STUDY ON THE ABSOLUTE BIOAVAILABILITY OF QUININE AND THEOPHYLLINE FROM TABLETS AFTER SINGLE-DOSE ORAL-ADMINISTRATION AS COMPARED TO INTRAVENOUS-INFUSION IN HEALTHY MALE NONSMOKING VOLUNTEERS

This investigation was aimed at the determination of the absolute bioavailability of theophylline and quinine after single oral dose administration of Limptar(R) tablets or Limptar N(R) tablets with reference to intravenous administration of Euphyllin(R) 0.48 short infusion and Chininum dihydrochloricum Buchler(R) solution for injection. The study design was characterized as single dose, three-factorial, four-treatment four-period Latin square design (factor A: period, factor B: treatment factor C: sequence). The target parameters were AUC(norm) AUC(0-infinity) ABA, and secondary parameters C-max, t(max), t(1/2)lambda(z). MRT, HVD. The study was carried out on 12 healthy non smoking male volunteers between 24 and 42 years of age and confined to a ward for 4 study days (but not during the remaining days of washout phases which lasted 1 week). The treatments (not blinded) were as follows: b(1), Chininum dihydrochloricum Buchler solution for injection, infusion of 163.3 mg quinine; b(2), Euphyllin(R) 0.48, short infusion 168.6 mg theophylline; b(3), Limptar(R) tablets, 1 tablet containing 215.5 mg quinine and 167.2 mg theophylline; b(4), Limptar N(R) tablets, 1 tablet containing 165.75 mg quinine. A validated HPLC-UV method was used to determine plasma concentrations of drugs. The absolute bioavailability of theophylline and quinine from the two formulations Limptar(R) and Limptar N(R) was nearly complete (90% on the average) Administration of Limptar N(R) tablets resulted in quinine concentrations which were higher and reached maximum faster as compared to administration of Limptar(R) Average quinine concentrations observed 8.0 h.p.a. of Limptar(R) exceeded those seen with Limptar N(R). Accordingly, this was as well reflected by a doubling of half duration time after Limptar(R) compared to Limptar N(R). With respect to the safety parameters such as hemodynamics, ECG, hematology, clinical chemistry and urinalysis, there were no clinically relevant findings. All adverse events observed or reported during the study (mainly blurred vision and headache) were mildly pronounced, rated as possibly drug-related or unrelated to the study drugs, and disappeared spontaneously within the confinement period in the ward. In conclusion, the medications tested were well tolerated. No major differences in tolerability of quinine or theophylline given alone or in combination were observed. The difference in pharmacokinetic behavior of quinine in the two oral formulations may result from differences in pharmaceutical characteristics of the formulations.