Inhibitory effects of trospium chloride on cytochrome P450 enzymes in human liver microsomes

被引:25
作者
Beckmann-Knopp, S
Rietbrock, S
Weyhenmeyer, R
Böcker, RH
Beckurts, KT
Lang, W
Fuhr, U
机构
[1] Univ Cologne, Inst Pharmacol, D-50931 Cologne, Germany
[2] Madaus AG, Cologne, Germany
[3] Univ Erlangen Nurnberg, Dept Expt & Clin Pharmacol & Toxicol, D-8520 Erlangen, Germany
[4] Univ Cologne, Dept Visceral & Vasc Surg, D-5000 Cologne, Germany
来源
PHARMACOLOGY & TOXICOLOGY | 1999年 / 85卷 / 06期
关键词
D O I
10.1111/j.1600-0773.1999.tb02026.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Trospium chloride, an atropine derivative used for the treatment of urge incontinence, was tested for inhibitory effects on human cytochrome P-450 enzymes. Metabolic activities were determined in liver microsomes from two donors using the following selective substrates: dextromethorphan (CYP2D6), denitronifedipine (CYP3A4), caffeine (CYP1A2), chlorzoxazone (CYP2E1), S-(+)-mephenytoin (CYP2C19), S-(-)-warfarin (CYP2C9) and coumarin (CYP2A6). Incubations with each substrate were carried out without a possible inhibitor and in the presence of trospium chloride at varying concentrations (37-3000 mu M) at 37 degrees in 0.1 M KH2PO4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by high-performance liquid chromatography (HPLC) in all cases except CYP2A6 where direct fluorescence spectroscopy was used. First, trospium chloride IC50 values were determined for each substrate at respective K-M concentrations. Trospium chloride did not show relevant inhibitory effects on the metabolism of most substrates (IC50 values considerably higher than 1 mM). The only clear inhibition was seen for the CYP2D6-dependent high-affinity O-demethylation of dextromethorphan, where IC50 values of 27 mu M and 44 mu M were observed. Therefore, additional dextromethorphan concentrations (0.4-2000 mu M) were tested. Trospium chloride was a competitive inhibitor of the reaction with Ki values of 20 and 51 mu M, respectively. Thus, trospium chloride has negligible inhibitory effects on CYP3A4, CYP1A2, CYP2E1, CYP2C19, CYP2C9 and CYP2A6 activity but is a reasonably potent inhibitor of CYP2D6 in vitro. Compared to therapeutic trospium chloride peak plasma concentrations below 50 nM, the 1000-times higher competitive inhibition constant K-i however suggests that inhibition of CYP2D6 by trospium chloride is without any clinical relevance.
引用
收藏
页码:299 / 304
页数:6
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