Methoxsalen is a potent inhibitor of the metabolism of caffeine in humans.

The acute effect of a single oral dose of methoxsalen on the pharmacokinetics of caffeine was investigated in five nonsmoking volunteers with psoriasis. Caffeine, 200 mg orally, was administered to each subject at baseline before treatment with methoxsalen. One week later each subject was given a single oral dose of 1.2 mg/kg methoxsalen 1 hour before administrations of another oral dose of 200 mg caffeine. The clearance of caffeine declined markedly from 110 +/- 17 ml/min (mean +/- SE) in the control study to 34 +/- 5 ml/min after methoxsalen. During the period of maximum inhibition the mean elimination half-life of caffeine increased from 5.6 hours at baseline to 57 hours after administration of methoxsalen. The peak concentration of caffeine and the time to reach the peak concentration of caffeine were not affected by pretreatment with methoxsalen. Thus, methoxsalen, administered acutely, is a potent inhibitor of caffeine metabolism in humans with psoriasis. Results of this investigation suggest that the elimination of concurrently administered drugs may be inhibited in patients receiving methoxsalen. In comparison with other drugs, methoxsalen is the most potent inhibitor of drug metabolism in humans. Other work has shown that inhibition of drug metabolism by methoxsalen is associated with both extensive covalent binding of metabolite(s) of methoxsalen to liver microsomal protein in vitro and in vivo and inactivation of cytochrome P-450.

Inhibition and induction of drug biotransformation in vivo by 8-methoxypsoralen: studies of caffeine, phenytoin and hexobarbital metabolism in the rat.

The effects of 8-methoxypsoralen (8-MOP) on drug metabolism in vivo were studied in catheterized rats. Rats were pretreated with a single i.p. injection of 5.4 or 27 mg/kg of 8-MOP, 30 min before an i.v. injection of either caffeine (CA; 10 mg/kg), hexobarbital (HB; 40 mg/kg), phenytoin (DPH; 15 mg/kg) or 5-(4'-hydroxyphenyl)-5-phenylhydantoin (HPPH; 15 mg/kg). Clearance of CA, HB and DPH, respectively (drugs eliminated primarily by phase-1 biotransformation), decreased from 0.25 +/- 0.02, 2.9 +/- 0.2 and 1.6 +/- 0.1 liters/kg/hr (means +/- S.E.) in control rats to 0.062 +/- 0.006, 0.65 +/- 0.15 and 0.09 +/- 0.03 liters/kg/hr in rats pretreated once with 27 mg/kg of 8-MOP. In contrast, the clearance of HPPH, which is eliminated primarily by glucuronidation, decreased only slightly from 1.3 +/- 0.1 liters/kg/hr in controls to 0.89 +/- 0.02 liters/kg/hr in rats pretreated with a single injection of 27 mg/kg of 8-MOP. Induction of drug metabolism by 8-MOP was studied in vivo in rats pretreated with 50 mg/kg/day of 8-MOP for 3 days and given an i.v. injection of CA, HB, DPH or HPPH 24 hr after their last pretreatment. This regimen increased the clearance of CA from 0.25 +/- 0.02 liters/kg/hr in controls to 1.08 +/- 0.04 liters/kg/hr in pretreated rats but had no significant effect on the elimination of HB, DPH and HPPH. Thus, acutely, 8-MOP is a potent, nonselective inhibitor of phase-1 metabolism in vivo. In contrast, chronically, it is a specific inducer of the metabolism of CA.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of 8-methoxypsoralen in the rat. Induction of metabolism in vivo and in vitro and identification of urinary metabolites by thermospray mass spectrometry.

The pharmacokinetics and metabolism of 8-methoxypsoralen (8-MOP) were measured in the catheterized rat after pretreatment for 3 days with phenobarbital (PB), beta-naphthoflavone (BNF), 8-MOP, or vehicle. After an iv injection of 10 mg/kg of [14C]8-MOP, timed blood samples were collected and analyzed using a sensitive and specific assay for [14C]8-MOP. Total body clearance of 8-MOP increased from 0.55 +/- 0.06 liter/kg/hr in control rats to 5.6 +/- 0.4, 2.7 +/- 0.4, and 1.2 +/- 0.0 liters/kg/hr in rats pretreated with BNF, PB, and 8-MOP, respectively, indicating that all three compounds are inducers of 8-MOP metabolism. The pattern of urinary metabolites was altered by the enzyme inducers. The urinary excretion of the sulfate conjugate of 5-hydroxy-8-methoxypsoralen was increased from 10 to 40% of the dose after pretreatment with PB. This intact conjugate was identified using thermospray and fast atom bombardment mass spectrometry. Pretreatment with 8-MOP and BNF increased 2- and 3-fold, respectively, the urinary excretion of a labile sulfate conjugate of 5,8-dihydroxypsoralen. Metabolism of 8-MOP was demonstrated in the 9000 g supernatant and microsomes of rat liver and shown to be inducible by pretreatment of rats with BNF, PB, and 8-MOP. 8-MOP was metabolized in incubations with liver microsomes at rates of 0.22 +/- 0.06, 0.38 +/- 0.06, 0.78 +/- 0.07, and 0.91 +/- 0.03 nmol/min/mg of protein for vehicle, 8-MOP-, PB-, and BNF-pretreated rats, respectively. Results of our investigation indicate that the success of therapy with 8-MOP may be influenced by pharmacokinetic interactions with other drugs.