The effect of gemfibrozil on the pharmacokinetics of rosuvastatin.
BACKGROUND
Coadministration of statins and gemfibrozil is associated with an increased risk for myopathy, which may be due in part to a pharmacokinetic interaction. Therefore the effect of gemfibrozil on rosuvastatin pharmacokinetics was assessed in healthy volunteers. Rosuvastatin has been shown to be a substrate for the human hepatic uptake transporter organic anion transporter 2 (OATP2). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. The effect of gemfibrozil on rosuvastatin uptake by cells expressing OATP2 was also examined.


METHODS
In a randomized, double-blind, 2-period crossover trial, 20 healthy volunteers were given oral doses of gemfibrozil, 600 mg, or placebo twice daily for 7 days. On the fourth morning of each dosing period, a single oral dose of rosuvastatin, 80 mg, was coadministered. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and rosuvastatin-lactone were measured. In addition, the effect of gemfibrozil on the uptake of radiolabeled rosuvastatin by OATP2-transfected Xenopus oocytes was studied.


RESULTS
Gemfibrozil increased the rosuvastatin area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration [AUC(0-t)] 1.88-fold (90% confidence interval, 1.60-2.21) and the maximum observed rosuvastatin plasma concentration (C(max)) 2.21-fold (90% confidence interval, 1.81-2.69) compared with placebo. N-desmethyl rosuvastatin AUC(0-t) and C(max) decreased by 48% and 39%, respectively. Pharmacokinetics of rosuvastatin-lactone was unchanged. The in vitro results indicate that the maximum gemfibrozil inhibition of rosuvastatin OATP2-mediated uptake was 50%; the inhibition constant for the inhibitory process was 4.0 +/- 1.3 micromol/L.


CONCLUSIONS
Gemfibrozil increased rosuvastatin plasma concentrations approximately 2-fold, which is similar to the effect of gemfibrozil on pravastatin, simvastatin acid, and lovastatin acid plasma concentrations and substantially less than the effect observed for cerivastatin. Gemfibrozil inhibition of OATP2-mediated rosuvastatin hepatic uptake may contribute to the mechanism of the drug-drug interaction. Care is warranted when gemfibrozil is coadministered with rosuvastatin and other statins.
Schneck
Dennis W
DW
AstraZeneca, Willmington, DE 19850, USA. dennis.schneck@astrazeneca.com
Birmingham
Bruce K
BK
Zalikowski
Julie A
JA
Mitchell
Patrick D
PD
Wang
Yi
Y
Martin
Paul D
PD
Lasseter
Kenneth C
KC
Brown
Colin D A
CD
Windass
Amy S
AS
Raza
Ali
A
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D019540:Area Under Curve; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015248:Gemfibrozil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012016:Reference Values; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014981:Xenopus
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D027361:Organic Anion Transporters; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D015248:Gemfibrozil