PT - JOURNAL ARTICLE AU - Cuiping Chen AU - Jian Lin AU - Teresa Smolarek AU - Larry Tremaine TI - P-glycoprotein Has Differential Effects on the Disposition of Statin Acid and Lactone Forms in <em>mdr1a/b</em> Knockout and Wild-Type Mice AID - 10.1124/dmd.107.015677 DP - 2007 Oct 01 TA - Drug Metabolism and Disposition PG - 1725--1729 VI - 35 IP - 10 4099 - http://dmd.aspetjournals.org/content/35/10/1725.short 4100 - http://dmd.aspetjournals.org/content/35/10/1725.full SO - Drug Metab Dispos2007 Oct 01; 35 AB - In the present study we examined the disposition of atorvastatin, lovastatin, and simvastatin in acid and lactone forms and pravastatin in acid form in multidrug-resistant gene (mdr1a/b) knockout (KO), and wild-type (WT) mice. Each statin was administered s.c. to mdr1a/b KO and WT mice at 3.0 mg/kg (n ≥ 3 mice/time point). Blood, brain, and liver samples were harvested at 0, 0.5, 1.5, and 3 h postdose. Plasma and tissue concentrations of the acid and lactone (only the acid form was determined for pravastatin) were determined using a liquid chromatography-mass spectrometry method. Both lactone and acid were observed in plasma when lactones were administered, but only acids were detected when the acid forms were administered. The plasma and liver concentrations of acid or lactone were similar between the KO and WT mice. Two- to 23-fold higher concentrations were observed in liver than in plasma, suggesting potential uptake transporters involved. A significantly higher (p &lt; 0.05) brain penetration in the KO compared with the WT mice was observed for lovastatin acid (but the brain/plasma ratio was low for both KO and WT mice) and lactone and simvastatin lactone but not for atorvastatin or pravastatin. The present results suggest that mouse P-glycoprotein does not affect the lactone-acid interconversion or liver-plasma distribution. Furthermore, P-glycoprotein plays a limited role in restricting the brain penetration of the acid forms of atorvastatin, pravastatin, simvastatin, lovastatin, and atorvastatin lactone but may limit the brain availability of the lactone forms of simvastatin and lovastatin. The American Society for Pharmacology and Experimental Therapeutics