Cytochrome P450 Specificity of Metabolism and Interactions of Oxybutynin in Human Liver Microsomes

Abstract

Ahstyuct; Oxybutynin has an extensive first pass metabolism after oral administration. the main active metabolite being N-desethyloxybutynin. The purpose of this study was to investigate the CYP isoform specificity of oxybutynin N-deethylation and possible interactions. Oxybutynin N-deethylation in human liver microsomes in vifro was potently inhibited by ketoconazole (ICso 4.5 pM), less and variably by itraconazole and not by quinidine or several other reference inhibitors, suggesting that CYP3A enzymes are predominant catalysts of the reaction. Recombinant CYP3A5 enzyme had higher activity in oxybutynin N-deethylation than recombinant CYP3A4. Ketoconazole inhibited oxybutynin N-deethylation by the recombinant CYP3A4 and CYP3A5 almost completely, whereas itraconazole inhibited the activity of CYP3A4 more potently than that of CYP3A5. Oxybutynin inhibited CYP3A4-and CYP2D6-associated activities (testosterone 68-hydroxylase and dextromethorphan 0-demethylase. respectively) in human liver microsomes. CYPl A l/2-, CYPZAh-, CYP2C9-and CYPZEI-associated activities were inhibited less potently or not at all by oxybutynin when compared with reference inhibitors. Although the reasons for the weak and variable inhibition by itraconazole remain to be studied. it seems that oxybutynin is predominantly metabolized by CYP3A4 and CYP3A5 hut not by CYP2D6. However, it seems to have some affinity also to the latter enzyme.

Effect of CYP3A5 Expression on the Inhibition of CYP3A-Catalyzed Drug Metabolism: Impact on Modeling CYP3A-Mediated Drug-Drug Interactions

“…Such an observation is supported by the ;2-fold increase in fluconazole K i with CYP3A5 expresser (versus CYP3A5 nonexpresser) HLM (Isoherranen et al, 2008). There are reports that itraconazole (ITZ) is rCYP3A4 selective with substrates such as oxybutynin and midazolam (MDZ) (Lukkari et al, 1998;Yamazaki et al, 2010). The latter authors reported a K i ratio of ;30 (rCYP3A5/rCYP3A4) as well as a K i ratio of ;2 in HLMs (CYP3A5 expressers versus nonexpressers).…”

Midazolam α‐Hydroxylation by Human Liver Microsomes in vitro: Inhibition by Calcium Channel Blockers, Itraconazole and Ketoconazole

“…The patient had been treated with diazepam immediately before death; no other medications were given. The liver samples were frozen in liquid nitrogen and stored at -80" until preparation of microsomes as described previously (Lukkari et al 1998). The microsomal protein concentration of the preparation used was 16.2 mg ml-'.…”

Carbamazepine toxicity following Oxybutynin and Dantrolene administration: a case report

“…Several studies demonstrated that Oxybutynin is metabolized by oxidation via cytochrome P450 (CYP3A subfamily), 18,19 which also catalyzes Carbamazepine and influences activities of this and other cytochromes in human liver microsomes. 20 The exact pathway of Dantrolene metabolism is unknown, but some reports suggest that Dantrolene decreases the activity of cytochrome P450 21 and that this inhibition is dose dependent.…”