title: Inhibition and induction of theophylline metabolism by 8-methoxypsoralen. In vivo study in rats and humans.
abstract: The effects of 8-methoxypsoralen (8-MOP) on the metabolism of theophylline were studied in rats and humans. Rats were randomized into three groups and prepared with iv jugular catheters. Group I (N = 4) received a single ip injection of 27 mg/kg of 8-MOP, group II (N = 5) vehicle (corn oil), and group III (N = 4) 50 mg/kg/day of 8-MOP for 3 days. Rats were subsequently administered 15 mg/kg of theophylline iv, and timed blood samples (0.2 ml) were assayed for theophylline by HPLC. Theophylline clearance (ml/min/kg; mean +/- SD) was 1.7 +/- 0.3, 2.4 +/- 0.5, and 9.5 +/- 1.6 in groups I, II, and III, respectively. The half-life (harmonic mean) from 0.5 to 12 hr was 7.2, 3.6, and 0.8 hr. Urinary excretion of unchanged theophylline (mean +/- SD) from 0 to 24 hr was 60 +/- 10, 41 +/- 6, and 13 +/- 3% of the administered dose. In a crossover study, three healthy, male, nonsmokers received 600 mg of oral theophylline. Urine and plasma were collected for 48 hr. One week later, subjects received 1.2 mg/kg of oral 8-MOP followed in 1 hr by 600 mg of oral theophylline. Mean residence time of theophylline increased from 10.7, 17.2, and 12.2 hr in the control period, to 20.3, 19.0, and 18.4 hr after 8-MOP. The AUC (microgram.hr/ml) of theophylline increased from 204, 213, and 204, to 555, 364, and 432, while clearance (ml/min/kg) decreased from 0.74, 0.57 and 0.63, to 0.27, 0.33, and 0.30, respectively. Urinary excretion of unchanged theophylline from 0 to 48 hr increased from 14, 14, and 15, to 24, 21, and 20%. We conclude that 8-MOP administered acutely is a potent inhibitor of theophylline metabolism and chronically in the rat is a powerful inducer.
authors.affiliation: Department of Pharmacology, College of Medicine, Ohio State University, Columbus 43210.
authors.forename: G
authors.initials: G
authors.lastname: Apseloff
authors.forename: D R
authors.initials: DR
authors.lastname: Shepard
authors.forename: M A
authors.initials: MA
authors.lastname: Chambers
authors.forename: S
authors.initials: S
authors.lastname: Nawoot
authors.forename: D C
authors.initials: DC
authors.lastname: Mays
authors.forename: N
authors.initials: N
authors.lastname: Gerber
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D008730:Methoxsalen / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013806:Theophylline / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D013806:Theophylline; D008730:Methoxsalen