Proguanil Metabolism is Determined by the Mephenytoin Oxidation Polymorphism in Vietnamese Living in Denmark

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 1993 Aug 1

PMID 8398577

Citations 7

Authors

K Brosen

E Skjelbo

H Flachs

Affiliations

Soon will be listed here.

Abstract

1. A sparteine/mephenytoin phenotyping test was carried out in 37 Vietnamese living in Denmark. By visual inspection the urinary S/R-mephenytoin ratio appeared to show a bimodal frequency distribution. Eight putative poor metabolizers of mephenytoin, PMm (22%), had S/R-mephenytoin ratios from 0.79 to 1.12 and 29 putative extensive metabolizers of mephenytoin, EMm, had S/R-mephenytoin ratios < or = 0.55. All of the subjects were extensive metabolizers of sparteine with urinary metabolic ratios from 0.15 to 2.4. 2. The metabolism of the antimalarial prodrug proguanil was studied in 34 of the subjects after a single oral dose of 100 mg. The median 12 h urinary recoveries of the active metabolite cycloguanil and the minor metabolite 4-chlorphenylbiguanide were 5.8 and 1.9% of the dose, respectively, in 26 EMm compared with 1.6 and 0.4%, respectively, in 8 PMm (P < 0.001, Mann-Whitney U-test). 3. There was no statistically significant correlation (Spearmans rs) between any index of proguanil metabolism and the sparteine metabolic ratio.

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References

Vinks A, Inaba T, Otton S, KALOW W . Sparteine metabolism in Canadian Caucasians. Clin Pharmacol Ther. 1982; 31(1):23-9. DOI: 10.1038/clpt.1982.4. View

Eichelbaum M, Bertilsson L, Sawe J, Zekorn C . Polymorphic oxidation of sparteine and debrisoquine: related pharmacogenetic entities. Clin Pharmacol Ther. 1982; 31(2):184-6. DOI: 10.1038/clpt.1982.29. View

Setiabudy R, Chiba K, Kusaka M, Ishizaki T . Caution in the use of a 100 mg dose of racemic mephenytoin for phenotyping southeastern Oriental subjects. Br J Clin Pharmacol. 1992; 33(6):665-6. PMC: 1381363. View

Sohn D, Kusaka M, Ishizaki T, Shin S, Jang I, Shin J . Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther. 1992; 52(2):160-9. DOI: 10.1038/clpt.1992.125. View

Funck-Brentano C, Bosco O, Jacqz-Aigrain E, Keundjian A, Jaillon P . Relation between chloroguanide bioactivation to cycloguanil and the genetically determined metabolism of mephenytoin in humans. Clin Pharmacol Ther. 1992; 51(5):507-12. DOI: 10.1038/clpt.1992.55. View

Bertilsson L, Lou Y, Du Y, Liu Y, Kuang T, Liao X . Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther. 1992; 51(4):388-97. DOI: 10.1038/clpt.1992.38. View

Furuya H, Meyer U, Gelboin H, Gonzalez F . Polymerase chain reaction-directed identification, cloning, and quantification of human CYP2C18 mRNA. Mol Pharmacol. 1991; 40(3):375-82. View

Ward S, Helsby N, Skjelbo E, Brosen K, Gram L, Breckenridge A . The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism--a panel study. Br J Clin Pharmacol. 1991; 31(6):689-92. PMC: 1368581. DOI: 10.1111/j.1365-2125.1991.tb05594.x. View

Clasen K, Madsen L, Brosen K, Alboge K, Misfeldt S, Gram L . Sparteine and mephenytoin oxidation: genetic polymorphisms in east and west Greenland. Clin Pharmacol Ther. 1991; 49(6):624-31. DOI: 10.1038/clpt.1991.79. View

10.

Zhang Y, Blouin R, McNamara P, Steinmetz J, Wedlund P . Limitation to the use of the urinary S-/R-mephenytoin ratio in pharmacogenetic studies. Br J Clin Pharmacol. 1991; 31(3):350-2. PMC: 1368365. DOI: 10.1111/j.1365-2125.1991.tb05542.x. View

11.

Petersen E, Flachs H, Hogh B, Hanson A, Bjorkman A, Hvidberg E . Plasma, erythrocyte and urine concentrations of chlorproguanil and two metabolites in man after different doses. J Trop Med Hyg. 1991; 94(3):199-205. View

12.

Alvan G, Bechtel P, Iselius L, Gundert-Remy U . Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol. 1990; 39(6):533-7. DOI: 10.1007/BF00316090. View

13.

Romkes M, Faletto M, Blaisdell J, Raucy J, Goldstein J . Cloning and expression of complementary DNAs for multiple members of the human cytochrome P450IIC subfamily. Biochemistry. 1991; 30(13):3247-55. DOI: 10.1021/bi00227a012. View

14.

Helsby N, Ward S, Howells R, Breckenridge A . In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme. Br J Clin Pharmacol. 1990; 30(2):287-91. PMC: 1368230. DOI: 10.1111/j.1365-2125.1990.tb03777.x. View

15.

CARRINGTON H, CROWTHER A, DAVEY D, LEVI A, ROSE F . A metabolite of paludrine with high antimalarial activity. Nature. 1951; 168(4288):1080. DOI: 10.1038/1681080a0. View

16.

Kupfer A, Preisig R . Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol. 1984; 26(6):753-9. DOI: 10.1007/BF00541938. View

17.

Wedlund P, Aslanian W, McALLISTER C, Wilkinson G, Branch R . Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther. 1984; 36(6):773-80. DOI: 10.1038/clpt.1984.256. View

18.

Jurima M, Inaba T, KADAR D, KALOW W . Genetic polymorphism of mephenytoin p(4')-hydroxylation: difference between Orientals and Caucasians. Br J Clin Pharmacol. 1985; 19(4):483-7. PMC: 1463809. DOI: 10.1111/j.1365-2125.1985.tb02673.x. View

19.

Nakamura K, Goto F, Ray W, McALLISTER C, Jacqz E, Wilkinson G . Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther. 1985; 38(4):402-8. DOI: 10.1038/clpt.1985.194. View

20.

Brosen K, Otton S, Gram L . Sparteine oxidation polymorphism in Denmark. Acta Pharmacol Toxicol (Copenh). 1985; 57(5):357-60. DOI: 10.1111/j.1600-0773.1985.tb00058.x. View