Clinical pharmacokinetics of pioglitazone

Summary:

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%, t_max 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, C_max 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 C_max 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.

Key words:

Pioglitazone - pharmacokinetics - renal insufficiency - hepatic insufficiency - drug interactions

References

• 1 Carey R, Liu Y. Pioglitazone does not alter oral contraceptive or hormone replacement therapy pharmacokinetics.  Diabetes 49 ((Suppl 1)) A 405-P May 2000; 
• 2 Crijns-Kortboyer J, Eckland D. Pioglitazone has low potential for drug interactions.  Diabetologia 42 ((Suppl 1)) A228 1999; 
• 3 Edwards G, Eckland D J. Pharmacokinetics of pioglitazone in patients with renal impairment.  Diabetologia 42 ((Suppl 1)) A230 1999; 
• 4 Füchtenbusch M, Standl E, Schatz H. Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitus.  Exp Clin Endocrinol Diabetes. 108 151-163 2000; 
• 5 Geerlof J, Lebrizzi R, Carey R. Effect of food on the pharmacokinetics of pioglitazone. Pioglitazone 036 Study Group.  Diabetes 49 ((Suppl 1)) A357 2000; 
• 6 Loi C M, Stern R, Koup J R, Vassos A B, Knowlton P, Sedman A J. Effect of troglitazone on the pharmacokinetics of an oral contraceptive agent.  J Clin Pharmacol. 39(4) 410-417 1999; 
• 7 Yamashita K, Murakami H, Okuda T, Motohashi M. High-performance liquid chromatographic determination of pioglitazone and its metabolites in human serum and urine.  J Chromatogr B Biomed Appl. 677 141-146 1996; 
• 8 Yamazaki H, Suzuki M, Tane K, Shimada N, Nakajima M, Yokoi T. In vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: comparison with pioglitazone and rosiglitazone.  Xenobiotica. 30 61-70 2000; 
• 9 Zhong W Z, Lakings D B. Determination of pioglitazone in dog serum using solid-phase extraction and high-performance liquid chromatography with ultraviolet (229 nm) detection.  J Chromatogr. 490 377-385 1989; 
• 10 Zhong W Z, Williams M G. Simultaneous quantitation of pioglitazone and its metabolites in human serum by liquid chromatography and solid phase extraction.  J Pharm Biomed Anal. 14 465-473 1996;