Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects

Abstract

AimsCase reports suggest that gemfobrozil can increase the anticoagulant effect of warfarin. Because gemfibrozil inhibits CYP2C9 in vitro , we studied its effects on the pharmacokinetics and pharmacodynamics of racemic warfarin. MethodsIn a randomized cross-over study, 10 healthy subjects ingested 600 mg gemfibrozil or placebo twice daily for 8 days. On day 3, they were administered a single dose of 10 mg racemic R-S-warfarin orally. The concentrations of R-and S-warfarin in plasma and thromboplastin time were monitored up to 168 h. ResultsGemfibrozil decreased the mean ( ± SD) area under the plasma concentration-time curve [AUC (0-• ) ] of S-warfarin by 11%, from 19.9 ± 5.2 mg l -1 h to 17.6 ± 4.7 mg l -1 h (95% CI on the difference -3.7, -0.78; P < 0.01) and that of R-warfarin by 6% from 31.3 ± 7.5 mg l -1 h during the gemfibrozil phase to 29.5 ± 6.9 mg l -1 h during the placebo phase (95% CI -3.3, -0.33; P < 0.05). There were no significant differences in the elimination half-lives of S-or R-warfarin between the phases. Gemfibrozil did not alter the anticoagulant effect of warfarin. ConclusionUnexpectedly, gemfibrozil slightly decreased the plasma concentrations of R-and Swarfarin. Displacement of warfarin from plasma albumin by gemfibrozil or its interference with the absorption of warfarin could explain the present findings. Usual therapeutic doses of gemfibrozil seem to have limited effects on the pharmacokinetics and pharmacodynamics of single dose warfarin in healthy subjects.

Glucuronidation Converts Gemfibrozil to a Potent, Metabolism-Dependent Inhibitor of Cyp2c8: Implications for Drug-Drug Interactions

“…This approach has proven reliable on numerous occasions, especially when a drug candidate has been evaluated as both a direct-acting and a metabolism-dependent inhibitor of the major drugmetabolizing P450 enzymes in human liver microsomes. Gemfibrozil represents an exception to the rule, because it inhibits CYP2C9 more potently than it inhibits CYP2C8 in vitro, and yet the opposite is observed in vivo, where gemfibrozil does not inhibit the CYP2C9-dependent metabolism of warfarin and has only minimal effect on the metabolism of the CYP2C9-substrate nateglinide (Lilja et al, 2005;Niemi et al, 2005), but does inhibit the metabolism of several CYP2C8 substrates, including cerivastatin, repaglinide, rosiglitazone, and pioglitazone Niemi et al, 2003a,b;Jaakkola et al, 2005). In the present study, we have confirmed the previous finding of Shitara et al (2004) that gemfibrozil 1-O-␤-glucuronide is a direct inhibitor of CYP2C8 and, moreover, that the potency with which gemfibrozil inhibits P450 enzymes is shifted from CYP2C9 to CYP2C8 by glucuronidation (Table 1).…”

“…However, in the clinic, gemfibrozil is a more potent inhibitor of CYP2C8 than of CYP2C9. Coadministration of gemfibrozil with the CYP2C9 substrate warfarin does not increase the plasma concentrations of either R-or S-warfarin (in fact, it actually decreases them) (Lilja et al, 2005). An important step in providing a potential explanation for why gemfibrozil is a more potent inhibitor of CYP2C9 than CYP2C8 in vitro but is a more potent inhibitor of CYP2C8 than CYP2C9 in vivo was provided by Shitara et al (2004), who demonstrated that gemfibrozil 1-O-␤-glucuronide is a more potent inhibitor than gemfibrozil of CYP2C8.…”

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…In healthy volunteers, gemfibrozil (600 mg twice daily) slightly (by 23%) increased the AUC of a CYP2C9 substrate drug glimepiride (Niemi et al, 2001) but did not increase the exposure to racemic warfarin (Lilja et al, 2005). Gemfibrozil even caused a small but statistically significant decrease (211%) in the AUC of the CYP2C9 substrate S-warfarin.…”

“…In vitro, parent gemfibrozil inhibits CYP2C9 activity with a fairly low 226 K i (about 6 mM), but its inhibitory effects on the other main CYP enzymes are much weaker Wen et al, 2001;Wang et al, 2002). In clinical studies, gemfibrozil at a dose of 600 mg twice daily has not increased the concentrations of the CYP2C9 substrate warfarin (Lilja et al, 2005) or had any effect that could be due to inhibition of CYP3A4 on the concentrations of the parent lactone forms of simvastatin and lovastatin Kyrklund et al, 2001). On the other hand, gemfibrozil has drastically, up to 18.6-fold, increased the AUCs of CYP2C8 substrate drugs ( Fig.…”

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

“…However, in vivo these effects are short-lived because of the short half-life of gemfibrozil and much weaker than those on CYP2C8. For example, the CYP2C9-inhibitory effect of gemfibrozil in vitro does not translate into any significant effect on the elimination of S-warfarin in humans (Lilja et al, 2005).…”