Organic anion-transporting polypeptides 1a/1b control the hepatic uptake of pravastatin in mice.
Organic anion-transporting polypeptides (OATPs) mediate the hepatic uptake of many drugs. Hepatic uptake is crucial for the therapeutic effect of pravastatin, a cholesterol-lowering drug and OATP1A/1B substrate. We aimed to gain empirical insight into the relationship between OATPs and pravastatin pharmacokinetics and toxicity. We therefore compared the distribution and toxicity of pravastatin in wild-type and Oatp1a/1b-null mice. Intestinal absorption of pravastatin was not affected by Oatp1a/1b absence, but systemic plasma exposure (AUC) increased up to 30-fold after oral bolus administration. This increased plasma exposure resulted from reduced hepatic uptake, as evident from 10 to 100-fold lower liver-to-plasma concentration ratios. However, the reductions in liver exposure were far smaller (<2-fold) than the increases in plasma exposure. Reduced pravastatin liver uptake in Oatp1a/1b-null mice was more obvious shortly after intravenous administration, with 8-fold lower biliary pravastatin excretion. Although mice chronically exposed to pravastatin for 60 days evinced little muscular toxicity, Oatp1a/1b-null mice displayed 10-fold higher plasma concentrations and 8-fold lower liver concentrations than wild-type mice. Thus, Oatp1a/1b transporters importantly control the hepatic uptake of pravastatin. Activity-reducing human OATP1B polymorphisms may therefore both reduce pravastatin therapeutic efficacy in the liver and increase systemic toxicity risks, thus compromising its therapeutic index in a two-edged way.
Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Dilek
D
Iusuf
Rolf W
RW
Sparidans
Anita
A
van Esch
Mike
M
Hobbs
Kathryn E
KE
Kenworthy
Evita
E
van de Steeg
Els
E
Wagenaar
Jos H
JH
Beijnen
Alfred H
AH
Schinkel
D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D027361:Organic Anion Transporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017035:Pravastatin / Q000493:pharmacokinetics*
D027361:Organic Anion Transporters; D017035:Pravastatin