Lack of single-dose disulfiram effects on cytochrome P-450 2C9, 2C19, 2D6, and 3A4 activities: evidence for specificity toward P-450 2E1.

Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of cytochrome P-450 2E1 (CYP2E1)1 in vitro. Single-dose disulfiram diminishes CYP2E1 activity in vivo and has been used to identify CYP2E1 participation in human drug metabolism and prevent CYP2E1-mediated toxification. Specificity of single-dose disulfiram toward CYP2E1 in vivo, however, remains unknown. This investigation determined single-dose disulfiram effects on human CYP 2C9, 2C19, 2D6, and 3A4 activities in vivo. In four randomized crossover experiments, volunteers received isoform-selective probes (oral tolbutamide, mephenytoin, dextromethorphan, or i.v. midazolam) on two occasions, 10 h after oral disulfiram or after no pretreatment (controls). Plasma and/or urine parent and/or metabolite concentrations were measured by HPLC or gas chromatography-mass spectrometry. CYP2C9, 2C19, 2D6, and 3A4 activities were determined from the tolbutamide metabolic ratio, 4'-hydroxymephenytoin excretion, and dextromethorphan/dextrorphan ratios in urine and midazolam systemic clearance, respectively. Midazolam clearance (670 +/- 190 versus 700 +/- 240 ml/min, disulfiram versus controls), dextromethorphan/dextrorphan metabolic ratio (0.013 +/- 0.033 versus 0.015 +/- 0.035), 4'-hydroxymephenytoin excretion (122 +/- 22 versus 128 +/- 25 micromol), and tolbutamide metabolite excretion (577 +/- 157 versus 610 +/- 208 micromol) were not significantly altered by disulfiram pretreatment, although the tolbutamide metabolic ratio was slightly diminished after disulfiram (60 +/- 17 versus 81 +/- 40, p <.05). Results show that single-dose disulfiram does not cause clinically significant inhibition of human CYP2C9, 2C19, 2D6, and 3A4 activities in vivo. When single-dose disulfiram is used as an in vivo probe for P-450, inhibition of drug metabolism suggests selective involvement of CYP2E1. Single-dose disulfiram should not cause untoward drug interactions from inhibition of other P-450 isoforms.

[1]  I. Wainer,et al.  Dextromethorphan as an in vivo probe for the simultaneous determination of CYP2D6 and CYP3A activity. , 1996, Journal of chromatography. B, Biomedical applications.

[2]  J. Miners,et al.  Validation of the tolbutamide metabolic ratio for population screening with use of sulfaphenazole to produce model phenotypic poor metabolizers , 1990, Clinical pharmacology and therapeutics.

[3]  R. Vestal,et al.  Dose‐dependent inhibition of theophylline metabolism by disulfiram in recovering alcoholics , 1989, Clinical pharmacology and therapeutics.

[4]  F. Gonzalez,et al.  Specificity of substrate and inhibitor probes for cytochrome P450s: evaluation of in vitro metabolism using cDNA-expressed human P450s and human liver microsomes. , 1996, Xenobiotica; the fate of foreign compounds in biological systems.

[5]  E. Kharasch,et al.  Clinical enflurane metabolism by cytochrome P450 2E1. , 1994, Clinical pharmacology and therapeutics.

[6]  C. S. Yang,et al.  Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats. , 1991, Toxicology and applied pharmacology.

[7]  W. Trager,et al.  Use of midazolam as a human cytochrome P450 3A probe: I. In vitro-in vivo correlations in liver transplant patients. , 1994, The Journal of pharmacology and experimental therapeutics.

[8]  P. Beaune,et al.  Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P-450IIE1. , 1991, Chemical research in toxicology.

[9]  F. Guengerich,et al.  Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. , 1991, Chemical research in toxicology.

[10]  H. Yamazaki,et al.  Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. , 1992, Carcinogenesis.

[11]  D. Jones,et al.  Determination of cytochrome P450 3A4/5 activity in vivo with dextromethorphan N‐demethylation , 1996, Clinical pharmacology and therapeutics.

[12]  A. Somogyi,et al.  Simultaneous Determination of Dextromethorphan and Three Metabolites in Plasma and Urine Using High‐Performance Liquid Chromatography with Application to Their Disposition in Man , 1990, Therapeutic drug monitoring.

[13]  S. Loft,et al.  Inhibition of antipyrine elimination by disulfiram and cimetidine: the effect of concomitant administration. , 1986, British journal of clinical pharmacology.

[14]  K. Chiba,et al.  Incidence of S‐mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics , 1992, Clinical pharmacology and therapeutics.

[15]  P. Neuvonen,et al.  Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole , 1994 .

[16]  E. Kharasch,et al.  Clinical enflurane metabolism by cytochrome P450 2E1 , 1994 .

[17]  A. Hiller,et al.  A potentially hazardous interaction between erythromycin and midazolam , 1993 .

[18]  C. Funck-Brentano,et al.  CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans. , 1993, Pharmacogenetics.

[19]  A. Artru,et al.  Clinical Sevoflurane Metabolism and Disposition: II. The Role of Cytochrome P450 2E1 in Fluoride and Hexafluoroisopropanol Formation , 1995, Anesthesiology.

[20]  E. Kharasch,et al.  The Role of Cytochrome P450 3A4 in Alfentanil Clearance: Implications for Interindividual Variability in Disposition and Perioperative Drug Interactions , 1997, Anesthesiology.

[21]  E. Kharasch,et al.  Single‐dose disulfiram does not inhibit CYP2A6 activity , 1998, Clinical pharmacology and therapeutics.

