearch: Zhu 2012 Pharmacogenet.Genomics 22 215 PubMedID: 22237548 Gene_locus related to this paper: human-CES1 Abstract Human carboxylesterase 1 (hCES1), encoded by the CES1 gene, is the predominant hepatic hydrolase responsible for the metabolism of many therapeutic agents, toxins, and endogenous substances. Genetic variants of CES1 can affect hCES1 function and expression and ultimately influence clinical response to drugs serving as hCES1 substrates. The CES1 gene consists of three isoforms including the functional CES1A1 and CES1A2 genes and the nonfunctional pseudogene CES1A3. Natural variants of these isoforms exert differing impacts on hCES1 function. However, the existing CES1 genotyping methods are incapable of determining whether these variants belong to CES1A1, CES1A2, or CES1A3 because of the high similarity among these three genes, as a consequence they are unable to discriminate between heterozygotes and homozygotes. We report the development of a novel long-range PCR-based, discriminative genotyping assay capable of specifically detecting the variants among CES1A1, CES1A2, and CES1A3 genes. The comparison of the genotyping results between this novel assay and those previously reported methods highlighted the necessity of applying the discriminative genotyping assay in pharmacogenetic studies involving CES1 gene. Title: Enantiospecific determination of dl-methylphenidate and dl-ethylphenidate in plasma by liquid chromatography-tandem mass spectrometry: Application to human ethanol interactions Zhu HJ, Patrick KS, Markowitz JS Ref: Journal of Chromatography B Analyt Technol Biomed Life Sciences, 879:783, 2011 : PubMed ESTHER: Zhu_2011_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_879_783 PubMedSearch: Zhu 2011 J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci 879 783 PubMedID: 21402502 Abstract In humans, concomitant DL-methylphenidate (DL-MPH) and ethanol results in the carboxylesterase 1 (hCES1) mediated biotransformation of MPH to the transesterification metabolite DL-ethylphenidate (DL-EPH). The separate enantiomers of MPH and EPH are found at low ng/ml to pg/ml plasma concentrations. Substantial pharmacological differences exist between D- and L-isomers of MPH and EPH, both in terms of pharmacological potencies and receptor selectivity, as well as in pharmacokinetic properties. Accordingly, a sensitive, accurate and precise enantiospecific analytical method is required in order to fully explore pharmacokinetic-pharmacodynamic correlations regarding the MPH-ethanol interaction. The present study describes a novel liquid chromatographic-tandem mass spectrometric method for simultaneous analysis of D- and L-MPH as well as D- and L-EPH concentrations from human plasma. This assay provides baseline resolution of the individual MPH and EPH isomers utilizing a vancomycin-based chiral column. The lower limit of quantification was 0.025 ng/ml for each isomer when extracting 0.5 ml plasma aliquots. Calibration curves were linear over the range from 0.025 ng/ml to 25 ng/ml for all analytes (r(2)>0.995). Assay accuracy and precision were excellent and stability studies and assessment of potential matrix effects contributed to the validation of the method. Application of the method to human plasma samples collected after the administration of dl-MPH with or without ethanol is included, and the implications of this pharmacokinetic drug interaction discussed. Title: Identification of selected therapeutic agents as inhibitors of carboxylesterase 1: potential sources of metabolic drug interactions Zhu HJ, Appel DI, Peterson YK, Wang Z, Markowitz JS Ref: Toxicology, 270:59, 2010 : PubMed ESTHER: Zhu_2010_Toxicology_270_59 PubMedSearch: Zhu 2010 Toxicology 270 59 PubMedID: 20097249 Abstract A series of studies were designed and carried out in order to explore the potential for the major human hepatic hydrolase, carboxylesterase 1 (hCES1), to serve as a target of metabolic inhibition by a variety of medications. The risk of adverse drug-drug interaction(s) is present when metabolic inhibitors are combined with known or suspected substrates of a given enzyme. In the present report the abundantly expressed hepatic enzyme, hCES1, was examined as a potential target of metabolic inhibition by a number of routinely prescribed medications. hCES1 has been seldom assessed in this regard despite its role in the metabolism and detoxification of many compounds. The psychostimulant methylphenidate (MPH) was chosen as an hCES1 selective substrate. In vitro studies