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

Publication ,  Journal Article
Kharasch, ED; Hankins, DC; Taraday, JK
Published in: Drug Metab Dispos
January 2000

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.

Duke Scholars

Published In

Drug Metab Dispos

ISSN

0090-9556

Publication Date

January 2000

Volume

28

Issue

1

Start / End Page

28 / 33

Location

United States

Related Subject Headings

  • Umbelliferones
  • Pharmacology & Pharmacy
  • Molecular Probes
  • Mixed Function Oxygenases
  • Methoxsalen
  • Male
  • Humans
  • Female
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 Enzyme Inhibitors
 

Citation

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ICMJE
MLA
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Kharasch, E. D., Hankins, D. C., & Taraday, J. K. (2000). Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity. Drug Metab Dispos, 28(1), 28–33.
Kharasch, E. D., D. C. Hankins, and J. K. Taraday. “Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity.Drug Metab Dispos 28, no. 1 (January 2000): 28–33.
Kharasch ED, Hankins DC, Taraday JK. Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity. Drug Metab Dispos. 2000 Jan;28(1):28–33.
Kharasch, E. D., et al. “Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity.Drug Metab Dispos, vol. 28, no. 1, Jan. 2000, pp. 28–33.
Kharasch ED, Hankins DC, Taraday JK. Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity. Drug Metab Dispos. 2000 Jan;28(1):28–33.

Published In

Drug Metab Dispos

ISSN

0090-9556

Publication Date

January 2000

Volume

28

Issue

1

Start / End Page

28 / 33

Location

United States

Related Subject Headings

  • Umbelliferones
  • Pharmacology & Pharmacy
  • Molecular Probes
  • Mixed Function Oxygenases
  • Methoxsalen
  • Male
  • Humans
  • Female
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 Enzyme Inhibitors