Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes

AIMS: To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be 'normalised' by low doses of the CYP2D6 inhibitor quinidine and whether this is dose-dependent. METHODS: Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4-hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated. RESULTS: Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose-effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1-2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively. CONCLUSIONS: A dose-effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increased doses of the drug. Normalizing the metabolic capacity of CYP2D6, by giving a low dose of quinidine, may solve the problem of 'treatment resistance' caused by ultrarapid metabolism.     

The CYP2D6 polymorphism in relation to the metabolism of amitriptyline and nortriptyline in the Faroese population

AIM

To determine the frequency of CYP2D6 poor metabolizers (PMs) in a Faroese patient group medicated with amitriptyline (AT) and to investigate plasma concentrations of AT and metabolites in relation to CYP2D6.

METHODS

CYP2D6 phenotype and genotype were determined in 23 Faroese patients treated with AT. Plasma concentrations of AT and metabolites were determined by high-performance liquid chromatography and investigated in relation to CYP2D6 activity.

RESULTS

Of the 23 patients phenotyped and genotyped, five (22%) (95% confidence interval 7.5, 43.7) were CYP2D6 PMs. No difference was found in AT daily dosage between PMs (median 25 mg day⁻¹; range 5–80) and extensive metabolizers (EMs) (median 27.5 mg day⁻¹; range 10–100). The (E)-10-OH-nortriptyline (NT)/dose concentrations were higher in EMs than in PMs and the NT/(E)-10-OH-NT and AT/(E)-10-OH-AT ratios were higher in PMs compared with EMs. The log sparteine metabolic ratio correlated positively with the NT/(E)-10-OH-NT ratio (r_s = 0.821; P < 0.0005) and the AT/(E)-10-OH-AT ratio (r_s = 0.605; P < 0.006).

CONCLUSION

A high proportion of CYP2D6 PMs was found in a Faroese patient group medicated with AT. However, similar doses of AT and concentrations of AT and NT were noted in EMs and PMs, probably due to varying doses and indications for AT treatment.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The metabolisms of amitriptyline (AT) to (E)-10-hydroxyamitriptyline and of nortripyline (NT) to (E)-10-hydroxynortriptyline are catalysed by CYP2D6.
• A correlation between the sparteine metabolic ratio and the NT/(E)-10-hydroxynortriptyline and the AT/(E)-10-hydroxyamitriptyline ratios, respectively, has been observed in patients in treatment with the same dose of AT or NT.
• The frequency of CYP2D6 poor metabolizers (PMs) is 15% (twofold compared with other Whites) among healthy Faroese.
• This frequency has not been investigated in Faroese patients in AT treatment and the consequences of the CYP2D6 PM phenotype for dose and plasma concentrations of AT and metabolites are not known in these patients.

WHAT THIS STUDY ADDS

• In patients treated with different daily dosages (5–100 mg) of AT a correlation between the sparteine metabolic ratio and the NT/(E)-10-hydroxynortriptyline and AT/(E)-10-hydroxyamitriptyline ratios was observed.
• A high proportion (22%) of CYP2D6 PMs in a Faroese patient group medicated with AT was observed.
• However, similar doses of AT and concentrations of AT and NT were noted in extensive metabolizers and in PMs.

     

ASA法测定细胞色素P4502D6酶缺陷等位基因CYP2D6E

目的：建立细胞色素Ｐ４５０ ２Ｄ６（ＣＹＰ２Ｄ６）第３０２３位Ａ→Ｃ突变成ＣＹＰ２Ｄ６酶活性缺陷的等位基因ＣＹＰ２Ｄ６Ｅ的测定方法。方法：利用等位基因特异扩增法（ＡＳＡ）为基本原理,设计两对引物分别扩增野生型等位基因和突变型等位基因。结果：经３９６例测定,发现２例ＣＹＰ２Ｄ６Ｅ与ＣＹＰ２Ｄ６Ｂ的异突变型纯合子,其表现型均为慢代谢者。     

Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans

1 Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia.
2 Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-α-methoxy-9,10-dihydrolysergol (MMDL), which is further N -demethylated to form 10-α-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms.
3 After a single, oral 30  mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes.
4 The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL C _max 59  nmol l⁻¹ and AUC (0, t h) 144  nmol l⁻¹h, mean MDL C _max 183  nmol l⁻¹ and AUC 2627  nmol l⁻¹h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL C _max 356  nmol l⁻¹ and AUC 10512  nmol l⁻¹h, MDL concentrations below limit of quantitation).
5 We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.     

