RT Journal Article
SR Electronic
T1 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, AND INTESTINAL AND HEPATIC METABOLISM
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1175
OP 1181
DO 10.1124/dmd.105.009076
VO 34
IS 7
A1 Yvonne Y. Lau
A1 Hideaki Okochi
A1 Yong Huang
A1 Leslie Z. Benet
YR 2006
UL http://dmd.aspetjournals.org/content/34/7/1175.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics