ritonavir and 3-hydroxyquinidine

To evaluate the pharmacokinetic interactions between ritonavir and quinine in healthy volunteers.. Ten healthy volunteers were each given 600-mg single oral doses of quinine alone, ritonavir alone (200 mg every 12 h for 9 days), and quinine in combination with ritonavir, in a three-period pharmacokinetic nonrandomized sequential design study. Quinine was co-administered with the 15th dose of ritonavir. Blood samples collected at predetermined time intervals were analysed for ritonavir, quinine and its major metabolite, 3-hydroxyquinine, using a validated high-performance liquid chromatography method.. Concurrent ritonavir administration resulted in about fourfold increases in both the C(max) and AUC(T)[C(max) 2.79 +/- 0.22 vs. 10.72 +/- 0.32 mg l(-1), 95% confidence interval (CI) 7.81, 8.04; AUC 50.06 +/- 2.52 vs. 220.47 +/- 6.68 mg h(-1) l(-1), 95% CI 166.3, 175.3], a significant increase (P < 0.01) in the elimination half-life (11.15 +/- 0.80 vs. 13.37 +/- 0.33 h, 95% CI 1.64, 2.77) and about a 4.5-fold decrease in CL/F (12.01 +/- 0.61 vs. 2.71 +/- 0.09 l h(-1)) of quinine. Also, with ritonavir, there was a pronounced reduction of AUC(metabolite)/AUC(unchanged drug) ratio of quinine (1.35 +/- 0.10 vs. 0.13 +/- 0.02) along with a marked decrease in C(max) (1.80 +/- 0.12 vs. 0.96 +/- 0.09 mg l(-1)) and AUC(0-48h) (62.80 +/- 6.30 vs. 25.61 +/- 2.44 mg h(-1) l(-1)) of the metabolite. Similarly, quinine caused modest but significant increases (P < 0.01) in the C(max), AUC and elimination T((1/2)) of ritonavir.. Downward dosage adjustment of quinine appears necessary when concurrently administered with ritonavir.

Topics: Administration, Oral; Adult; Aged; Anti-HIV Agents; Antimalarials; Cross-Over Studies; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Male; Middle Aged; Quinidine; Quinine; Ritonavir

In regions with high prevalence of HIV and malaria, co-infection of both diseases is common; hence, there is a high possibility of concurrent administration of antiretroviral and antimalarial drugs. This study describes a new ion-pair reversed-phase high-performance liquid chromatographic (HPLC) method for simultaneous determinations of ritonavir (RTV), quinine (QN), and its major metabolite, 3-hydroxyquinine (3-HQN), in human plasma. Following a simple extraction with diethyl-ether under alkaline conditions, chromatographic separation was achieved on a 5-mum particle size C-18 column (200 mm x 4.6mm I.D.) using a mobile phase consisting of methanol:acetonitrile:0.02 M potassium dihydrogen phosphate (15:10:75) containing 75 mmol/L perchloric acid (pH 2.8). Retention times for RTV, 3-HQN, QN and the internal standard were 2.8, 4.0, 7.0 and 12 min, respectively. The limits of detection and validated lower limits of quantitation were 10 and 12.5 ng/ml for RTV while the corresponding values were 5 and 70 ng/ml for both QN and 3-HQN, respectively. The new HPLC method is simple, rapid, selective, reproducible and cost-effective. As demonstrated in three volunteers, it will facilitate the conducting of simultaneous therapeutic monitoring of quinine and ritonavir in patients concurrently receiving both drugs.

Topics: Calibration; Chromatography, High Pressure Liquid; Humans; Quinidine; Quinine; Reference Standards; Ritonavir; Sensitivity and Specificity