ASA法测定细胞色素P450 2D6酶缺陷等位基因CYP2D6E

目的 :建立细胞色素P4 50 2D6(CYP2D6)第 3 0 2 3位A→C突变造成CYP2D6酶活性缺陷的等位基因CYP2D6E的测定方法。方法 :利用等位基因特异扩增法 (ASA)为基本原理 ,设计两对引物分别扩增野生型等位基因和突变型等位基因。结果 :经 3 96例测定 ,发现 2例CYP2D6E与CYP2D6B的异突变型纯合子 ,其表现型均为慢代谢者。阳性对照说明本法重复性好 ,阴性对照显示本法无污染问题。结论 :本法比PCR -RFLP法更为快捷、更少污染。对CYP2D6E的测定有助于准确预测CYP2D6表现型     

Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype.

The present study investigated the role of specific human cytochrome P450 (CYP) enzymes in the in vitro metabolism of valproic acid (VPA) by a complementary approach that used individual cDNA-expressed CYP enzymes, chemical inhibitors of specific CYP enzymes, CYP-specific inhibitory monoclonal antibodies (MAbs), individual human hepatic microsomes, and correlational analysis. cDNA-expressed CYP2C9*1, CYP2A6, and CYP2B6 were the most active catalysts of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation. The extent of 4-OH-VPA and 5-OH-VPA formation by CYP1A1, CYP1A2, CYP1B1, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP4A11, CYP4F2, CYP4F3A, and CYP4F3B was only 1-8% of the levels by CYP2C9*1. CYP2A6 was the most active in catalyzing VPA 3-hydroxylation, whereas CYP1A1, CYP2B6, CYP4F2, and CYP4F3B were less active. Correlational analyses of VPA metabolism with CYP enzyme-selective activities suggested a potential role for hepatic microsomal CYP2A6 and CYP2C9. Chemical inhibition experiments with coumarin (CYP2A6 inhibitor), triethylenethiophosphoramide (CYP2B6 inhibitor), and sulfaphenazole (CYP2C9 inhibitor) and immunoinhibition experiments (including combinatorial analysis) with MAb-2A6, MAb-2B6, and MAb-2C9 indicated that the CYP2C9 inhibitors reduced the formation of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA by 75-80% in a panel of hepatic microsomes from donors with the CYP2C9*1/*1 genotype, whereas the CYP2A6 and CYP2B6 inhibitors had a small effect. Only the CYP2A6 inhibitors reduced VPA 3-hydroxylation (by approximately 50%). The extent of inhibition correlated with the catalytic capacity of these enzymes in each microsome sample. Overall, our novel findings indicate that in human hepatic microsomes, CYP2C9*1 is the predominant catalyst in the formation of 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA, whereas CYP2A6 contributes partially to 3-OH-VPA formation.     

CYP2D6 and CYP2C19 genotypes in an elderly Swedish population

Objective: Eighty-three healthy elderly Swedish subjects (age 87 ± 4 years, mean ± SD, range 80–98 years) were genotyped with respect to the two genetic polymorphisms of oxidative drug metabolism, CYP2D6 and CYP2C19, using allele-specific polymerase chain reaction (PCR). A control population consisted of 248 younger unrelated healthy volunteers (age 31 ± 9 years, range 19–63 years) for CYP2D6, and 162 (age 30 ± 8 years, range 19–55 years) for CYP2C19. Results: No significant differences were found between the control groups and the elderly subjects with respect to the frequencies of the defect alleles CYP2D6*3, CYP2D6*4, CYP2C19*2 and CYP2C19*3. Neither were there any differences in the genotype frequencies, or the predicted phenotype frequencies. The study indicates that the CYP2D6 and CYP2C19 genotypes play no major role in the probability of reaching high age. Conclusion: No genetically determined differences in the pharmacokinetics of drugs metabolized by these two polymorphic enzymes are to be expected in the oldest age groups compared with younger adults. Received: 10 March 1998 / Accepted: 1 May 1998     

Semi-quantitative CYP2D6 gene doses in relation to metabolic ratios of psychotropics

