Abstract
Pharmacokinetic coadministration experiments with atorvastatin (ATV) and rifampicin (RIF) in rats were performed to investigate the potential involvement of hepatic uptake transporters, Oatps (organic anion-transporting polypeptides), 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 were compared between control and RIF-treatment groups. RIF markedly increased the plasma concentrations of ATV and its metabolites when ATV was administered orally. The area under the plasma concentration-time curve (AUC0-∞) 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 contribute to the low oral bioavailability of ATV in rats. In the presence of RIF, the liver metabolic extraction was significantly reduced, most likely because of 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 because 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.
Footnotes
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This study was supported in part by National Institutes of Health Grant GM-61390, in part through facilities of the University of California, San Francisco Liver Center (DK-26743), and by an unrestricted grant from Amgen, Inc. Dr. Benet serves as a consultant to Amgen.
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A portion of these data was presented at the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting, Nashville, TN, November 6–10, 2005. Y.Y.L. was supported in part by an American Foundation for Pharmaceutical Education Pre-doctoral Fellowship.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.009076.
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ABBREVIATIONS: ATV, atorvastatin; P-gp, P-glycoprotein; MRP2/Mrp2, multidrug resistance-associated protein 2; Oatp, organic anion-transporting polypeptide; IPRL, isolated perfused rat liver; P450, cytochrome P450; AUC, area under the plasma concentration-time curve; 2-OH ATV, ortho- or 2-hydroxy atorvastatin; 4-OH ATV, para- or 4-hydroxy atorvastatin; RIF, rifampicin; B/P, blood to plasma concentration ratio; CLiv, total intravenous blood clearance; Vss, steady-state volume of distribution; F, oral bioavailability; Fabs × FG, gut processes affecting availability; ERH, hepatic extraction ratio; FH, hepatic availability; ER, extraction ratio.
- Received December 21, 2005.
- Accepted April 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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