Irinotecan hydrochloride (CPT-11) is a useful drug for cancer chemotherapy but sometimes induces severe diarrhea clinically. CPT-11 is mainly activated to SN-38 by carboxylesterase (CES) and then detoxified to SN-38 glucuronide (SN-38G) by UDP-glucuronosyltransferase (UGT) in the liver. SN-38G is excreted via bile and de-conjugated to SN-38 by beta-glucuronidase (beta-GLU) in the intestinal content. In order to clarify the alleviative effect of antibiotics on CPT-11-induced diarrhea, we examined whether penicillin G and streptomycin (SM) alleviate CPT-11-induced delayed-onset diarrhea using three diarrheal models, i.e., Wistar rats with repeated dosing of CPT-11 (60 mg/kg/day i.v. for 4 consecutive days) and Wistar and Gunn rats with a single dosing of CPT-11 (200 and 20 mg/kg i.v., respectively). Gunn rats have an inherited deficiency of UGT1A and cannot conjugate SN-38 to SN-38G. Therefore, onset of CPT-11-induced diarrhea in Gunn rats is not affected by beta-GLU activity. SM alleviated diarrhea in all three diarrheal models. The alleviation of diarrhea by SM in Gunn rats indicated that the effect of SM occurred by a mechanism other than the inhibition of beta-GLU activity. SM decreased CPT-11 and/or SN-38 concentrations in intestinal tissues and alleviated epithelial damage from the ileum to colon. SM did not inhibit beta-GLU activity in the cecal content. SM also inhibited the intestinal absorption of CPT-11 and decreased CES activity and increased UGT activity in the intestinal epithelium. These findings indicated that SM decreased the exposure of CPT-11 and SN-38 to the intestinal epithelium by inhibiting the absorption of CPT-11 from the intestinal lumen and the change of CES and UGT activities in the intestinal epithelium and alleviated delayed-onset diarrhea.
Title: Direct determination of E2020 enantiomers in plasma by liquid chromatography-mass spectrometry and column-switching techniques Matsui K, Oda Y, Ohe H, Tanaka S, Asakawa N Ref: Journal of Chromatography A, 694:209, 1995 : PubMed
High-performance liquid chromatography with column switching and mass spectrometry (MS) was applied to the on-line determination and resolution of the enantiomers of E2020 (acetylcholinesterase inhibitor) in plasma. This system employs two avidin columns and fast atom bombardment (FAB)-MS. A plasma sample was injected directly into an avidin trapping column (10 mm x 4.0 mm I.D.). The plasma protein was washed out from the trapping column immediately while E2020 was retained. After the column-switching procedure, E2020 was separated enantioselectivity in an avidin analytical column. The separated E2020 enantiomers were specifically detected by FAB-MS without interference from metabolites of E2020 and plasma constituents. The limit of quantification for each enantiomer of E2020 in plasma was 1.0 ng/ml and the intra- and inter-assay relative standard deviations for the method were less than 5.2%. The assay was validated for enantioselective pharmacokinetic studies in the dog.
Title: Kinetic study on the inhibition of acetylcholinesterase by 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride (E2020) Nochi S, Asakawa N, Sato T Ref: Biol Pharm Bull, 18:1145, 1995 : PubMed
E2020 (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine hydrochloride) is currently being developed as a treatment for senile dementia of the Alzheimer type. Its mechanism of action is to increase central cholinergic activity by inhibiting acetylcholinesterase (AChE) in the brain. In this study, the kinetics of the inhibitory action of E2020 on AChE was examined in comparison with its derivatives (2A1050 and 2A1034) and the reference compound tetrahydroaminoacridine (THA) all of which have a similar action. Analysis of the data using Lineweaver-Burk plots shows that inhibition by the test compounds fell into the category of mixed type. Inhibitor dissociation constants for the free enzyme (KI) and acetyl-enzyme (KI) of E2020 are one or two orders of magnitude lower than those of 2A1050, 2A1034 and THA. These findings indicate the strong inhibitory effect of E2020 on AChE.
