Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S-mephenytoin oxidation in Tanzanians.

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 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.

• Authors: E Skjelbo, T K Mutabingwa, I b Bygbjerg, K K Nielsen, L F Gram, K Brøosen
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 59 Issue 3 Pg. 304-11 (Mar 1996) ISSN: 0009-9236 [Print] United States
• PMID: 8653993 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Antimalarials
• Cytochrome P-450 Enzyme System
• Mixed Function Oxygenases
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19
• Mephenytoin
• Proguanil

Topics

• Adult
• Aged
• Anticonvulsants (urine)
• Antimalarials (pharmacokinetics, therapeutic use)
• Aryl Hydrocarbon Hydroxylases
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 Enzyme System (metabolism)
• Female
• Humans
• Malaria (prevention & control)
• Male
• Mephenytoin (urine)
• Middle Aged
• Mixed Function Oxygenases (metabolism)
• Oxidation-Reduction
• Proguanil (pharmacokinetics, therapeutic use)
• Tanzania