CHLOROGUANIDE METABOLISM IN RELATION TO THE EFFICACY IN MALARIA PROPHYLAXIS AND THE S-MEPHENYTOIN OXIDATION IN TANZANIANS

S-Mephenytoin and chloroguanide (proguanil) oxidation was studied in 2 16 Tanzanians, The mephenytoin S/R ratio in urine ranged from <0.1 to 1.16, The distribution was skewed to the right, without evidence of a bimodal distribution, Ten subjects (4.6%, 2.2% to 8.3%, 95% CI) with a n S/R mephenytoin ratio >0.9, were arbitrarily defined as poor metabol izers of mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the mephenyto in S/R ratio and the chloroguanide/cycloguanil ratios (r(s) = 0.73; p < 0.00001), This indicates that cytochrome P4502C19 or CYP2C19 is a ma jor enzyme that catalyzes the bioactivation of chloroguanide to cyclog uanil. Chloroguanide is a pro-drug, and hence a low CYP2C19 activity m ap lead to prophylactic failure caused by inadequate formation of cycl oguanil, Fifty-eight women who previously took either 200 mg chlorogua nide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroqu ine weekly (n = 32) in a malaria chemoprophylaxis study showed that th ere was a significant correlation between the number of earlier breakt hrough parasitemia episodes and the chloroguanide/cycloguanil ratio (r (s) = 0.30; p = 0.02), The breakthrough rate did not correlate with th e S/R mephenytoin ratio, However, other factors, such as exposure to m osquitoes and sensitivity of the plasmodium to cycloguanil, are probab ly more important.