Effect of troglitazone on urinary excretion of 6beta-hydroxycortisol.
Coadministration of troglitazone reduces the plasma concentrations of terfenadine and ethinyl estradiol. Because these drugs are metabolized at least in part by cytochrome P450 3A (CYP3A), it is possible that troglitazone induces CYP3A activity, thereby reducing plasma concentrations of these agents. Known inducers of CYP3A, such as rifampin, phenytoin, carbamazepine, and phenobarbital, increase the urinary excretion of 6beta-hydroxycortisol and the ratio of 6beta-hydroxycortisol to cortisol. This evaluation examined the effect of troglitazone on urinary excretion of 6beta-hydroxycortisol and the ratio of 6beta-hydroxycortisol to cortisol as a marker for CYP3A induction. Urine samples were collected from 11 subjects who completed a study evaluating the effect of multiple-dose administration of troglitazone 400 mg once daily (days 11-20) on the steady-state pharmacokinetics of digoxin (0.25 mg daily on days 1-20). A single urine sample was collected at baseline on day 1, and 24-hour urine samples were collected on days 10 and 20. Mean +/- standard deviation 24-hour excretion rate of cortisol was unchanged, whereas that of 6beta-hydroxycortisol increased during troglitazone administration. The ratio of 24-hour urinary 6beta-hydroxycortisol to cortisol excretion increased from 7.4 +/- 2.7 on day 10 to 16.1 +/- 6.2 on day 20. The ratio observed on day 10 was similar to that obtained at baseline. These results are consistent with the hypothesis that troglitazone induces CYP3A activity.
Koup
J R
JR
Department of Pharmacokinetics, Dynamics, and Metabolism, Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, Ann Arbor, Michigan 48105, USA.
Anderson
G D
GD
Loi
C M
CM
D001189:Aryl Hydrocarbon Hydroxylases; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004077:Digoxin / Q000493:pharmacokinetics / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000378:metabolism; D012680:Sensitivity and Specificity; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002316:Cardiotonic Agents; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; C001380:6 beta-hydroxycortisol; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000077288:Troglitazone; D006854:Hydrocortisone