title: Pioglitazone: effect on CYP3A4 activity.
abstract: Clinical studies demonstrate CYP3A4 enzyme induction with troglitazone, a thiazolidinedione derivative structurally related to pioglitazone. The objective of this prospective, open-label study conducted in healthy volunteers was to evaluate the influence of multiple-dose pioglitazone therapy on the urinary excretion ratio of 6-beta-hydroxycortisol to cortisol, an endogenous marker of CYP3A4 activity. Twelve subjects were given pioglitazone hydrochloride 45 mg daily for 14 days. Urine was collected over a 24-hour period before pioglitazone and after administration of the last tablet. Baseline and posttreatment CYP3A4 activity was assessed with the urinary 6-beta-hydroxycortisol/cortisol ratio. The mean +/- SD 6-beta-hydroxycortisol/cortisol ratios before and after treatment were 8.3 +/- 4.4 and 9.4 +/- 4.0, respectively (p = 0.29). The mean change from baseline was a nonsignificant 20.2%. Nine subjects had a small increase and 3 subjects had a reduction in the ratio. Using the ratio as a marker of CYP3A4 activity, the data support a lack of inductive effect on CYP3A4 by multiple-dose pioglitazone therapy. Thus, administration of pioglitazone should not result in clinically significant effects on the pharmacokinetics of other CYP3A4 substrates.
authors.affiliation: Wayne State University, Department of Pharmacy Practice, Detroit, Michigan, USA.
authors.forename: Sandra N
authors.initials: SN
authors.lastname: Nowak
authors.forename: David J
authors.initials: DJ
authors.lastname: Edwards
authors.forename: Anthony
authors.initials: A
authors.lastname: Clarke
authors.forename: Gail D
authors.initials: GD
authors.lastname: Anderson
authors.forename: Linda A
authors.initials: LA
authors.lastname: Jaber
mesh_terms: D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000652:urine; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D000077205:Pioglitazone; D011446:Prospective Studies; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
chemical_list: D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone; D000077205:Pioglitazone