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Simultaneous Measurement of In Vivo P‐glycoprotein and Cytochrome P450 3A Activities
Author(s) -
Kirby Brian,
Kharasch Evan D.,
Thummel Kenneth T.,
Narang Vishal S.,
Hoffer Christine J.,
Unadkat Jashvant D.
Publication year - 2006
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270006292625
Subject(s) - midazolam , cyp3a , digoxin , pharmacokinetics , pharmacology , crossover study , p glycoprotein , drug interaction , in vivo , cyp3a4 , pharmacokinetic interaction , chemistry , urine , medicine , cytochrome p450 , antibiotics , biology , metabolism , biochemistry , pathology , heart failure , alternative medicine , microbiology and biotechnology , multiple drug resistance , sedation , placebo
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.