P-glycoprotein has differential effects on the disposition of statin acid and lactone forms in mdr1a/b knockout and wild-type mice.
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 > or = 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 < 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.
Chen
Cuiping
C
Global Preclinical Development, Johnson and Johnson, Mountain View, CA 94039, USA. tchen3@alzus.jnj.com
Lin
Jian
J
Smolarek
Teresa
T
Tremaine
Larry
L
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood / Q000493:pharmacokinetics*; D000069059:Atorvastatin; D001921:Brain / Q000378:metabolism; D006538:Heptanoic Acids / Q000097:blood / Q000493:pharmacokinetics*; D007783:Lactones / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017035:Pravastatin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics*; D019821:Simvastatin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D000069059:Atorvastatin; D006538:Heptanoic Acids; D007783:Lactones; D008148:Lovastatin; D017035:Pravastatin; D011758:Pyrroles; D019821:Simvastatin; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C063287:simvastatin acid