Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose

Aims To investigate the kinetics of the (+)RS- and (-)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (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 and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method. Results A two-compartment model adequately 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 clearance (0.92 +/- 0.25 vs 2.14 +/- 0.63 1 h, 95% CI for the difference 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 dose. Clearance of (+)RS-MQ and (-)SR-MQ was significantly correlated within subjects (r = 0.69, P < 0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (-)SR-MQ. The elimination of MMQ was disposition fate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound. Conclusions The MQ enantiomers 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 inadequate.