Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S‐mephenytoin oxidation in Tanzanians
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Date
1996
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Clinical Pharmacology & Therapeutics
Abstract
S‐Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216 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 an S/R mephenytoin ratio >0.9, were arbitrarily defined as poor metabolizers of mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the mephenytoin S/R ratio and the chloroguanide/cycloguanil ratios (rs = 0.73; p < 0.00001). This indicates that cytochrome P4502C19 or CYP2C19 is a major enzyme that catalyzes the bioactivation of chloroguanide to cycloguanil. Chloroguanide is a pro‐drug, and hence a low CYP2C19 activity may lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty‐eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria chemoprophylaxis study showed that there was a significant correlation between the number of earlier breakthrough parasitemia episodes and the chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did not correlate with the S/R mephenytoin ratio. However, other factors, such as exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are probably more important.
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Keywords
Chloroguanide metabolism, malaria prophylaxis and the S‐mephenytoin oxidation, Tanzanians
Citation
Skjelbo, E., Mutabingwa, T.K., Bygbjerg, I.B., Nielsen, K.K., Gram, L.F. and Brøsen, K., 1996. Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S‐mephenytoin oxidation in Tanzanians. Clinical Pharmacology & Therapeutics, 59(3), pp.304-311.