Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype

Background: We have previously found decreased CYP2C19 activity in Tanzania ns tested with mephenytoin and omeprazole in relation to genotype when comp ared with white and Asian subjects. Objective: We investigated the impact of CYP2C19 genotype and phenotype on chloroguanide (INN, proguanil) metabolism to its metabolites cycloguanil an d 4-chlorophenylbiguanide. Methods: A single oral chloroguanide dose was given to 25 healthy Tanzanian subjects with CYP2C19 genotypes (CYP2C19*1, CYP2C19*2 and CYP2C19*3). Homo zygous wild-type and mutated genotype groups were chosen randomly but the h eterozygous genotype group was chosen with a range in phenotype. We used a novel HPLC method for drug determination. Results: Pharmacokinetics of chloroguanide did not differ between groups. M aximum plasma concentration (C-max) and area under the plasma concentration versus time [AUC(0-infinity)] for cycloguanil was significantly lower (t t est P <.05) in the homozygously mutated group compared with the homozygousl y wild-type group. There were similar significant group differences of medi an urinary excretion, The chloroguanide/cycloguanil ratio closely correlate d (r(s) =.87) with omeprazole metabolic ratio, confirming that Tanzanian su bjects are generally slower CYP2C19 metabolizers, It also confirms that CYP 2C19 genotype and phenotype predicts cycloguanil formation, In addition, a a-hour plasma sample metabolic ratio also seems to be a proper time for ome prazole phenotyping in Tanzanian subjects. Because the plasma concentration s of cycloguanil and 4-chlorophenylbiguanide covary (r(s) =.89), it is now suggested that their formation be catalyzed by the same enzyme tie, CYP2C19 ) through a common intermediate, the structure of which is also presented. Conclusions: As shown in an earlier study, also with a third substrate, Tan zanians have a lower capacity to form cycloguanil than white and Asian subj ects, Individuals with two mutated alleles have lower metabolic capacity th an individuals with two wild-type alleles or individuals in the heterozygou s group, which may lead to chloroguanide therapeutic failure. This knowledg e should be important when selecting appropriate patients and doses of chlo roguanide in different populations.