title: Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype.
abstract: BACKGROUND
  We have previously found decreased CYP2C19 activity in Tanzanians tested with mephenytoin and omeprazole in relation to genotype when compared with white and Asian subjects.
  
  
  OBJECTIVE
  We investigated the impact of CYP2C19 genotype and phenotype on chloroguanide (INN, proguanil) metabolism to its metabolites cycloguanil and 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). Homozygous wild-type and mutated genotype groups were chosen randomly, but the heterozygous 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. Maximum plasma concentration (Cmax) and area under the plasma concentration versus time [AUC(0-infinity)] for cycloguanil was significantly lower (t test P < .05) in the homozygously mutated group compared with the homozygously wild-type group. There were similar significant group differences of median urinary excretion. The chloroguanide/cycloguanil ratio closely correlated (r(s) = .87) with omeprazole metabolic ratio, confirming that Tanzanian subjects are generally slower CYP2C19 metabolizers. It also confirms that CYP2C19 genotype and phenotype predicts cycloguanil formation. In addition, a 3-hour plasma sample metabolic ratio also seems to be a proper time for omeprazole phenotyping in Tanzanian subjects. Because the plasma concentrations of cycloguanil and 4-chlorophenylbiguanide covary (r(s) = .89), it is now suggested that their formation be catalyzed by the same enzyme (ie, CYP2C19) through a common intermediate, the structure of which is also presented.
  
  
  CONCLUSIONS
  As shown in an earlier study, also with a third substrate, Tanzanians have a lower capacity to form cycloguanil than white and Asian subjects. Individuals with two mutated alleles have lower metabolic capacity than individuals with two wild-type alleles or individuals in the heterozygous group, which may lead to chloroguanide therapeutic failure. This knowledge should be important when selecting appropriate patients and doses of chloroguanide in different populations.
authors.affiliation: Department of Medical Laboratory Sciences and Technology, Karolinska Institutet at Huddinge University Hospital, Sweden. Karin.Herrlin@labtek.ki.se
authors.forename: K
authors.initials: K
authors.lastname: Herrlin
authors.forename: A Y
authors.initials: AY
authors.lastname: Massele
authors.forename: G
authors.initials: G
authors.lastname: Rimoy
authors.forename: C
authors.initials: C
authors.lastname: Alm
authors.forename: M
authors.initials: M
authors.lastname: Rais
authors.forename: O
authors.initials: O
authors.lastname: Ericsson
authors.forename: L
authors.initials: L
authors.lastname: Bertilsson
authors.forename: L L
authors.initials: LL
authors.lastname: Gustafsson
mesh_terms: D000962:Antimalarials / Q000097:blood / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D002727:Proguanil / Q000097:blood / Q000378:metabolism*; D013636:Tanzania; D014227:Triazines / Q000097:blood; D044465:White People / Q000235:genetics
chemical_list: D000962:Antimalarials; D014227:Triazines; C026009:cycloguanil; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D002727:Proguanil