Received for publication December 29, 2005.
Revised April 6, 2006.
Accepted for publication April 11, 2006.

Pharmacokinetics of atorvastatin and its hydroxy metabolites in rats and the effects of concomitant rifampicin single doses: Relevance of first-pass effect from hepatic uptake transporters, intestinal and hepatic metabolism

Abstract

Pharmacokinetic coadministration experiments with atorvastatin (ATV) and rifampicin (RIF) in rats were performed to investigate the potential involvement of hepatic uptake transporters, Oatps, during hepatic drug elimination, as an in vivo extension of our recently published cellular and isolated perfused liver studies. ATV was administered orally (10 mg/kg) and intravenously (2 mg/kg) to rats in the absence and presence of a single intravenous dose of RIF (20 mg/kg) and pharmacokinetic parameters compared between control and RIF-treatment groups. RIF markedly increased the plasma concentrations of ATV and its metabolites when ATV was administered orally. The AUC_0- for ATV also increased significantly after intravenous dosing of ATV with RIF, but the extent was much less than that observed for oral ATV dosing. Significant increases in plasma levels were observed for both metabolites as well. The 7-fold higher AUC ratio of metabolites to parent drug following oral versus intravenous ATV dosing suggests that ATV undergoes extensive gut metabolism. Both hepatic and intestinal metabolism contributes to the low oral bioavailability of ATV in rats. In the presence of RIF, the liver metabolic extraction was significantly reduced, most likely due to RIF's inhibition on Oatp-mediated uptake, which leads to reduced hepatic amounts of parent drug for subsequent metabolism. Gut extraction was also significantly reduced, but we were unable to elucidate the mechanism of this effect since intravenous RIF caused gut changes in availability. These studies reinforce our hypothesis that hepatic uptake is a major contributor to the elimination of ATV and its metabolites in vivo.

Key words: cytochrome P450, drug transport, first-pass metabolism, hepatic elimination, hepatic uptake, intestinal bioavailability, metabolite kinetics, pharmacokinetics, transporters

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