Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1995 Mar;39(3):297–303. doi: 10.1111/j.1365-2125.1995.tb04452.x

Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population.

R Setiabudy 1, M Kusaka 1, K Chiba 1, I Darmansjah 1, T Ishizaki 1
PMCID: PMC1365007  PMID: 7619672

Abstract

1. The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin. 2. The mean ( +/- s.d.) values of the elimination half-life (t 1/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 +/- 3.1 vs 14.6 +/- 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 +/- 1.89 vs 3.68 +/- 0.83 (0.58 to 2.91) micrograms ml-1 h). 3. Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 +/- 0.13 vs 0.88 +/- 0.50 (-0.14 to 0.96) micrograms ml-1 h). 4. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.05) with the t 1/2 (rs = -0.661) and AUC (rs = -0.652) of PG. 5. PG, CG and CPB were detectable in urine at 12 h in all subjects. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.01) with urinary PG/CG (rs = -0.876), PG/CPB (rs = -0.833) and PG/(CG + CPB) (rs = -0.831) metabolic ratios.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
297

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alván G., Bechtel P., Iselius L., Gundert-Remy U. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol. 1990;39(6):533–537. doi: 10.1007/BF00316090. [DOI] [PubMed] [Google Scholar]
  2. Birkett D. J., Rees D., Andersson T., Gonzalez F. J., Miners J. O., Veronese M. E. In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. Br J Clin Pharmacol. 1994 May;37(5):413–420. doi: 10.1111/j.1365-2125.1994.tb05707.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brøsen K., Skjelbo E., Flachs H. Proguanil metabolism is determined by the mephenytoin oxidation polymorphism in Vietnamese living in Denmark. Br J Clin Pharmacol. 1993 Aug;36(2):105–108. doi: 10.1111/j.1365-2125.1993.tb04204.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bulpitt C. J. Confidence intervals. Lancet. 1987 Feb 28;1(8531):494–497. doi: 10.1016/s0140-6736(87)92100-3. [DOI] [PubMed] [Google Scholar]
  5. CARRINGTON H. C., CROWTHER A. F., DAVEY D. G., LEVI A. A., ROSE F. L. A metabolite of paludrine with high antimalarial activity. Nature. 1951 Dec 22;168(4288):1080–1080. doi: 10.1038/1681080a0. [DOI] [PubMed] [Google Scholar]
  6. Edstein M. D., Veenendaal J. R., Scott H. V., Rieckmann K. H. Steady-state kinetics of proguanil and its active metabolite, cycloguanil, in man. Chemotherapy. 1988;34(5):385–392. doi: 10.1159/000238597. [DOI] [PubMed] [Google Scholar]
  7. 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 May;51(5):507–512. doi: 10.1038/clpt.1992.55. [DOI] [PubMed] [Google Scholar]
  8. Guttendorf R. J., Britto M., Blouin R. A., Foster T. S., John W., Pittman K. A., Wedlund P. J. Rapid screening for polymorphisms in dextromethorphan and mephenytoin metabolism. Br J Clin Pharmacol. 1990 Apr;29(4):373–380. doi: 10.1111/j.1365-2125.1990.tb03653.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Helsby N. A., Ward S. A., Edwards G., Howells R. E., Breckenridge A. M. The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism. Br J Clin Pharmacol. 1990 Oct;30(4):593–598. doi: 10.1111/j.1365-2125.1990.tb03818.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Helsby N. A., Ward S. A., Howells R. E., Breckenridge A. M. 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 Aug;30(2):287–291. doi: 10.1111/j.1365-2125.1990.tb03777.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Horai Y., Nakano M., Ishizaki T., Ishikawa K., Zhou H. H., Zhou B. I., Liao C. L., Zhang L. M. Metoprolol and mephenytoin oxidation polymorphisms in Far Eastern Oriental subjects: Japanese versus mainland Chinese. Clin Pharmacol Ther. 1989 Aug;46(2):198–207. doi: 10.1038/clpt.1989.126. [DOI] [PubMed] [Google Scholar]
