Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity

Methoxsalen (8-methoxypsoralen) is an effective and selective mechanism-bas ed inhibitor of human hepatic cytochrome P-450 (CYP)2A6 in vitro, and may h ave 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-hydroxyla tion. 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 th e curve of plasma 7-hydroxycoumarin versus time by 24% (2.40 +/- 0.48 versu s 3.20 +/- 0.55 mu g.h.ml(-1); P < .001), and also decreased plasma 7-hydro xycoumarin C-max (0.80 +/- 0.26 versus 1.4 +/- 0.5 mu g/ml; P < .05); howev er, 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 ther eafter, and total excretion was unchanged. Considerable individual variabil ity in methoxsalen plasma concentrations was observed. There were significa nt correlations between the decrease in plasma 7-hydroxycoumarin Cmax and p lasma methoxsalen Cmax, but not between the decrease in plasma 7-hydroxycou marin 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 CY P2A6 inhibition appeared attributable to variability in the absorption and first-pass clearance of methoxsalen. Alternative doses, timing, and/or rout es of methoxsalen administration are required for greater, longer, and more reproducible CYP2A6 inhibition than that provided by single-dose methoxsal en.