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Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S ‐mephenytoin oxidation in Tanzanians
Author(s) -
Skjelbo Erik,
Mutabingwa Theonest K.,
Bygbjerg Ib,
Nielsen Karin K.,
Gram Lars F.,
Brøsen Kim
Publication year - 1996
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(96)80008-7
Subject(s) - mephenytoin , proguanil , pharmacology , cyp2c19 , medicine , urine , malaria , chemistry , chloroquine , metabolism , cytochrome p450 , immunology
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 ( r s = 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 ( r s = 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. Clinical Pharmacology & Therapeutics (1996) 59 , 304–311; doi: