Received for publication March 7, 2007.
Revised July 17, 2007.
Accepted for publication July 18, 2007.

P-GLYCOPROTEIN HAS DIFFERENTIAL EFFECTS ON THE DISPOSITION OF STATIN ACID AND LACTONE FORMS IN MDR1A/B KNOCKOUT AND WIDE-TYPE MICE

Abstract

The present study examined the disposition of atorvastatin, lovastatin, and simvastatin in acid and lactone forms and pravastatin in acid form in multi-drug resistant gene, mdr1a/b knockout (KO) and wild type (WT) mice. Each statin was administered subcutaneously 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 post dose. Plasma and tissue concentrations of the acid and lactone (only acid form was determined for pravastatin) were determined using a liquid chromatography-mass spectrometric 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. A 2-23 fold higher concentrations were observed in liver than those in plasma, suggesting potential uptake transporters involved. A significantly higher (p < 0.05) brain penetration in KO compared to the WT mice was observed for lovastatin acid (but brain/plasma 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 inter-conversion or liver-plasma distribution. Furthermore, P-glycoprotein plays a limited role in restricting the brain penetration of the acid form of atorvastatin, pravastatin, simvastatin and lovastatin, and atorvastatin lactone, but may limit the brain availability of lactone form of simvastatin and lovastatin.

Key words: blood-CNS transport, drug disposition, p-glycoprotein, pharmacokinetics

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