Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects.

1. Plasma and whole blood concentrations of proguanil and its two major metabolites cycloguanil (CG) and 4‐chlorophenylbiguanide (CPB) were measured by a sensitive h.p.l.c. technique in nine healthy adult male volunteers after a single oral dose of proguanil 200 mg. 2. Proguanil was absorbed with a median time to peak plasma concentration of 3 h (range 2‐4 h). 3. Peak plasma concentrations of proguanil ranged between 150 and 220 (median 170) ng ml‐1 compared with 12 to 69 (median 41) ng ml‐1 for the active antimalarial metabolite CG, and 3 to 16 (median 11) ng ml‐1 for CPB. Peak (mean +/‐ s.d.) plasma CG concentrations occurred 5.3 +/‐ 0.9 h and peak CPB concentrations occurred 6.3 +/‐ 1.4 h after oral administration of proguanil. 4. Whole blood concentrations of proguanil were approximately five times higher, and whole blood CPB concentrations were four times higher than corresponding plasma values, whereas plasma and whole blood concentrations of CG were similar. 5. A triexponential function was fitted to these data; mean (+/‐ s.d.) values for the AUC were 3046 +/‐ 313 ng ml‐1 h for proguanil, 679 +/‐ 372 ng ml‐1 h for CG and 257 +/‐ 155 ng ml‐1 h for CPB. 6. Plasma and whole blood concentrations of proguanil and its metabolites declined in parallel with terminal elimination half‐lives estimated as 16.1 +/‐ 2.9 h and 15.7 +/‐ 2.4 h, respectively. Mean residence times in plasma and whole blood were estimated as 21.2 +/‐ 4.9 and 19.3 +/‐ 2.4 h.