title: Drug-drug interaction after single oral doses of the furanocoumarin methoxsalen and cyclosporine.
abstract: Furanocoumarins increase the bioavailability of drugs that are CYP3A4 substrates. A possible interaction of methoxsalen with cyclosporine was evaluated in 12 healthy volunteers following oral administration of 40 mg methoxsalen, 200 mg cyclosporine, or a combination of both in a randomized crossover study. Methoxsalen increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of cyclosporine by 29% (range, -20% to 172%; P < .05) and 8% (range, -10% to 26%; P < .05), respectively, compared to cyclosporine alone. The AUC geometric means ratio (95% confidence interval) for cyclosporine plus methoxsalen/cyclosporine alone was 1.14 (1.02, 1.27), and treatments were therefore not bioequivalent. Methoxsalen causes a clinically significant interaction with cyclosporine in some susceptible individuals. The reasons for susceptibility and the clinical implications for chronic cyclosporine administration have not been established. Caution is recommended in combination therapy, and more frequent monitoring of cyclosporine plasma levels and clinical monitoring is advised.
authors.affiliation: Department of Pharmacology, North-West University, South Africa.
authors.forename: Malie
authors.initials: M
authors.lastname: Rheeders
authors.forename: Marlène
authors.initials: M
authors.lastname: Bouwer
authors.forename: Theunis C
authors.initials: TC
authors.lastname: Goosen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008730:Methoxsalen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D003879:Dermatologic Agents; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008730:Methoxsalen