[22]  M. Relling,et al.  Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. , 1990, The Journal of pharmacology and experimental therapeutics.

[23]  E. Kharasch,et al.  Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis , 1996, The Lancet.

[24]  J. Miners,et al.  Tolbutamide hydroxylation in humans: lack of bimodality in 106 healthy subjects. , 1993, Pharmacogenetics.

[25]  R. Branch,et al.  Polymorphic metabolism of mephenytoin in man: Pharmacokinetic interaction with a co‐regulated substrate, mephobarbital , 1986, Clinical pharmacology and therapeutics.

[26]  E. Kharasch,et al.  Single‐dose disulfiram inhibition of chlorzoxazone metabolism: A clinical probe for P450 2E1 , 1993, Clinical pharmacology and therapeutics.

[27]  F. Guengerich,et al.  Human cytochrome P-450 enzymes. , 1992, Life sciences.

[28]  P. Henderson,et al.  Excretion of TTCA in human urine after administration of disulfiram. , 1982, Toxicology letters.

[29]  S. Loft,et al.  Disulfiram therapy –adverse drug reactions and interactions , 1992, Acta psychiatrica Scandinavica. Supplementum.

[30]  U. Klotz,et al.  No Evidence of a Genetic Polymorphism in the Oxidative Metabolism of Midazolam , 1988, Clinical pharmacokinetics.

[31]  P. Wedlund,et al.  Dextromethorphan: Enhancing its systemic availability by way of low‐dose quinidine‐mediated inhibition of cytochrome P4502D6 , 1992, Clinical pharmacology and therapeutics.

[32]  H. Zhou,et al.  Evidence for the effect of gender on activity of (S)-mephenytoin 4'-hydroxylase (CYP2C19) in a Chinese population. , 1997, Pharmacogenetics.

[33]  P. Srivastava,et al.  Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Saccharomyces cerevisiae. , 1989, Biochemistry.

[34]  S. Huang,et al.  High-performance liquid chromatographic determination of urinary 4'-hydroxymephenytoin, a metabolic marker for the hepatic enzyme CYP2C19, in humans. , 1995, Journal of chromatography. B, Biomedical applications.

[35]  C. Lieber,et al.  Cytochrome P-4502E1: its physiological and pathological role. , 1997, Physiological reviews.

[36]  T Ishizaki,et al.  Genotyping of S‐mephenytoin 4′‐hydroxylation in an extended Japanese population , 1996, Clinical pharmacology and therapeutics.

[37]  G. Wilkinson,et al.  Mephenytoin hydroxylation deficiency in Caucasians: Frequency of a new oxidative drug metabolism polymorphism , 1984, Clinical pharmacology and therapeutics.

[38]  P. Watkins.  Use of midazolam as a human cytochrome P450 3A probe: II. Characterization of inter- and intraindividual hepatic CYP3A variability after liver transplantation , 1995 .

[39]  E. Petersen.  The pharmacology and toxicology of disulfiram and its metabolites , 1992, Acta psychiatrica Scandinavica. Supplementum.

[40]  S. Wrighton,et al.  Isolation and characterization of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4'-hydroxylation. , 1993, Archives of biochemistry and biophysics.

[41]  M. Relling,et al.  Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans. , 1993, The Journal of clinical investigation.

[42]  D. Mays,et al.  Inhibition of elimination of caffeine by disulfiram in normal subjects and recovering alcoholics , 1986, Clinical pharmacology and therapeutics.

[43]  L. Vereczkey,et al.  Simple high-performance liquid chromatographic method for the determination of tolbutamide and its metabolites in human plasma and urine using photodiode-array detection. , 1989, Journal of chromatography.

[44]  A. Hiller,et al.  A potentially hazardous interaction between erythromycin and midazolam. , 1993, Clinical pharmacology and therapeutics.

[45]  D. Waxman,et al.  Evaluation of triacetyloleandomycin, alpha-naphthoflavone and diethyldithiocarbamate as selective chemical probes for inhibition of human cytochromes P450. , 1994, Archives of biochemistry and biophysics.

[46]  R. Branch,et al.  Genetic polymorphism of S-mephenytoin hydroxylation. , 1989, Pharmacology & therapeutics.

[47]  G. Wilkinson,et al.  Differences between white subjects and Chinese subjects in the in vivo inhibition of cytochrome P450s 2C19, 2D6, and 3A by omeprazole , 1996, Clinical pharmacology and therapeutics.

[48]  J. Bircher,et al.  Polymorphic dextromethorphan metabolism: Co‐segregation of oxidative O‐demethylation with debrisoquin hydroxylation , 1985, Clinical pharmacology and therapeutics.

[49]  W. Valentine,et al.  The measurement of 2-thiothiazolidine-4-carboxylic acid as an index of the in vivo release of CS2 by dithiocarbamates. , 1996, Chemical research in toxicology.

[50]  J. Goldstein,et al.  Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. , 1997, Pharmacogenetics.

[51]  W. Pryor.  Cytochrome P450: Structure, mechanism, and biochemistry , 1996 .

[52]  C. Funck-Brentano,et al.  Comparison of chloroguanide and mephenytoin for the in vivo assessment of genetically determined CYP2C19 activity in humans , 1995, Clinical pharmacology and therapeutics.

[53]  P. Simon,et al.  Dietary habits, a non-negligible source of 2-thiothiazolidine-4-carboxylic acid and possible overestimation of carbon disulfide exposure , 1994, International archives of occupational and environmental health.

[54]  E. Sellers,et al.  Pharmacokinetics of dextromethorphan and metabolites in humans: influence of the CYP2D6 phenotype and quinidine inhibition. , 1995, Journal of clinical psychopharmacology.