Urinary excretion of 6β‐hydroxycortisol as an in vivo marker for CYP3A induction: Applications and recommendations

Objective To evaluate the usefulness of 6β‐hydroxycortisol as a screen for CYP3A induction in early‐phase drug development. Methods Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24‐hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6β‐hydroxycortisol and 17‐hydroxycorticosteroid concentrations. Results Subjects in the rifampin group had a significant increase from predose value in the 24‐hour urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to 17‐hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6β‐hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter. Conclusions Urinary excretion of 6β‐hydroxycortisol may be useful as a screening tool in early‐phase development to assess the potential for an investigational drug to induce CYP3A. Clinical Pharmacology & Therapeutics (1998) 63, 617–622; doi: