The xenobiotic inhibitor profile of cytochrome P4502C8

Abstract

Aims To investigate inhibition of recombinant CYP2C8 by: (i) prototypic CYP isoform selective inhibitors (ii) imidazole/triazole antifungal agents (known inhibitors of CYP), and (iii) certain CYP3A substrates (given the apparent overlapping substrate speci®city of CYP2C8 and CYP3A). Methods CYP2C8 and NADPH-cytochrome P450 oxidoreductase were coexpressed in Spodoptera frugiperda (Sf21) cells using the baculovirus expression system. CYP isoform selective inhibitors, imidazole/triazole antifungal agents and CYP3A substrates were screened for their inhibitory effects on CYP2C8-catalysed torsemide tolylmethylhydroxylation and, where appropriate, the kinetics of inhibition were characterized. The conversion of torsemide to its tolylmethylhydroxy metabolite was measured using an h.p.l.c. procedure. Results At concentrations of the CYP inhibitor`probes' employed for isoform selectivity, only diethyldithiocarbamate and ketoconazole inhibited CYP2C8 by >10%. Ketoconazole, at an added concentration of 10 mM, inhibited CYP2C8 by 89%. Another imidazole, clotrimazole, also potently inhibited CYP2C8. Ketoconazole and clotrimazole were both noncompetitive inhibitors of CYP2C8 with apparent K i values of 2.5 mM. The CYP3A substrates amitriptyline, quinine, terfenadine and triazolam caused near complete inhibition (82±91% of control activity) of CYP2C8 at concentrations ®ve-fold higher than the known CYP3A K m . Kinetic studies with selected CYP3A substrates demonstrated that most inhibited CYP2C8 noncompetitively. Apparent K i values for midazolam, quinine, terfenadine and triazolam ranged from 5 to 25 mM.Conclusions Inhibition of CYP2C8 occurred at concentrations of ketoconazole and diethyldithiocarbamate normally employed for selective inhibition of CYP3A and CYP2E1, respectively. Some CYP3A substrates have the capacity to inhibit CYP2C8 activity and this may have implications for inhibitory drug interactions in vivo.

Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

“…There have been several reports that CYP3A4 plays a role in the metabolism of CYP2C8 substrates (e.g., cervistatin and paclitaxel) (Sonnichsen et al, 1995;Mück, 1998). What is more, it has been reported that ketoconazole, a potent inhibitor of CYP3A4, inhibits the CYP2C8-catalysed metabolisms of torsemide and paclitaxel (Ong et al, 2000;Bun et al, 2003). These results suggest agents that act as CYP3A4 substrates have the capacity to interact with CYP2C8.…”

Human Liver Expression of CYP2C8: Gender, Age, and Genotype Effects

“…CYP3A4 substrates with minor CYP2C8 contribution include carbamazapine (Kerr et al, 1994), verapamil (Tracy et al, 1999), zopiclone (Becquemont et al, 1999), and buprenorphine (Chang et al, 2006). Furthermore, some substrates, such as amiodarone, amitriptyline, quinine, and triazolam, which are metabolized completely or in part by CYP3A, caused Ͼ50% inhibition of CYP2C8 activity at concentrations that corresponded to their CYP3A K m values, suggesting similar affinities for both enzymes (Ong et al, 2000).…”

Effect of Concomitant Artesunate Administration and Cytochrome P4502C8 Polymorphisms on the Pharmacokinetics of Amodiaquine in Ghanaian Children with Uncomplicated Malaria

“…The artemisinin derivatives induce their own elimination, resulting in decreasing concentrations (2), and the hepatic metabolism of artemisinin is mediated in vitro by CYP2B6, as well as by enzymes of the CYP3A subfamily (28). There is evidence for overlapping substrate specificity between CYP2C8 (which is responsible for AQ metabolism) and CYP3A4, an isoform of the CYP3A subfamily (22). Moreover, artemisinin, AQ, and their respective metabolites (DEAQ and dihydroartemisinin) exhibit a range of interactions in vitro (19), and the pharmacokinetics of mefloquine, a quinoline, is altered by concomitant AS administration (16).…”