Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

Abstract

Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. EXPERIMENTAL APPROACHTwo groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg -1 racemic warfarin i.v., and the test group (n = 13) 1 mg·kg -1 of racemic warfarin followed by 25 mg·kg -1 ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. KEY RESULTSETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. CONCLUSION AND IMPLICATIONSOur data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance. Abbreviations

Puerarin offsets the anticoagulation effect of warfarin in rats by inducing rCyps, upregulating vitamin K epoxide reductase and inhibiting thrombomodulin

“…The t 1/2 of S ‐ and R ‐warfarin was determined to be 20.2 and 7.5 h respectively in our study, which is consistent with previous reports . Despite warfarin being given to rats as a racemic mixture consisting of equal amounts of the R ‐ and S ‐enantiomers in the current study, S ‐warfarin actually showed significantly higher AUC 0–96 h (~3.5‐fold) than R ‐warfarin in all the warfarin treated rats, which could be ascribed to the faster elimination rate of R ‐warfarin (Table ).…”

Warfarin is an Effective Modifier of Multiple UDP-Glucuronosyltransferase Enzymes: Evaluation of its Potential to Alter the Pharmacokinetics of Zidovudine

“…doses (1 mg/kg) and an p.o. dose (2 mg/kg) were often used for evaluation of warfarin pharmacokinetics and pharmacodynamics in rats . Accordingly, the same doses for i.v.…”

Oral Liquid Formulation of Etravirine for Enhanced Bioavailability

“…The absolute bioavailability of etravirine has not been determined because of the lack of an intravenous formulation [6]. In vivo, etravirine is an inducer of CYP3A4 and an inhibitor of the CYP2C subfamily [7,23]. Etravirine has a terminal elimination half-life in plasma of approximately 30-40 h. The drug should be taken following a meal to enhance bioavailability [8].…”