  12. Inaba T., Jurima M., Nakano M., Kalow W. Mephenytoin and sparteine pharmacogenetics in Canadian Caucasians. Clin Pharmacol Ther. 1984 Nov;36(5):670–676. doi: 10.1038/clpt.1984.238. [DOI] [PubMed] [Google Scholar]
  13. Nakamura K., Goto F., Ray W. A., McAllister C. B., Jacqz E., Wilkinson G. R., Branch R. A. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther. 1985 Oct;38(4):402–408. doi: 10.1038/clpt.1985.194. [DOI] [PubMed] [Google Scholar]
  14. Nevill C. G., Watkins W. M., Carter J. Y., Munafu C. G. Comparison of mosquito nets, proguanil hydrochloride, and placebo to prevent malaria. BMJ. 1988 Aug 6;297(6645):401–403. doi: 10.1136/bmj.297.6645.401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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 Jun;33(6):665–666. [PMC free article] [PubMed] [Google Scholar]
  16. Setiabudy R., Kusaka M., Chiba K., Darmansjah I., Ishizaki T. Dapsone N-acetylation, metoprolol alpha-hydroxylation, and S-mephenytoin 4-hydroxylation polymorphisms in an Indonesian population: a cocktail and extended phenotyping assessment trial. Clin Pharmacol Ther. 1994 Aug;56(2):142–153. doi: 10.1038/clpt.1994.117. [DOI] [PubMed] [Google Scholar]
  17. Sohn D. R., Kusaka M., Ishizaki T., Shin S. G., Jang I. J., Shin J. G., Chiba K. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther. 1992 Aug;52(2):160–169. doi: 10.1038/clpt.1992.125. [DOI] [PubMed] [Google Scholar]
  18. Ward S. A., Helsby N. A., Skjelbo E., Brøsen K., Gram L. F., Breckenridge A. M. The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism--a panel study. Br J Clin Pharmacol. 1991 Jun;31(6):689–692. doi: 10.1111/j.1365-2125.1991.tb05594.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ward S. A., Watkins W. M., Mberu E., Saunders J. E., Koech D. K., Gilles H. M., Howells R. E., Breckenridge A. M. Inter-subject variability in the metabolism of proguanil to the active metabolite cycloguanil in man. Br J Clin Pharmacol. 1989 Jun;27(6):781–787. doi: 10.1111/j.1365-2125.1989.tb03440.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Watkins W. M., Chulay J. D., Sixsmith D. G., Spencer H. C., Howells R. E. A preliminary pharmacokinetic study of the antimalarial drugs, proguanil and chlorproguanil. J Pharm Pharmacol. 1987 Apr;39(4):261–265. doi: 10.1111/j.2042-7158.1987.tb06263.x. [DOI] [PubMed] [Google Scholar]
  21. Watkins W. M., Mberu E. K., Nevill C. G., Ward S. A., Breckenridge A. M., Koech D. K. Variability in the metabolism of proguanil to the active metabolite cycloguanil in healthy Kenyan adults. Trans R Soc Trop Med Hyg. 1990 Jul-Aug;84(4):492–495. doi: 10.1016/0035-9203(90)90010-c. [DOI] [PubMed] [Google Scholar]
  22. Watkins W. M., Sixsmith D. G., Chulay J. D. The activity of proguanil and its metabolites, cycloguanil and p-chlorophenylbiguanide, against Plasmodium falciparum in vitro. Ann Trop Med Parasitol. 1984 Jun;78(3):273–278. doi: 10.1080/00034983.1984.11811816. [DOI] [PubMed] [Google Scholar]
  23. Wattanagoon Y., Taylor R. B., Moody R. R., Ochekpe N. A., Looareesuwan S., White N. J. Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects. Br J Clin Pharmacol. 1987 Dec;24(6):775–780. doi: 10.1111/j.1365-2125.1987.tb03245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wedlund P. J., Aslanian W. S., McAllister C. B., Wilkinson G. R., Branch R. A. Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther. 1984 Dec;36(6):773–780. doi: 10.1038/clpt.1984.256. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES