Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

Abstract

The glucose-lowering drug pioglitazone undergoes hepatic CYP2C8-mediated biotransformation to its main metabolites. The antiplatelet drug clopidogrel is metabolized to clopidogrel acyl-b-D-glucuronide, which was recently found to be a strong time-dependent inhibitor of CYP2C8 in humans. Therefore, we studied the effect of clopidogrel on the pharmacokinetics of pioglitazone. In a randomized crossover study, 10 healthy volunteers ingested either 300 mg of clopidogrel on day 1, and 75 mg on days 2 and 3, or placebo. Pioglitazone 15 mg was administered 1 hour after placebo and clopidogrel on day 1. Plasma concentrations of pioglitazone, clopidogrel, and their main metabolites were measured up to 72 hours. Clopidogrel increased the area under the plasma concentration-time curve (AUC 0-' ) of pioglitazone 2.1-fold [P < 0.001, 90% confidence interval (CI) 1.8-2.6] and prolonged its half-life from 6.7 to 11 hours (P = 0.002). The peak concentration of pioglitazone was unaffected but the concentration at 24 hours was increased 4.5-fold (range 1.6-9.8; P < 0.001, 90% CI 3.17-6.45) by clopidogrel. The M-IV-to-pioglitazone AUC 0-' ratio was 49% (P < 0.001, 90% CI 0.40-0.59) of that during the control phase, indicating that clopidogrel inhibited the CYP2C8-mediated biotransformation of pioglitazone. Clopidogrel increases the exposure to pioglitazone by inhibiting its CYP2C8-mediated biotransformation. In consequence, use of clopidogrel may increase the risk of fluid retention and other concentration-related adverse effects of pioglitazone.

Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel

“…CYP2C8 has a major role in the metabolism of dasabuvir, while clopidogrel inhibits the metabolism of CYP2C8 substrates . Dasabuvir is usually administered as a component of the 3D regimen, which includes ritonavir, a strong inhibitor of CYP3A4, whereas the formation of clopidogrel's active metabolite responsible for the antithrombotic effect is partially CYP3A4‐mediated .…”

“…In recent years, clopidogrel has been found to significantly increase the exposure to several CYP2C8 substrates, e.g., repaglinide, pioglitazone, and montelukast. [22][23][24][25] The main mechanism of the aforementioned DDIs is the strong time-dependent CYP2C8 inactivation by clopidogrel's phase II acyl-b-D-glucuronide metabolite. 22 Along with CYP2C8 inhibition, additional interaction mechanisms, e.g., inhibition of CYP3A4 and organic anion transporting polypeptide (OATP) 1B1, a hepatic influx transporter, by clopidogrel have been suggested to explain these DDIs.…”

“…In recent years, clopidogrel has been found to significantly increase the exposure to several CYP2C8 substrates, e.g., repaglinide, pioglitazone, and montelukast . The main mechanism of the aforementioned DDIs is the strong time‐dependent CYP2C8 inactivation by clopidogrel's phase II acyl‐ β ‐D‐glucuronide metabolite .…”

Effect of gemfibrozil and rifampicin on the pharmacokinetics of selexipag and its active metabolite in healthy subjects

“…The effect of moderate inhibitors of CYP2C8 (e.g. clopidogrel, deferasirox, teriflunomide) on the exposure to selexipag and ACT‐333679 has not yet been studied but, based on the observed effect of gemfibrozil on the PK of ACT‐333679 in the present study, a PK interaction between moderate inhibitors of CYPC28 and selexipag cannot be excluded. Therefore, caution is required when using these drugs concomitantly with selexipag.…”

Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate

“…Drug interactions associated with clopidogrel could be frequently encountered in patient care (Kim et al, 2016;Xie et al, 2011). Recent studies documented that phase II metabolitesglucuronidescould be the ligands of human CYP2C8 (Ma, Fu, Khojasteh, Dalvie, & Zhang, 2017), and that CAG is known to be a potent, time-dependent inhibitor of CYP2C8 (Backman, Filppula, Niemi, & Neuvonen, 2016;Bergmann et al, 2016;Itkonen et al, 2016;Kim et al, 2016;Tornio et al, 2014). High plasma CAG concentrations would strongly inhibit the metabolism of the substrate drugs of CYP2C8, such as cerivastatin (Floyd et al, 2012), dasabuvir (Arya, Zhao, Reynolds, Mishra, & Younis, 2017;Shebley, Fu, Badri, Bow, & Fischer, 2017), desloratadine (Kazmi, Barbara, Yerino, & Parkinson, 2015), paclitaxel (Agergaard et al, 2017;Backman et al, 2016;Bergmann et al, 2016), pioglitazone (Itkonen et al, 2016;Kim et al, 2016), repaglinide (Tornio et al, 2014;Kim et al, 2016), and more, which would result in serious adverse drug reactions, such as cerivastatin-induced rhabdomyolysis (Floyd et al, 2012), pioglitazone-associated fluid retention (Itkonen et al, 2016), paclitaxel-related neurotoxicity (Bergmann et al, 2016), and repaglinide-mediated hypoglycemia (Tornio et al, 2014).…”