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. 1990 Jun;29(6):665–671. doi: 10.1111/j.1365-2125.1990.tb03687.x

Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects.

J H Schellens 1, J H van der Wart 1, D D Breimer 1
PMCID: PMC1380168  PMID: 2378787

Abstract

1. In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4-hydroxy metabolites (OH-). 2. On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4-hydroxy metabolites of all compounds were measured by h.p.l.c. 3. Urinary recovery of OH-phenytoin was 31.0 +/- 11.7%, of OH-methylphenytoin 3.4 +/- 2.7% and of OH-phenobarbitone 1.4 +/- 1.2%. No correlation was found between the recovery of OH-mephenytoin and OH-phenytoin. A subject who produced virtually no OH-phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4. The correlation coefficient for OH-mephenytoin and OH-methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH-methylphenytoin, suggesting a cosegregation of the 4-hydroxylation pathways. No correlation was found between the urinary recovery of OH-phenobarbitone and that of the other 4-hydroxy metabolites.

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Selected References

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  1. Bertilsson L., Henthorn T. K., Sanz E., Tybring G., Säwe J., Villén T. Importance of genetic factors in the regulation of diazepam metabolism: relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther. 1989 Apr;45(4):348–355. doi: 10.1038/clpt.1989.40. [DOI] [PubMed] [Google Scholar]
  2. Eadie M. J. Plasma level monitoring of anticonvulsants. Clin Pharmacokinet. 1976;1(1):52–66. doi: 10.2165/00003088-197601010-00005. [DOI] [PubMed] [Google Scholar]
  3. Eichelbaum M., Reetz K. P., Schmidt E. K., Zekorn C. The genetic polymorphism of sparteine metabolism. Xenobiotica. 1986 May;16(5):465–481. doi: 10.3109/00498258609050252. [DOI] [PubMed] [Google Scholar]
  4. Eichelbaum M., Spannbrucker N., Steincke B., Dengler H. J. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1979 Sep;16(3):183–187. doi: 10.1007/BF00562059. [DOI] [PubMed] [Google Scholar]
  5. Fritz S., Lindner W., Roots I., Frey B. M., Küpfer A. Stereochemistry of aromatic phenytoin hydroxylation in various drug hydroxylation phenotypes in humans. J Pharmacol Exp Ther. 1987 May;241(2):615–622. [PubMed] [Google Scholar]
  6. Hvidberg E. F., Dam M. Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet. 1976;1(3):161–188. doi: 10.2165/00003088-197601030-00001. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Jacqz E., Hall S. D., Branch R. A., Wilkinson G. R. Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital. Clin Pharmacol Ther. 1986 Jun;39(6):646–653. doi: 10.1038/clpt.1986.113. [DOI] [PubMed] [Google Scholar]
  9. 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 Apr;19(4):483–487. doi: 10.1111/j.1365-2125.1985.tb02673.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jurima M., Inaba T., Kalow W. Sparteine oxidation by the human liver: absence of inhibition by mephenytoin. Clin Pharmacol Ther. 1984 Mar;35(3):426–428. doi: 10.1038/clpt.1984.54. [DOI] [PubMed] [Google Scholar]
  11. KUTT H., WOLK M., SCHERMAN R., MCDOWELL F. INSUFFICIENT PARAPHYDROXYLATION AS A CAUSE OF DIPHENYLHYDANTOIN TOXICITY. Neurology. 1964 Jun;14:542–548. doi: 10.1212/wnl.14.6.542. [DOI] [PubMed] [Google Scholar]
  12. Küpfer A., Branch R. A. Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. Clin Pharmacol Ther. 1985 Oct;38(4):414–418. doi: 10.1038/clpt.1985.196. [DOI] [PubMed] [Google Scholar]
  13. Küpfer A., Brilis G. M., Watson J. T., Harris T. M. A major pathway of mephenytoin metabolism in man. Aromatic hydroxylation to p-hydroxymephenytoin. Drug Metab Dispos. 1980 Jan-Feb;8(1):1–4. [PubMed] [Google Scholar]
  14. Küpfer A., Desmond P. V., Schenker S., Branch R. A. Stereoselective metabolism and disposition of the enantiomers of mephenytoin during chronic oral administration of the racemic drug in man. J Pharmacol Exp Ther. 1982 Jun;221(3):590–597. [PubMed] [Google Scholar]
  15. Küpfer A., Patwardhan R., Ward S., Schenker S., Preisig R., Branch R. A. Stereoselective metabolism and pharmacogenetic control of 5-phenyl-5-ethylhydantoin (nirvanol) in humans. J Pharmacol Exp Ther. 1984 Jul;230(1):28–33. [PubMed] [Google Scholar]
  16. Küpfer A., Preisig R. Pharmacogenetics of mephenytoin: a new drug hydroxylation polymorphism in man. Eur J Clin Pharmacol. 1984;26(6):753–759. doi: 10.1007/BF00541938. [DOI] [PubMed] [Google Scholar]
  17. Küpfer A., Roberts R. K., Schenker S., Branch R. A. Stereoselective metabolism of mephenytoin in man. J Pharmacol Exp Ther. 1981 Jul;218(1):193–199. [PubMed] [Google Scholar]
  18. Meier U. T., Dayer P., Malè P. J., Kronbach T., Meyer U. A. Mephenytoin hydroxylation polymorphism: characterization of the enzymatic deficiency in liver microsomes of poor metabolizers phenotyped in vivo. Clin Pharmacol Ther. 1985 Nov;38(5):488–494. doi: 10.1038/clpt.1985.213. [DOI] [PubMed] [Google Scholar]
  19. Richens A. Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet. 1979 May-Jun;4(3):153–169. doi: 10.2165/00003088-197904030-00001. [DOI] [PubMed] [Google Scholar]
  20. Schellens J. H., van der Wart J. H., Brugman M., Breimer D. D. Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design. J Pharmacol Exp Ther. 1989 May;249(2):638–645. [PubMed] [Google Scholar]
  21. Shimada T., Misono K. S., Guengerich F. P. Human liver microsomal cytochrome P-450 mephenytoin 4-hydroxylase, a prototype of genetic polymorphism in oxidative drug metabolism. Purification and characterization of two similar forms involved in the reaction. J Biol Chem. 1986 Jan 15;261(2):909–921. [PubMed] [Google Scholar]
  22. Vasko M. R., Bell R. D., Daly D. D., Pippenger C. E. Inheritance of phenytoin hypometabolism: a kinetic study of one family. Clin Pharmacol Ther. 1980 Jan;27(1):96–103. doi: 10.1038/clpt.1980.15. [DOI] [PubMed] [Google Scholar]
  23. Wedlund P. J., Aslanian W. S., Jacqz E., McAllister C. B., Branch R. A., Wilkinson G. R. Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. J Pharmacol Exp Ther. 1985 Sep;234(3):662–669. [PubMed] [Google Scholar]
  24. Wedlund P. J., Sweetman B. J., McAllister C. B., Branch R. A., Wilkinson G. R. Direct enantiomeric resolution of mephenytoin and its N-demethylated metabolite in plasma and blood using chiral capillary gas chromatography. J Chromatogr. 1984 Apr 13;307(1):121–127. doi: 10.1016/s0378-4347(00)84078-5. [DOI] [PubMed] [Google Scholar]
  25. de Wolff F. A., Vermeij P., Ferrari M. D., Buruma O. J., Breimer D. D. Impairment of phenytoin parahydroxylation as a cause of severe intoxication. Ther Drug Monit. 1983 Jun;5(2):213–215. doi: 10.1097/00007691-198306000-00011. [DOI] [PubMed] [Google Scholar]

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