title: Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195-7610, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kirby
authors.forename: Evan D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Thummel
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Narang
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Hoffer
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004077:Digoxin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam