Lacking effect of grapefruit juice on theophylline pharmacokinetics

Int J Clin Pharmacol Ther. 1995 Jun;33(6):311-4.

Abstract

Grapefruit juice inhibits the biotransformation of several drugs, including caffeine (23% clearance reduction), which is metabolized by the cytochrome P450 isoform CYP1A2. Since CYP1A2 also participates in theophylline biotransformation, a randomized change-over study on a possible interaction between grapefruit juice and theophylline was conducted. Twelve healthy young male nonsmokers were included (median 26 (range 23-30) years, weight 73 (65-85) kg). Theophylline was given as a single dose of 200 mg in solution (Euphyllin 200), diluted by 100 ml of either water or grapefruit juice (751 mg/l naringin). Subsequently, additional fractionated 0.91 of water or juice were administered until 16 hours postdose. Theophylline concentrations in plasma withdrawn up to 24 hours postdose were measured by HPLC, and its pharmacokinetics were estimated using compartment model independent methods. To compare between the 2 treatments, ANOVA based point estimates and 90% confidence intervals (given in parentheses) were calculated for the test (= grapefruit coadministration) to reference (= water coadministration) ratios (Tmax: differences). These were: Cmax 0.90 (0.81-1.00), AUC 1.02 (0.95-1.11), Cmax/AUC 0.88 (0.81-0.95), T 1/2el 1.03 (0.98-1.09), Tmax 0.15 h (-0.11h-0.41 h). Thus, no pharmacokinetic interaction between grapefruit juice and theophylline was observed. This finding is in contrast to the effect of grapefruit juice reported on caffeine metabolism and may be due to the contribution of enzymes other than CYP1A2 to primary theophylline metabolism or to differences in naringin and/or naringenin kinetics between studies.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Absorption
  • Administration, Oral
  • Adult
  • Analysis of Variance
  • Antioxidants / pharmacokinetics
  • Antioxidants / pharmacology
  • Beverages*
  • Biotransformation
  • Chemical Fractionation
  • Chromatography, High Pressure Liquid
  • Citrus / metabolism*
  • Cross-Over Studies
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 Enzyme System / metabolism
  • Dose-Response Relationship, Drug
  • Flavanones*
  • Flavonoids / pharmacokinetics
  • Flavonoids / pharmacology
  • Food-Drug Interactions*
  • Half-Life
  • Humans
  • Male
  • Oxidoreductases / metabolism
  • Reference Values
  • Theophylline / administration & dosage
  • Theophylline / blood
  • Theophylline / pharmacokinetics*

Substances

  • Antioxidants
  • Flavanones
  • Flavonoids
  • Cytochrome P-450 Enzyme System
  • Theophylline
  • Oxidoreductases
  • Cytochrome P-450 CYP1A2
  • naringenin
  • naringin