title: Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity.
abstract: Methoxsalen (8-methoxypsoralen) is an effective and selective mechanism-based inhibitor of human hepatic cytochrome P-450 (CYP)2A6 in vitro, and may have utility as a clinical probe for CYP2A6-catalyzed xenobiotic metabolism in humans in vivo. This investigation explored single-dose oral methoxsalen effects on human CYP2A6 activity in vivo, assessed by coumarin 7-hydroxylation. Eleven volunteers received 50 mg of oral coumarin on two occasions in a randomized crossover, 90 min after oral methoxsalen or nothing (controls). Plasma and urine 7-hydroxycoumarin and plasma methoxsalen concentrations were determined by HPLC. Methoxsalen pretreatment diminished area under the curve of plasma 7-hydroxycoumarin versus time by 24% (2.40 +/- 0.48 versus 3.20 +/- 0.55 microg. h. ml(-1); P <.001), and also decreased plasma 7-hydroxycoumarin C(max) (0.80 +/- 0.26 versus 1.4 +/- 0.5 microg/ml; P <.05); however, 7-hydroxycoumarin concentrations were only diminished 0.75 to 2 h after coumarin administration, but not thereafter. Methoxsalen diminished urine 7-hydroxycoumarin excretion in 0- to 1- and 1- to 2-h samples, but not thereafter, and total excretion was unchanged. Considerable individual variability in methoxsalen plasma concentrations was observed. There were significant correlations between the decrease in plasma 7-hydroxycoumarin C(max) and plasma methoxsalen C(max), but not between the decrease in plasma 7-hydroxycoumarin area under the curve and methoxsalen disposition. These results show that single-dose oral methoxsalen, in conventional doses, was a moderately effective inhibitor of human CYP2A6 activity in vivo, however, the duration of inhibition was limited. Interindividual variability in the extent of CYP2A6 inhibition appeared attributable to variability in the absorption and first-pass clearance of methoxsalen. Alternative doses, timing, and/or routes of methoxsalen administration are required for greater, longer, and more reproducible CYP2A6 inhibition than that provided by single-dose methoxsalen.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle 98195, USA. kharasch@u.washington.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: D C
authors.initials: DC
authors.lastname: Hankins
authors.forename: J K
authors.initials: JK
authors.lastname: Taraday
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D065637:Cytochrome P-450 CYP2A6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008730:Methoxsalen / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015335:Molecular Probes; D014468:Umbelliferones / Q000097:blood / Q000652:urine
chemical_list: D000925:Anticoagulants; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D015335:Molecular Probes; D014468:Umbelliferones; C031477:7-hydroxycoumarin; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D008730:Methoxsalen