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The pharmacokinetics of proguanil and its active metabolite, cycloguanil, were determined at steady-state in 6 healthy male volunteers after daily administration of 2 Paludrine® tablets (200 mg proguanil hydrochloride). A maximum plasma proguanil concentration of 130.3 ± 16.0 ng/ml (mean ± SD) was reached at 3.8 ± 1.3 h while a maximum cycloguanil concentration of 52.0 ± 15.2 ng/ml was obtained at 5.3 ± 1.0 h after dosing. The elimination half-lives of proguanil and cycloguanil were 14.5 ± 3.0 h and 11.7 ± 3.1 h, respectively. The plasma clearance of proguanil was 1.43 ± 0.33 1/h/kg and the apparent volume of distribution was 30.7 ± 12.3 1/kg. Renal clearance of proguanil (0.33 ± 0.19 1/h/kg) was about 23% of the plasma clearance and 35.6 ± 9.6% of the oral dose was recovered as proguanil and cycloguanil.

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Using low folate, low p-aminobenzoic acid medium, 2 isolates of Plasmodium falciparum were tested in vitro against a wide range of antimetabolite compounds with known or potential antimalarial activity. ID50 values (the concentration of compound causing 50% inhibition of [3H]hypoxanthine incorporation) were determined for each compound against both isolates. The compounds tested may affect folate, pyrimidine or purine metabolism in malaria parasites and various combinations of compounds were examined for further synergistic antimalarial effects. The combination of any of the dihydrofolate reductase inhibitors cycloguanil, pyrimethamine or WR 99210 with the sulphone drug dapsone demonstrated strongly synergistic antimalarial activity. Combinations of dihydrofolate reductase inhibitors with the antipyrimidine compounds pyrazofurin or menoctone, or with the antipurine compounds tubercidin, bredinin or hadacidin, or with primaquine, failed to demonstrate synergistic activity. Most combinations of an antipurine with an antipyrimidine compound also failed to show any synergistic effect. However, weak synergism was consistently seen in the tubercidin/pyrazofurin and tubercidin/menoctone combinations. Over the 48 h intraerythrocytic cycle using tightly synchronized parasites, tubercidin demonstrated both a cytotoxic and a cytostatic effect.