were performed using previously developed cell lines which overexpress hCES1 with both p-nitrophenyl acetate and d-MPH serving as known substrates. Aripiprazole, perphenazine, thioridazine, and fluoxetine were determined to be the potent hCES1 inhibitors. A complementary animal study followed in vitro screening studies to further evaluate the inhibitory effect of aripiprazole on CES1 activity in FVB mice. The results suggest that the concurrent administration of racemic (i.e. dl-) MPH with aripiprazole significantly increased the plasma concentrations of both total MPH as well as the less active l-isomer. The ratio of d-MPH and l-MPH plasma concentrations was significantly decreased in the mice treated with aripiprazole compared to the control animals, indicating an overall decrease of CES1 catalytic activity in aripiprazole treated animals. Additionally, a quantitative structure-activity relationship based analysis identified a number of structural similarities of CES1 inhibitors. In conclusion, drug-drug interactions with MPH are likely mediated via CES1 inhibition as a result of concomitant drug therapies. CES1 inhibition represents an overlooked and little studied source of variability in MPH disposition, tolerability, and response. Title: Role of carboxylesterase 1 and impact of natural genetic variants on the hydrolysis of trandolapril Zhu HJ, Appel DI, Johnson JA, Chavin KD, Markowitz JS Ref: Biochemical Pharmacology, 77:1266, 2009 : PubMed ESTHER: Zhu_2009_Biochem.Pharmacol_77_1266 PubMedSearch: Zhu 2009 Biochem.Pharmacol 77 1266 PubMedID: 19185566 Gene_locus related to this paper: human-CES1 Abstract Carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2) are the major hydrolytic enzymes responsible for the metabolism of numerous therapeutic agents as well as endogenous substrates. CES1 and CES2 differ distinctly in their substrate specificity and tissue distribution. In this study, we investigated the role of CES1 and CES2 in converting the antihypertensive prodrug trandolapril to its more active form trandolaprilat, and determined the influence of two newly identified CES1 mutations p.Gly143Glu and p.Asp260fs on trandolapril metabolism. Western blot analysis demonstrated that CES1 is expressed in human liver microsomes (HLM) but not in human intestinal microsomes (HIM). In vitro incubation studies were conducted to contrast the enzymatic activity of HLM as well as HIM upon trandolapril hydrolysis. Trandolapril was rapidly hydrolyzed to its principal active metabolite trandolaprilat after incubation with HLM. In contrast, in HIM, where CES2 is predominantly expressed, incubations did not produce any detectable trandolapril hydrolysis. Furthermore, hydrolysis of trandolapril catalyzed by wild type (WT) and mutant CES1 were assessed utilizing transfected Flp-In-293 cells stably expressing WT CES1 and two variants. WT CES1 efficiently hydrolyzed trandolapril to trandolaprilat with V(max) and K(m) values of 103.6+/-2.2 nmole/min/mg protein and 639.9+/-32.9muM, respectively. However, no appreciable trandolapril hydrolysis could be found after incubation with both p.Gly143Glu and p.Asp260fs variants. Thus, trandolapril appears to be a CES1 selective substrate while CES2 exerts little to no catalytic activity towards this compound. CES1 mutations p.Gly143Glu and p.Asp260fs are essentially dysfunctional enzymes with regard to the conversion of trandolapril to its more active metabolite trandolaprilat. Title: Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants Zhu HJ, Markowitz JS Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, 37:264, 2009 : PubMed ESTHER: Zhu_2009_Drug.Metab.Dispos_37_264 PubMedSearch: Zhu 2009 Drug.Metab.Dispos 37 264 PubMedID: 19022936 Gene_locus related to this paper: human-CES1 Abstract Oseltamivir phosphate is an ethyl ester prodrug widely used in the treatment and prevention of both Influenzavirus A and B infections. The conversion of oseltamivir to its active metabolite oseltamivir carboxylate is dependent on ester hydrolysis mediated by carboxylesterase 1 (CES1). We recently identified two functional CES1 variants p.Gly143Glu and p.Asp260fs in a research subject who displayed significant impairment in his ability to metabolize the selective CES1 substrate, methylphenidate. In vitro functional studies demonstrated that the presence of either of the two mutations can result in severe reductions in the catalytic efficiency of CES1 toward methylphenidate, which is required for hydrolysis and pharmacological deactivation. The