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Titolo:
Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype
Autore:
Herrlin, K; Massele, AY; Rimoy, G; Alm, C; Rais, M; Ericsson, O; Bertilsson, L; Gustafsson, LL;
Indirizzi:
Huddinge Univ Hosp, Karolinska Inst, Div Clin Pharmacol, S-14186 Huddinge,Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 acol, S-14186 Huddinge,Sweden Huddinge Univ Hosp, Karolinska Inst, Dept Med Lab Sci & Technol, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 nol, S-14186 Huddinge, Sweden Muhimbili Med Ctr, Dept Clin Pharmacol, Dar Es Salaam, Tanzania Muhimbili Med Ctr Dar Es Salaam Tanzania macol, Dar Es Salaam, Tanzania
Titolo Testata:
CLINICAL PHARMACOLOGY & THERAPEUTICS
fascicolo: 2, volume: 68, anno: 2000,
pagine: 189 - 198
SICI:
0009-9236(200008)68:2<189:SCMITC>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
S-MEPHENYTOIN HYDROXYLASE; PERFORMANCE LIQUID-CHROMATOGRAPHY; HUMAN LIVER-MICROSOMES; OXIDATION POLYMORPHISM; PROGUANIL METABOLISM; POOR METABOLIZERS; IN-VITRO; OMEPRAZOLE; POPULATION; CYCLOGUANIL;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Herrlin, K Huddinge Univ Hosp, Karolinska Inst, Div Clin Pharmacol, S-14186 Huddinge,Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 86 Huddinge,Sweden
Citazione:
K. Herrlin et al., "Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype", CLIN PHARM, 68(2), 2000, pp. 189-198

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 onchloroguanide (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 anovel HPLC method for drug determination. Results: Pharmacokinetics of chloroguanide did not differ between groups. Maximum plasma concentration (C-max) 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, aa-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 nowsuggested 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, 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.

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Documento generato il 25/01/20 alle ore 09:31:41