Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities.

Author(s): Kirby B, Kharasch ED, Thummel KT, Narang VS, Hoffer CJ, Unadkat JD

Affiliation(s): Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195-7610, USA.

Publication date & source: 2006-11, J Clin Pharmacol., 46(11):1313-9.

Publication type: Randomized Controlled Trial; Research Support, N.I.H., Extramural

Digoxin and midazolam are routinely used as probe drugs to measure in vivo activity of P-glycoprotein (P-gp) and cytochrome P450 3A4/5 (CYP3A), respectively. We investigated whether digoxin and midazolam could be coadministered to simultaneously determine P-gp and CYP3A activity without a significant pharmacokinetic interaction. In a randomized crossover design, digoxin (0.5 mg oral) or midazolam (2.0 mg oral) was administered individually or in combination (digoxin 1 hour after midazolam) to 14 healthy volunteers. Blood and urine samples were collected for up to 48 hours. Pharmacokinetic parameters of digoxin, midazolam and 1'-OH midazolam were evaluated to determine the presence of an interaction. The geometric mean ratios of all measured pharmacokinetic parameters of digoxin and midazolam were not significantly affected by coadministration. Coadministration of digoxin and midazolam can be used to simultaneously phenotype P-gp and CYP3A activity without a significant pharmacokinetic interaction.