LACKING EFFECT OF GRAPEFRUIT JUICE ON THEOPHYLLINE PHARMACOKINETICS

Grapefruit juice inhibits the biotransformation of several drugs, incl uding caffeine (23% clearance reduction), which is metabolized by the cytochrome P450 isoform CYP1A2. Since CYP1A2 also participates in theo phylline biotransformation, a randomized change-over study on a possib le 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 o f 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 Theophylline concentrations in plasma withdrawn up to 24 hours postdose were measured by HPLC, and its pharmacokinetics were estimated using compartment model independent methods.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% confide nce intervals (given in parentheses) were calculated for the test (= g rapefruit coadministration) to reference (= water coadministration) ra tios (T-max:differences). These were: C-max 0.90 (0.81 - 1.00), AUC 1. 02 (0.95 - 1.11), C-max/AUC 0.88 (0.81 - 0.95), T-1/2el 1.03 (0.98 - 1 .09), T-max 0.15 h (-0.11 h - 0.41 h). Thus, no pharmacokinetic intera ction between grapefruit juice and theophylline was observed. This fin ding is in contrast to the effect of grapefruit juice reported on caff eine metabolism and may be due to the contribution of enzymes other th an CYP1A2 to primary theophylline metabolism or to differences in nari ngin and/or naringenin kinetics between studies.