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

Abstract

Hospital, Headington, Oxford OX3 9DU 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-' compared with 12 to 69 (median 41) ng ml-' for the active antimalarial metabolite CG, and 3 to 16 (median 11) ng ml-' 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-' h for proguanil, 679 ± 372 ng ml-' 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.

In vitro effects of artemisinin ether, cycloguanil hydrochloride (alone and in combination with sulfadiazine), quinine sulfate, mefloquine, primaquine phosphate, trifluoperazine hydrochloride, and verapamil on Toxoplasma gondii

“…Reported peak concentrations in serum and whole blood of cycloguanil following oral administration of proguanil were 12 to 69 ng/ml (24). Levels following intramuscular administration of cycloguanil have not been reported.…”

“…Cycloguanil has a relatively long half-life of 11 to 17 h, with peak concentrations 2 to 4 h after an oral dose of 200 mg of proguanil (24). Reported peak concentrations in serum and whole blood of cycloguanil following oral administration of proguanil were 12 to 69 ng/ml (24).…”

“…Despite cycloguanil use for over 40 years, studies of its pharmacokinetics have only recently been reported (22,24).…”

“…It is a dihydrofolate reductase inhibitor and is structurally similar to pyrimethamine (14). Cycloguanil was studied because, although there is only limited clinical experience with it, the parent drug, proguanil, has been used extensively and is considered the safest of the currently employed antimalarial agents (22,24). Additionally, cycloguanil has been used to treat pregnant women with cutaneous leishmaniasis without adverse effects on the fetus (14).…”

Antiparasitic Agent Atovaquone

“…Proguanil by itself has weak anti-Plasmodium activity, but following absorption and hepatic metabolism via the cytochrome P450 3A and 2C subfamilies, it is converted to the active metabolite cycloguanil (98), which is an effective dihydrofolate reductase inhibitor. The bioavailability of proguanil approaches 60% following oral ingestion (134). Steady-state levels of proguanil after oral dosing of atovaquone-proguanil (A-P) are about 40 ng/ml, and the levels of cycloguanil are about 10 ng/ml (6,8).…”