aim of the present study was to investigate the function of these mutations on activating (hydrolyzing) oseltamivir to oseltamivir carboxylate using the cell lines expressing wild type (WT) and each mutant CES1. In vitro incubation studies demonstrated that the S9 fractions prepared from the cells transfected with WT CES1 and human liver tissues rapidly convert oseltamivir to oseltamivir carboxylate. However, the catalytic activity of the mutant hydrolases was dramatically hindered. The V(max) value of p.Gly143Glu was approximately 25% of that of WT enzyme, whereas the catalytic activity of p.Asp260fs was negligible. These results suggest that the therapeutic efficacy of oseltamivir could be compromised in treated patients expressing either functional CES1 mutation. Furthermore, the potential for increased adverse effects or toxicity as a result of exposure to high concentrations of the nonhydrolyzed prodrug should be considered. Title: Age- and sex-related expression and activity of carboxylesterase 1 and 2 in mouse and human liver Zhu HJ, Appel DI, Jiang Y, Markowitz JS Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, 37:1819, 2009 : PubMed ESTHER: Zhu_2009_Drug.Metab.Dispos_37_1819 PubMedSearch: Zhu 2009 Drug.Metab.Dispos 37 1819 PubMedID: 19487248 Abstract Carboxylesterase (CES) 1 and CES2 are two major hepatic hydrolases responsible for the metabolism of numerous endogenous and exogenous compounds. In this study, age- and sex-dependent expression and activity of CES1 and CES2 were investigated using both animal models and individual human liver s9 samples. The expression and activity of mouse CES1 (mCES1) and mCES2 in the liver were markedly lower in newborns relative to adults and increased gradually with age, approximating levels of adult animals by age 2 to 4 weeks. Likewise, the average human CES1 (hCES1) expression in the subjects <1 year of age was significantly lower than that of pooled samples. In particular, hCES1 expression in the 13-day and 1-month-old subjects was just 20.3 and 11.1%, respectively, of the pooled sample values. In addition, the subjects <1 year of age exhibited a trend suggestive of low hCES2 expression, but this difference failed to reach statistical significance because of large interindividual variability. The expression and activity of mCES1 and mCES2 were not significantly altered after the animals were treated with human growth hormone, indicating growth hormone may not be associated with the low level of CES expression during early developmental stages. No significant differences of the expression and activity of mCES1 and mCES2 were observed between sexually mature male and female mice. In conclusion, the expression and activity of CES1 and CES2 are age-related but independent of growth hormone level. Sex seems to be an unlikely factor contributing to the regulation of CES1 and CES2. Title: Enantiospecific gas chromatographic-mass spectrometric analysis of urinary methylphenidate: implications for phenotyping LeVasseur NL, Zhu HJ, Markowitz JS, DeVane CL, Patrick KS Ref: Journal of Chromatography B Analyt Technol Biomed Life Sciences, 862:140, 2008 : PubMed ESTHER: Levasseur_2008_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_862_140 PubMedSearch: Levasseur 2008 J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci 862 140 PubMedID: 18155648 Abstract A chiral derivatization gas chromatographic-mass spectrometric (GC-MS) method for urine methylphenidate (MPH) analysis was developed and validated to investigate preliminary findings regarding a novel MPH poor metabolizer (PM). Detection was by electron impact (EI) ionization-selected ion monitoring of the N-trifluoroacetylprolylpiperidinium fragments from MPH and the piperidine-deuterated MPH internal standard. The PM eliminated approximately 70 times more l-MPH in urine (9% of the dose over 0-10h), and approximately 5 times more of the d-isomer (10% of the dose), than the mean values determined from 10 normal metabolizers of MPH. Only minor amounts of the metabolite p-hydroxy-MPH were found in the urine of both the PM and normal metabolizers, while the concentration of MPH lactam was not high enough to be detectable. The described method indirectly gauges the functional carboxylesterase-1 status of patients receiving MPH based on the evaluation of relative urine concentrations of d-MPH:l-MPH. Clinical implications concerning rational drug selection for an identified or suspected MPH PM are discussed. Title: Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL, Malcolm