Purpose  Genetic polymorphisms in cytochrome P450 (CYP) enzyme CYP2D6 have a substantial effect on the success of pharmacotherapy. Different models, including a predicted-phenotype model and a semi-quantitative gene dose (SGD) model, have been developed based on CYP genotype. The objective of this study was to investigate the surplus value of the SGD model in predicting the metabolic ratios (MRs) of the psychotropics venlafaxine, fluoxetine and risperidone. Methods  Phenotype prediction and semi-quantitative gene doses were conducted after genotyping for CYP2D6 *3, *4, *5, *6, *9, *10, *41 and gene multiplication. Results  The predicted-phenotype and SGD model showed increasing mean MRs with increasing predicted metabolic activity and decreasing SGD values, respectively, for all three psychotropics. The reliability of MR prediction was higher for the SGD model. Conclusions  Both models are suitable for venlafaxine, fluoxetine and risperidone. In this study, a surplus value of semi-quantitative gene dose model was present, but small, for all three psychotropics.     

细胞色素P-450 CYP2D6基因分型与表型的吻合率

目的:研究细胞色素P-450 2D6基因分型测定方法及其与表型的吻合率。方法:利用等位基因特异扩增法基本原理,对CYP2D6酶缺陷等位基因CYP2D6*3,*4,*6和*7进行测定。结果:通过168例基因分型,并将结果与表型对照,发现同时测定CYP2D6*3,*4,*6和*7等位基因时,125例快代谢者和43例慢代谢者的基因分型结果与表型结果的吻合率为100％。快代谢者至少有一个野生型CYP2D6等位基因,基因型为*1/*1,*1/*3和*1/*4。发现慢代谢者是CYP2D6突变型纯合子,基因型为*3/*4,*4/*4,*3/*6,*4/*7,*4/*6和*6/*6。结论:对CYP2D6*3,*4,*6和*7等位基因的测定能够准确预测其表型。     

CYP2D6基因与药物代谢

细胞色素P 45 0 (CYP)中的CYP2D6酶在抗抑郁药、安定药及某些抗心律失常药的代谢中起重要作用 ,CYP2D6基因位于 2 2号常染色体上为隐性遗传 ,CYP2D6基因呈多态性约有 70余种等位基因变异型 ,也存在特异人群差别 ,因而导致所编码的酶活性不同 ,这些数据有助于理解药物代谢的个体差异、有助于预测药物之间的相互作用。     

Interferon-beta treatment in patients with multiple sclerosis does not alter CYP2C19 or CYP2D6 activity

AIMS: To determine CYP2C19 and CYP2D6 activity in patients with multiple sclerosis (MS) before and during interferon (IFN)-beta treatment. METHODS: CYP2C19 and CYP2D6 activities were assessed using the probe drugs mephenytoin and debrisoquine, respectively. Urinary mephenytoin (S/R) and debrisoquine (debrisoquine/hydroxy-debrisoquine) metabolic ratios (MR) were determined in 10 otherwise healthy Caucasian multiple sclerosis (MS) patients in the initial stage of the disease, prior to and 1 month after commencing treatment with IFN-beta (Avonex, Rebif or Betaferon). In addition, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, and CYP2D6*5 genotyping was performed. RESULTS: There was no significant difference in the (S)/(R) mephenytoin ratio (mean difference 0.04; 95% CI -0.03, 0.11) or the debrisoquine MR (mean difference 0.29; 95% CI -0.44, 1.02) before and during regular IFN-beta treatment in extensive metabolizers (EM) (P = 0.5 and P = 0.4 for the respective probe drugs; n = 9 subjects). There were also no differences between the different IFN-beta treatments (P = 0.6 for the (S)/(R) mephenytoin ratio and P = 0.7 for the debrisoquine MR; anova; n = 10). CONCLUSIONS: IFN-beta treatment did not affect the activity of CYP2C19 or CYP2D6. The results suggest that it is safe to administer CYP2C19 or CYP2D6 substrates, without dose adjustment, to patients treated with IFN-beta.     

