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)
Mays
D C
DC
Department of Pharmacology, College of Medicine, Ohio State University, Columbus.
Nawoot
S
S
Hilliard
J B
JB
Pacula
C M
CM
Gerber
N
N
D000818:Animals; D001711:Biotransformation; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics*; D006591:Hexobarbital / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008730:Methoxsalen / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D002110:Caffeine; D010672:Phenytoin; D006591:Hexobarbital; D008730:Methoxsalen