RT Journal Article SR Electronic T1 Single-Dose Methoxsalen Effects on Human Cytochrome P-450 2A6 Activity JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 28 OP 33 VO 28 IS 1 A1 Evan D. Kharasch A1 Douglas C. Hankins A1 Julie K. Taraday YR 2000 UL http://dmd.aspetjournals.org/content/28/1/28.abstract AB 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 μg · h · ml−1;P < .001), and also decreased plasma 7-hydroxycoumarin Cmax (0.80 ± 0.26 versus 1.4 ± 0.5 μg/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-hydroxycoumarinCmax and plasma methoxsalenCmax, 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. The American Society for Pharmacology and Experimental Therapeutics