Clinical pharmacokinetics of pioglitazone

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Abstract
Pioglitazone is a thiazolidinedione antidiabetic agent that increases insulin sensitivity and decreases hepatic gluconeogenesis. Administered once daily without regard to meals, it is well absorbed, and is metabolised by the hepatic cytochrome P450 enzyme system. The half-life of the drug is approximately 9 hours, but two active metabolites (M-III and M-IV) contribute to extended glucose-lowering effects. In animals, after absorption the highest concentrations are found in the liver, plasma, and kidney. The mean absolute bioavailability is 83%, tmax is 1.5 (range 0.5-3.0) hours, and the absorption rate constant ranges from 0.04 to 1.17 hr-1. Mean clearance is 2.4 (range 1.72-4.17) L/hr. With single oral doses between 2 and 60 mg, Cmax and area-under-the-curve (AUC) increased linearly with dose: no changes were observed upon repeated administration. The AUC is not affected by food. The volume of distribution is 0.253 L/kg, probably due to extensive protein binding (> 97%). Drug interaction studies have not shown inhibition or induction of any cytochrome P450 enzymes involved in drug metabolism, thus the potential for drug interactions is low. The pharmacokinetics of pioglitazone do not differ significantly between healthy volunteers and patients with type 2 diabetes. Dosage adjustment is not necessary in patients with renal failure, or in those undergoing haemodialysis. In hepatic insufficiency, volume of distribution was increased, and Cmax was reduced. Age and gender appear to have no significant effect on the pharmacokinetics of pioglitazone, and there do not appear to be any differences between races.

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