ENANTIOSELECTIVE PHARMACOKINETICS OF MEFLOQUINE DURING LONG-TERM INTAKE OF THE PROPHYLACTIC DOSE

Aims To investigate the kinetics of the (+)RS- and (-)SR-enantiomers a nd the carboxylic acid metabolite (MMQ) of the antimalarial drug meflo quine (MQ) in healthy volunteers. Methods Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine a nd evaluated by individual kinetic modelling as well as by a nonparame tric population kinetic method. Results A two-compartment model adequa tely described the disposition of (+)RS-MP CL/F was 6.5 +/- 1.8 1 h(-1 ) V-ss/F 815 +/- 1651, and k 0.0081 +/- 0.0023 h(-1). The kinetics of (-)SR-MQ were time- and/or concentration dependent with a lower oral c learance (0.92 +/- 0.25 vs 2.14 +/- 0.63 1 h, 95% CI for the differenc e 0.86-1.60 1 h(-1)) and a longer half-life (345 vs 185 h, 95% CI for the difference 47-291 h) after the last dose compared with the first d ose. Clearance of (+)RS-MQ and (-)SR-MQ was significantly correlated w ithin subjects (r = 0.69, P < 0.05). Urinary recovery of unchanged sub stance was 8.7% for (+)RS-MQ and 12.3% for (-)SR-MQ. The elimination o f MMQ was disposition fate-limited and not determined by its rate of f ormation. Poor metabolizers of debrisoquine did not differ from extens ive metabolizers in the kinetics of any compound. Conclusions The MQ e nantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore i nadequate.