RT Journal Article
SR Electronic
T1 Murine Oatp1a/1b Uptake Transporters Control Rosuvastatin Systemic Exposure Without Affecting Its Apparent Liver Exposure
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 919
OP 929
DO 10.1124/mol.112.081927
VO 83
IS 5
A1 Dilek Iusuf
A1 Anita van Esch
A1 Michael Hobbs
A1 Maxine Taylor
A1 Kathryn E. Kenworthy
A1 Evita van de Steeg
A1 Els Wagenaar
A1 Alfred H. Schinkel
YR 2013
UL http://molpharm.aspetjournals.org/content/83/5/919.abstract
AB Organic anion–transporting polypeptides (OATPs) mediate the liver uptake and hence plasma clearance of a broad range of drugs. For rosuvastatin, a cholesterol-lowering drug and OATP1A/1B substrate, the liver represents both its main therapeutic target and its primary clearance organ. Here we studied the impact of Oatp1a/1b uptake transporters on the pharmacokinetics of rosuvastatin using wild-type and Oatp1a/1b-null mice. After oral administration (15 mg/kg), intestinal absorption of rosuvastatin was not impaired in Oatp1a/1b-null mice, but systemic exposure (area under the curve) was 8-fold higher in these mice compared with wild-type. Although liver exposure was comparable between the two mouse strains (despite the increased blood exposure), the liver-to-blood ratios were markedly decreased (>10-fold) in the absence of Oatp1a/1b transporters. After intravenous administration (5 mg/kg), systemic exposure was 3-fold higher in Oatp1a/1b-null mice than in the wild-type mice. Liver, small intestinal, and kidney exposure were slightly, but not significantly, increased in Oatp1a/1b-null mice. The biliary excretion of rosuvastatin was very fast, with 60% of the dose eliminated within 15 minutes after intravenous administration, and also not significantly altered in Oatp1a/1b-null mice. Rosuvastatin renal clearance, although still minor, was increased ∼15-fold in Oatp1a/1b-null males, suggesting a role of Oatp1a1 in the renal reabsorption of rosuvastatin. Absence of Oatp1a/1b uptake transporters increases the systemic exposure of rosuvastatin by reducing its hepatic extraction ratio. However, liver concentrations are not significantly affected, most likely due to the compensatory activity of high-capacity, low-affinity alternative uptake transporters at higher systemic rosuvastatin levels and the absence of efficient alternative rosuvastatin clearance mechanisms.