R, Johnson JA, Youngblood GL and Markowitz JS <2 more author(s)> Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL, Malcolm R, Johnson JA, Youngblood GL, Sweet DH, Langaee TY, Markowitz JS (- 2) Ref: American Journal of Human Genetics, 82:1241, 2008 : PubMed ESTHER: Zhu_2008_Am.J.Hum.Genet_82_1241 PubMedSearch: Zhu 2008 Am.J.Hum.Genet 82 1241 PubMedID: 18485328 Gene_locus related to this paper: human-CES1 Abstract The human carboxylesterase 1 (CES1) gene encodes for the enzyme carboxylesterase 1, a serine esterase governing both metabolic deactivation and activation of numerous therapeutic agents. During the course of a study of the pharmacokinetics of the methyl ester racemic psychostimulant methylphenidate, profoundly elevated methylphenidate plasma concentrations, unprecedented distortions in isomer disposition, and increases in hemodynamic measures were observed in a subject of European descent. These observations led to a focused study of the subject's CES1 gene. DNA sequencing detected two coding region single-nucleotide mutations located in exons 4 and 6. The mutation in exon 4 is located in codon 143 and leads to a nonconservative substitution, p.Gly143Glu. A deletion in exon 6 at codon 260 results in a frameshift mutation, p.Asp260fs, altering residues 260-299 before truncating at a premature stop codon. The minor allele frequency of p.Gly143Glu was determined to be 3.7%, 4.3%, 2.0%, and 0% in white, black, Hispanic, and Asian populations, respectively. Of 925 individual DNA samples examined, none carried the p.Asp260fs, indicating it is an extremely rare mutation. In vitro functional studies demonstrated the catalytic functions of both p.Gly143Glu and p.Asp260fs are substantially impaired, resulting in a complete loss of hydrolytic activity toward methylphenidate. When a more sensitive esterase substrate, p-nitrophenyl acetate was utilized, only 21.4% and 0.6% catalytic efficiency (V(max)/K(m)) were determined in p.Gly143Glu and p.Asp260fs, respectively, compared to the wild-type enzyme. These findings indicate that specific CES1 gene variants can lead to clinically significant alterations in pharmacokinetics and drug response of carboxylesterase 1 substrates. Title: Double-blind donepezil-placebo crossover augmentation study of atypical antipsychotics in chronic, stable schizophrenia: a pilot study Risch SC, Horner MD, McGurk SR, Palecko S, Markowitz JS, Nahas Z, DeVane CL Ref: Schizophr Res, 93:131, 2007 : PubMed ESTHER: Risch_2007_Schizophr.Res_93_131 PubMedSearch: Risch 2007 Schizophr.Res 93 131 PubMedID: 17391930 Abstract Thirteen outpatients with chronic but stable schizophrenia received donepezil and placebo augmentation of their maintenance antipsychotic medication regimen. Each subject received in a randomized, counterbalanced order 1) donepezil 5 mg for 6 weeks then donepezil 10 mg for six weeks and 2) placebo donepezil for 12 weeks. Serial ratings of the Positive and Negative Symptom Scale (PANSS) [Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13(2): 261-276] were performed by a trained rater blind to the donepezil order and condition: at baseline, 12 weeks and 24 weeks. On donepezil as compared to baseline or placebo, there was a significant improvement in PANSS negative scores (p=.018, n=13). These results are discussed with respect to other studies using cholinesterase inhibitors as an augmentation strategy in schizophrenia. Title: Donepezil effects on mood in patients with schizophrenia and schizoaffective disorder Risch SC, Horner MD, McGurk SR, Palecko S, Markowitz JS, Nahas Z, DeVane CL Ref: Int J Neuropsychopharmacol, 9:603, 2006 : PubMed ESTHER: Risch_2006_Int.J.Neuropsychopharmacol_9_603 PubMedSearch: Risch 2006 Int.J.Neuropsychopharmacol 9 603 PubMedID: 16202177 Abstract Donepezil, 5 mg/d for 6 wk then 10 mg/d for 6 wk, and placebo daily for 12 wk in a double-blind cross-over paradigm, was added to the therapeutic regimen of 13 patients with schizophrenia or schizoaffective disorders, clinically stable on atypical antipsychotic medications. Patients had varying degrees of depressive symptoms, ranging from no depression to clinically significant depression. There was no worsening or induction of depression in individual patients or the group as a whole. In addition there was a statistically significant antidepressant effect in the group as a whole during the donepezil condition and a clinically significant antidepressant effect in the patients with clinically significant depressive symptoms, although