Effect of gemfibrozil on the pharmacokinetics of pioglitazone.
OBJECTIVE
Our objective was to study the effects of gemfibrozil on the pharmacokinetics of pioglitazone and the active compounds, which are all the substrates of CYP2C8 and CYP3A4.


METHODS
In a randomized, two-phase crossover study, 10 healthy volunteers were pretreated for 2 days with either 600 mg oral gemfibrozil or placebo twice daily. On day 3, they received a single dose of 600 mg gemfibrozil or placebo, and 1 h later they received a single oral dose of 30 mg pioglitazone. Plasma concentrations of pioglitazone and both active metabolites M-III and M-IV were measured for up to 120 h.


RESULTS
Gemfibrozil raised the mean total area under the concentration-time curve (AUC) of parent pioglitazone 3.4-fold (P<0.001). No statistically significant changes were seen in the total AUC of M-III or M-IV after gemfibrozil pretreatment. Gemfibrozil reduced the M-III/pioglitazone and M-IV/pioglitazone AUC(0-infinity) ratio by 71% (P<0.001) and 65%(P<0.001), strikingly prolonging their t((1/2)).


CONCLUSIONS
Gemfibrozil greatly increased the plasma concentration of parent pioglitazone and also inhibited the further metabolism of M-III and M-IV. Careful blood glucose monitoring and dosage adjustments are suggested during coadministration of pioglitazone and gemfibrozil.
Deng
Li-Jing
LJ
Clinical Pharmaceutical Research Institute, The Second Xiangya Hospital, The Central South University, Changsha 410011, China. denglijing7117@163.com
Wang
Feng
F
Li
Huan-De
HD
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D015248:Gemfibrozil / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008297:Male; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000378:metabolism / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D045162:Thiazolidinediones; D015248:Gemfibrozil; D000077205:Pioglitazone