Effects of cyclosporin A and itraconazole on the pharmacokinetics of atorvastatin in rats.
OBJECTIVE
To evaluate the effects of cyclosporin A and itraconazole, which were used as inhibitors of P-glycoprotein (P-gp) and/or cytochrome P450 (CYP) 3A4 on the pharmacokinetics of atorvastatin in rats.


METHODS
The pharmacokinetic parameters of atorvastatin were measured after intravenous (2 mg/kg) and intragastric (10 mg/kg) administration of atorvastatin in rats, which were pretreated with cyclosporin A (5, 10, and 20 mg/kg) or itraconazole (5, 10, and 20 mg/kg).


RESULTS
Compared with the control rats, cyclosporin A and itraconazole altered the pharmacokinetics of atorvastatin significantly. The AUC0-t values of atorvastatin after intragastric administration, pretreated with cyclosporin A (5-20 mg/kg), increased by 32.3%, 61.8%, and 187.2%, respectively, but the CLbile values decreased (P<0.01, 5-20 mg/kg). With pretreatment of itraconazole (5-20 mg/kg), the AUC(0-t) values of atorvastatin increased by 88.2%, 102%, and 123%, respectively, but the CL(bile) values decreased (P<0.01, 5-20 mg/kg).


CONCLUSIONS
These data indicated that cyclosporin A could be effective in inhibiting the efflux of atorvastatin, and itraconazole could be effective in inhibiting both the metabolism and biliary excretion of atorvastatin.
Dong
Jing
J
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Yu
Xue
X
Wang
Lei
L
Sun
Ye-bin
YB
Chen
Xi-jing
XJ
Wang
Guang-ji
GJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D001646:Bile / Q000378:metabolism; D002138:Calibration; D016572:Cyclosporine / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D017964:Itraconazole; D016572:Cyclosporine; D000069059:Atorvastatin; D051544:Cytochrome P-450 CYP3A