there were not enough depressed patients in the group to conclude that donepezil may have antidepressant effects. Thus, in this study, donepezil did not induce or worsen depressive symptoms in schizophrenic and schizoaffective disorder patients. Title: Examination of nighttime sleep-related problems during double-blind, placebo-controlled trials of galantamine in patients with Alzheimer's disease Stahl SM, Markowitz JS, Papadopoulos G, Sadik K Ref: Curr Med Res Opin, 20:517, 2004 : PubMed ESTHER: Stahl_2004_Curr.Med.Res.Opin_20_517 PubMedSearch: Stahl 2004 Curr.Med.Res.Opin 20 517 PubMedID: 15119989 Abstract BACKGROUND: Acetylcholinesterase inhibitors (AChEI) are now widely used as treatment for Alzheimer's disease (AD). Their cholinomimetic action has the potential to influence sleep quality and donepezil has been associated with sleeprelated adverse events. This study examined whether galantamine, an AChEI with nicotinic modulation, is associated with nighttime sleeprelated problems. Title: Sleep-related outcomes in persons with mild to moderate Alzheimer disease in a placebo-controlled trial of galantamine Markowitz JS, Gutterman EM, Lilienfeld S, Papadopoulos G Ref: Sleep, 26:602, 2003 : PubMed ESTHER: Markowitz_2003_Sleep_26_602 PubMedSearch: Markowitz 2003 Sleep 26 602 PubMedID: 12938815 Abstract STUDY OBJECTIVES: To recognize the potential effect of acetylcholinesterase-inhibiting medications on sleep quality when used for the treatment of mild to moderate Alzheimer disease and describe sleep outcomes for patients treated with galantamine. DESIGN: This study examined sleep quality among individuals with mild to moderate Alzheimer disease using data from a 3-month, double-blind, flexible-dose trial of galantamine. The hypothesis was no difference in sleep quality between galantamine- and placebo-treated subjects. PATIENTS: 136 patients treated with galantamine 24 mg per day and 125 patients treated with placebo. MEASUREMENTS: Based on caregiver reports, the sleep-related outcome measures were the Pittsburgh Sleep Quality Index and the sleep disorders item from the Neuropsychiatric Inventory. Using a P-value of 0.05 (2-tailed), analysis of covariance was used to compare treatments on mean change from baseline to month 3 (Pittsburgh Sleep Quality Index) or mean score at month 3 (Neuropsychiatric Inventory), adjusted for baseline score and investigator. Title: Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study Nahas Z, George MS, Horner MD, Markowitz JS, Li X, Lorberbaum JP, Owens SD, McGurk S, DeVane L, Risch SC Ref: Neurocase, 9:274, 2003 : PubMed ESTHER: Nahas_2003_Neurocase_9_274 PubMedSearch: Nahas 2003 Neurocase 9 274 PubMedID: 12925933 Abstract Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia. Title: Co-use of donepezil and hypnotics among Alzheimer's disease patients living in the community Stahl SM, Markowitz JS, Gutterman EM, Papadopoulos G Ref: J Clin Psychiatry, 64:466, 2003 : PubMed ESTHER: Stahl_2003_J.Clin.Psychiatry_64_466 PubMedSearch: Stahl 2003 J.Clin.Psychiatry 64 466 PubMedID: 12716251 Abstract BACKGROUND: In clinical trials, sleep problems have been identified as side effects of donepezil, an acetylcholinesterase (AChE)-inhibiting medication for the treatment of Alzheimer's disease (AD). Poor sleep quality can exacerbate behavior problems among patients and add to the burden experienced by their caregivers. We examined the relationship between co-use of donepezil and hypnotics in a large sample of persons with AD living in the community. METHOD: This secondary data analysis used cross-sectional subjects from a multiwave, consumer-based survey of AD caregivers conducted in 1997 and 1998. Rates of hypnotic use among users and non-users of donepezil were compared using chi-square analysis for independent samples, and multivariate logistic regression was used to identify significant independent correlates of hypnotic use. Title: A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: functional MRI correlates Risch SC, McGurk S, Horner MD, Nahas Z, Owens SD, Molloy M, Gilliard C, Christie S, Markowitz JS and George MS <2 more author(s)> Risch SC, McGurk S, Horner MD, Nahas Z, Owens SD, Molloy M, Gilliard C, Christie S, Markowitz JS, DeVane CL, Mintzer J, George MS (- 2) Ref: Neurocase, 7:105, 2001 : PubMed ESTHER: Risch_2001_Neurocase_7_105 PubMedSearch: Risch 2001 Neurocase 7 105 PubMedID: 11320158 Abstract Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted. | |||||||
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