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The objective of this study was to examine the disposition of proguanil in malaria-infected Thai patients with acute uncomplicated falciparum malaria. Eleven patients were administered 500 mg of proguanil twice a day for three days (total dose = 3,000 mg). Four patients were tentatively classified as extensive metabolizers (EMs) and seven as poor metabolizers (PMs). The mean plasma clearances of proguanil for EMs and PMs were 1.31 and 1.10 L/hr/kg, respectively. The mean elimination half-life of proguanil was statistically longer in PMs than EMs (19.6 hr versus 16.1 hr; P = 0.01). Plasma clearance and elimination half-life of proguanil in the malaria patients were comparable with those reported in the literature for healthy Thai volunteers. In contrast to other ethnic groups, Thai EM patients had relatively low plasma concentrations of cycloguanil, the active metabolite of proguanil. None of the 11 patients treated with proguanil were cured of malaria and their phenotypic status did not affect the treatment outcome. Although high levels of parasite resistance to cycloguanil were probably responsible for the poor response to proguanil treatment, the inability of Thai EM and PM patients to produce cycloguanil may have also contributed to the treatment outcome.