The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline.
The potential for nonprescription cimetidine (200 mg twice daily) to affect the pharmacokinetics of sustained-release (SR) theophylline was assessed in 26 male subjects, 13 smokers and 13 nonsmokers. This was a concentration-controlled drug interaction study in which the subjects were administered a dose of SR theophylline every 12 hours to provide a mean steady-state concentration between 8 and 15 micrograms/ml. To determine individual theophylline dose, a test dose of aminophylline was administered, and baseline theophylline pharmacokinetics were determined. Subjects remained on SR theophylline for 23 days and were treated in the following sequence: run-in phase (4 days), treatment 1 (7 days), washout (5 days), and treatment 2 (7 days). During the treatment phases, subjects received cimetidine (200 mg at approximately 08:00 and 12:00) or placebo for 7 days in a randomized crossover fashion. Theophylline pharmacokinetics were determined on days 1, 4, and 7 of both treatment phases. A large day-to-day variability in the oral clearance of theophylline was evident for the theophylline-placebo treatment and the theophylline-cimetidine treatment. Nonprescription strength cimetidine resulted in a mean 5% decrease in theophylline oral clearance on day 1 and a mean 12% decrease on days 4 and 7 combined. There were no significant differences in the cimetidine-theophylline interaction between smokers and nonsmokers. Oral clearance during the nighttime dosing interval was 13% greater than the daytime oral clearance for nonsmokers and 22% greater for smokers, showing a greater circadian rhythm for smokers. In summary, nonprescription doses of cimetidine (400 mg/day) have the potential to produce small changes in theophylline concentrations during steady-state dosing with SR theophylline; however, this effect appears less than changes that occur as a consequence of theophylline's intrasubject variability.
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DE
Clinical Pharmacokinetics Laboratory, Millard Fillmore Health System, Buffalo, New York, USA.
Di Cicco
R A
RA
Miller
A K
AK
Boyle
D A
DA
Boike
S C
SC
Zariffa
N
N
Jorkasky
D K
DK
Schentag
J J
JJ
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002927:Cimetidine / Q000494:pharmacology*; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D016037:Single-Blind Method; D012907:Smoking; D013806:Theophylline / Q000097:blood / Q000493:pharmacokinetics*; D014665:Vasodilator Agents / Q000493:pharmacokinetics*
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D002927:Cimetidine; D013806:Theophylline