Gemfibrozil Is a Strong Inactivator of CYP2C8 in Very Small Multiple Doses

Abstract

Therapeutic doses of gemfibrozil cause mechanism-based inactivation of CYP2C8 via formation of gemfibrozil 1-O-β-glucuronide. We investigated the extent of CYP2C8 inactivation caused by three different doses of gemfibrozil twice dailyfor 5 days, using repaglinide as a probe drug, in 10 healthy volunteers. At the end of this 5-day regimen, there were dose-dependent increases in the area under the plasma concentration–time curve from 0 to infinity (AUC0–∞) of repaglinide by3.4-, 5.5-, and 7.0-fold corresponding to 30, 100, and 600 mg of gemfibrozil, respectively, as compared with the control phase (P < 0.001). On the basis of a mechanism-based inactivation model involving gemfibrozil 1-O-β-glucuronide, a gemfibrozil dose of 30 mg twice daily was estimated to inhibit CYP2C8 by >70% and 100 mg twice daily was estimated to inhibit it by >90%. Hence, gemfibrozil is a strong inactivator of CYP2C8 even in very small, subtherapeutic, multiple doses. Administration of small gemfibrozil doses may be useful in optimizing the pharmacokinetics of CYP2C8 substrate drugs and in reducing the formation of their potentially toxic metabolites via CYP2C8.

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…In addition, the OATP1B1 inhibitory effect of the glucuronide can lead to an up to ;50% transient inhibition of OATP1B1 in vivo. These effects are the main explanation to the effects of gemfibrozil on CYP2C8 and OATP1B1 substrates (Honkalammi et al, 2012). Similar estimations have been obtained with physiologically based pharmacokinetic modeling in a recent publication (Varma et al, 2015).…”

“…8;Honkalammi et al, 2011a). Also after multiple doses of gemfibrozil (30, 100, or 600 mg twice daily for 5 days), the exposure to repaglinide increased dose dependently, but the greatest AUC increase did not exceed that observed after the single 900 mg gemfibrozil dose (Honkalammi et al, 2012). Thus, the maximum inhibition of CYP2C8 can be achieved by a single 900-mg dose of gemfibrozil (Fig.…”

Analysis of the Repaglinide Concentration Increase Produced by Gemfibrozil and Itraconazole Based on the Inhibition of the Hepatic Uptake Transporter and Metabolic Enzymes

“…The repaglinide concentration increase produced by GEM reported in other interaction studies (Backman et al, 2009;Honkalammi et al, 2011Honkalammi et al, , 2012 were simulated based on the same PBPK model (Figs. 1, B and C ; together with the parameters estimated in the present study (Table 2).…”

“…(Honkalammi et al, 2011). Report 3: repaglinide was taken 1 hour after the last administration of gemfibrozil (30, 100, or 600 mg p.o., twice a day, for 3 days) (Honkalammi et al, 2012 (Hisaka and Sugiyama, 1998) was used for all the fitting and simulation analyses. The differential equations were numerically solved by using the Runge-Kutta-Fehlberg method.…”

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

“…In vitro f m,CYP2C8 of pitavastatin, pioglitazone, and cerivastatin were reported to be 0.0, 0.68, and 0.61, respectively (Fujino et al, 2003;Shitara et al, 2004;Jaakkola et al, 2006). By contrast, f m,CYP2C8 for repaglinide are various: 0.41-0.71 from in vitro experiments (Kajosaari et al, 2005a;Säll et al, 2012) and 0.80-0.89 from in vivo data with modeling (Honkalammi et al, 2011b(Honkalammi et al, , 2012Kudo et al, 2013). We used in vitro f m,CYP2C8 for the prediction to apply a unified method for all the substrates.…”