Stereoselective metabolism of rac-mexiletine by the fungus Cunninghamella echinulata yields the major human metabolites hydroxymethylmexiletine and p-hydroxymexiletine

Drug Metabolism and Disposition

Volumn 25, Issue 6, 1997, Pages 685-692

  Freitag, D G ^b   Foster, R T ^b   Coutts, R T ^b   Pickard, M A ^b   Pasutto, F M ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

ANTIARRHYTHMIC AGENT; DRUG METABOLITE; MEXILETINE;

ARTICLE; CONTROLLED STUDY; CULTURE MEDIUM; DRUG METABOLISM; ENANTIOMER; FERMENTATION; FUNGUS CULTURE; HEART VENTRICLE ARRHYTHMIA; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; NONHUMAN; PRIORITY JOURNAL; STEREOCHEMISTRY;

ANTI-ARRHYTHMIA AGENTS; CULTURE MEDIA; FUNGI; HYDROGEN-ION CONCENTRATION; MEXILETINE;

CUNNINGHAMELLA; CUNNINGHAMELLA ECHINULATA; FUNGI; MAMMALIA;

EID: 0030960018     PISSN: 00909556     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (29)

1. B. J. Schraeder and J. L. Bauman: Mexiletine: a new type I antiarrhythmic agent. Drug Intell. Clin. Pharm. 20, 255-261 (1986).
2. V. Haselbarth, J. E. Doevendans, and M. Wolf: Kinetics and bioavailability of mexiletine in healthy subjects. Clin. Pharmacol. Ther. 29, 729-736 (1981).
3. J. G. Kelly: Measurement of plasma mexiletine concentrations. Postgrad. Med. J. 53, (Suppl. I), 48-49 (1977).
4. N. P. Campbell, J. G. Kelly, A. A. Adgey, and R. G. Shanks: The clinical pharmacology of mexiletine. Br. J. Clin. Pharmacol. 6, 103-108 (1978).
5. L. Igwemezie, C. R. Kerr, and K. M. McErlane: The pharmacokinetics of the enantiomers of mexiletine in humans. Xenobiotica 19, 677-682 (1989).
6. K. M. McErlane and L. Igwemezie: Stereoselective analysis of the enantiomers of mexiletine by high-performance liquid chromatography using fluorescence detection and study their stereoselective disposition in man. J. Chromatogr. 415, 335-346 (1987).
7. R. J. Hill, H. J. Duff, and R. S. Sheldon: Determinants of stereospecific binding of type I antiarrhythmic drugs to cardiac sodium channels. Mol. Pharmacol. 34, 659-663 (1988).
8. J. Turgeon, A. C. G. Uprichard, P. M. Belanger, D. W. G. Harron, and O. Grech-Belanger: Resolution and electrophysiological effects of mexiletine enantiomers. J. Pharm. Pharmacol. 43, 630-635 (1990).
9. O. Grech-Belanger, J. A. Turgeon, and M. Gilbert: Stereoselective disposition of mexiletine in man. Br. J. Clin. Pharmacol. 21, 481-487 (1986).
10. N. Vandamme, F. Broly, C. Libersa, C. Courseau, and M. Lhermitte: Stereoselective hydroxylation of mexiletine in human liver microsomes: implication of P450IID6. A preliminary report. J. Cardiovasc. Pharmacol. 21, 77-83 (1993).
11. A. M. Gillis and R. E. Kates: Clinical pharmacokinetics of the newer antiarrhythmic agents. Clin. Pharmacokinet. 9, 375-403 (1984).
12. B. G. Mitchell, J. A. Clements, A. Pottage, and L. F. Prescott: Mexiletine disposition: individual variation in response to urine acidification and alkalinisation. Br. J Clin. Pharmacol. 16, 281-284 (1983).
13. O. Grech-Belanger, G. Barbeau, P. Kishka, C. Fiset, E. LeBoeuf, and M. Blouin: Pharmacokinetics of mexiletine in the elderly. J. Clin. Pharmacol. 29, 311-315 (1989).
14. O. Grech-Belanger, M. Gilbert, J. Turgeon, and P. P. LeBlanc: Effects of cigarette smoking on mexiletine kinetics. Clin. Pharmacol. Ther. 37, 638-643 (1985).
15. A. Klein, M. Sami, and K. Selinger: Mexiletine kinetics in healthy subjects taking cimetidine. Clin. Pharmacol. Ther. 37, 669-673 (1985).
16. P. J. Pentikainen, M. O. Halinen, and M. J. Helin: Pharmacokinetics of oral mexiletine in patients with acute myocardial infarction. Eur. J. Clin. Pharmacol. 25, 773-777 (1983).
17. L. P. Prescott, A. Pottage, and J. A. Clements: Absorption, distribution, and elimination of mexiletine. Postgrad. Med. J. 53, (Suppl. I), 50-55 (1977).
18. A. H. Beckett and C. Chidomere: The identification and analysis of mexiletine and its metabolic products in man. J. Pharm. Pharmacol. 29, 281-285 (1977).
19. J. Turgeon, J. R. Pare, M. Lalande, O. Grech-Belanger, and P. M. Belanger: Isolation and structural characterization by spectroscopic methods of two glucuronide metabolites of mexiletine after N-oxidation and deamination. Drug Metab. Dispos. 20, 762-769 (1992).
20. F. Broly, C. Libersa, and M. Lhermitte: Mexiletine metabolism in vitro by human liver. Drug Metab. Dispos. 18, 362-368 (1990).
21. K. Brosen: Recent developments in hepatic drug oxidation. Implications for clinical pharmacokinetics. Clin. Pharmacokinet. 18, 220-239 (1990).
22. J. Turgeon, C. Fiset, R. Giguere, M. Gilbert, K. Moerike, J. R. Rouleau, H. K. Kroemer, M. Eichelbaum, O. Grech-Belanger, and P. M. Belanger: Influence of debrisoquine phenotype and of quinidine on mexiletine disposition in man. J. Pharmacol. Exp. Ther. 259, 789-798 (1991).
23. F. Jamali, R. Mehvar, and F. M. Pasutto: Enantioselective aspects of drug action and disposition: therapeutic pitfalls. J. Pharm. Sci. 78, 695-715 (1989).
24. L. Igwemezie, G. N. Beatch, M. J. Walker, and K. M. McErlane: Tissue distribution of mexiletine enantiomers in rats. Xenobiotica 21, 1153-1158 (1991).
25. B. J. Auret, D. R. Boyd, P. M. Robinson, C. G. Watson, J. W. Daly, and D. M. Jerina: The NIH shift during the hydroxylation of aromatic substrates by fungi. Chem. Comm. (J. Amer. Chem. Soc., Sect. D) 24, 15885-15887 (1971).
26. A. M. Clark and C. D. Hufford: Use of microorganisms for the study of drug metabolism: an update. Med. Res. Rev. 11, 473-501 (1991).
27. J. D. Rizzo and P. J. Davis: Microbial models of mammalian metabolism: conversion of warfarin to 4′-hydroxywarfarin using Cunninghamella bainieri. J. Pharm. Sci. 78, 183-189 (1989).
28. D. G. Freitag, R. T. Foster, R. T. Coutts, and F. M. Pasutto: High-performance liquid chromatographic method for resolving the enantiomers of mexiletine and two major metabolites isolated from microbial fermentation media. J. Chromatogr. 616, 253-259 (1993).
29. B. Foster, D. L. Wilson, and I. McGilveray: Effect of sparteine and quinidine on the metabolism of methoxyphenamine by Cunninghamella bainieri. Xenobiotica 19, 445-452 (1989).