Inhibitory Effects of Trospium Chloride on Cytochrome P450 Enzymes in Human Liver Microsomes
Open Access
- 1 October 1999
- journal article
- Published by Wiley in Basic & Clinical Pharmacology & Toxicology
- Vol. 85 (s2) , 299-304
- https://doi.org/10.1111/j.1600-0773.1999.tb02026.x
Abstract
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 μM) at 37° in 0.1 M KH2PO4buffer 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 IC50values were determined for each substrate at respective KMconcentrations. Trospium chloride did not show relevant inhibitory effects on the metabolism of most substrates (IC50values considerably higher than 1 mM). The only clear inhibition was seen for the CYP2D6‐dependent high‐affinity O‐demethylation of dextromethorphan, where IC50values of 27 μM and 44 μM were observed. Therefore, additional dextromethorphan concentrations (0.4–2000 μM) were tested. Trospium chloride was a competitive inhibitor of the reaction with Kivalues of 20 and 51 μM, respectively. Thus, trospium chloride has negligible inhibitory effects on CYP3A4, CYP1A2, CYP2E1, CYP2C19, CYP2C9 and CYP2A6 activity but is a reasonably potent inhibitor of CYP2D6in vitro.Compared to therapeutic trospium chloride peak plasma concentrations below 50 nM, the 1000‐times higher competitive inhibition constant Kihowever suggests that inhibition of CYP2D6 by trospium chloride is without any clinical relevance.Keywords
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