title: 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.affiliation: Department of Clinical Pharmacology, Odense University, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Skjelbo
authors.forename: T K
authors.initials: TK
authors.lastname: Mutabingwa
authors.forename: I b
authors.initials: Ib
authors.lastname: Bygbjerg
authors.forename: K K
authors.initials: KK
authors.lastname: Nielsen
authors.forename: L F
authors.initials: LF
authors.lastname: Gram
authors.forename: K
authors.initials: K
authors.lastname: Brøosen
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000652:urine*; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D008288:Malaria / Q000517:prevention & control*; D008297:Male; D008617:Mephenytoin / Q000652:urine*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010084:Oxidation-Reduction; D002727:Proguanil / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013636:Tanzania
chemical_list: D000927:Anticonvulsants; D000962:Antimalarials; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin; D002727:Proguanil