Fenofibrate-induced decrease of expression of CYP2C11 and CYP2C6 in rat

This short communication is aimed to investigate whether the widely used hypolipidemic drug fenofibrate affects CYP2C11 and CYP2C6 in rats, both counterparts of human CYP2C9, known to metabolise many drugs including S-warfarin and largely used non-steroidal antiinflammatory drugs such as ibuprofen, diclofenac and others. The effects of fenofibrate on the expression of rat liver CYP2C11 and CYP2C6 were studied in both healthy Wistar rats and hereditary hypertriglyceridemic rats. Both strains of rats were fed on diet containing fenofibrate (0.1% w/w) for 20 days. Fenofibrate highly significantly suppressed the expression of mRNA of CYP2C11 and less that of CYP2C6 in liver microsomes of both rat strains; this effect was associated with a corresponding decrease in protein levels. The results indicate that the combination of fenofibrate with drugs metabolised by CYP2C9 in humans should be taken with caution as it may lead, for example, to the potentiation of warfarin effects. This type of drug interaction has been observed previously and the results presented here could contribute to the explanation of their mechanism.     

Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs

Cytochrome P450 CYP2D6 is the most extensively characterized polymorphic drug-metabolizing enzyme. A deficiency of the CYP2D6 enzyme is inherited as an autosomal recessive trait; these subjects (7% of Caucasians, about 1% of Orientals) are classified as poor metabolizers. Among the rest (extensive metabolizers), enzyme activity is highly variable, from extremely high in ultrarapid metabolizers, to markedly reduced in intermediate metabolizers. The CYP2D6 gene is highly polymorphic, with more than 70 allelic variants described so far. Of these, more than 15 encode an inactive or no enzyme at all. Others encode enzyme with reduced, "normal" or increased enzyme activity. The CYP2D6 gene shows marked interethnic variability, with interpopulation differences in allele frequency and existence of "population-specific" allelic variants, for instance among Orientals and Black Africans. The CYP2D6 enzyme catalyses the metabolism of a large number of clinically important drugs including antidepressants, neuroleptics, some antiarrhythmics, lipophilic beta-adrenoceptor blockers and opioids. The present-day knowledge on the influence of the genetic variability in CYP2D6 on the clinical pharmacokinetics and therapeutic effects/adverse effects of psychotropic drugs is reviewed.     

Influence of donor and recipient genotypes on CYP2D6 phenotype after liver transplantation: a study of mutations CYP2D6*3 and CYP2D6*4

Objective: After liver transplantation (LT), genotypic differences between the recipient and the transplanted liver, medications and post-LT complications may all affect drug metabolism. We have studied the effect of two CYP2D6 mutations in the donor and the recipient on post-LT CYP2D6 phenotype. Method: The CYP2D6 phenotype was assessed in 48 patients before and after LT with debrisoquine or␣dextromethorphan. CYP2D6*3 (CYP2D6A) and CYP2D6*4 (CYP2D6B) mutations were detected in the donor and the recipient using polymerase chain reaction. Results: Before LT, 40 subjects were classified as extensive metabolisers (EM) and 8 as poor metabolisers (PM); after transplantation, 41 were EMs and 7 were PMs. Genotype and phenotype were in agreement in 100% of EMs and 40% of PMs. The low percentage of agreement in PMs could not be explained by severely altered liver function. The phenotype of 13 subjects was apparently changed by LT: 6 EMs became PMs and 7 PMs became EMs. All four subjects in whom genotype changed following LT had a corresponding change in phenotype: two EM subjects became PMs and two PM subjects became EMs. Conclusion: The low percentage of agreement in PMs may be partly explained by mutations other than CYP2D6*3 and CYP2D6*4. Nevertheless, our study shows that the CYP2D6 genotype of the donor controls the phenotype of the recipient of a liver transplantation. Received: 2 June 1997 / Accepted in revised form: 9 October 1997     

Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes

AIMS: To determine the frequencies of 11 CYP2D6 mutant alleles (CYP2D6*2, *3, *4, *5, *8, *10, *11, *12, *14, *17 and *18), and their relation to the metabolic capacity of CYP2D6 in Japanese subjects. METHODS: One hundred and sixty-two unrelated healthy Japanese subjects were genotyped with the polymerase chain reaction amplification method and 35 subjects were phenotyped with dextromethorphan. RESULTS: The frequencies of CYP2D6*2,*5, *10 and *14 were 12.9, 6.2, 38.6 and 2.2% in our Japanese subjects, respectively. CYP2D6*3, *4, *8, *11, *12, *17 and *18 were not detected. The mean log metabolic ratio of dextromethorphan in subjects with genotypes predicting intermediate metabolizers was significantly greater than that of heterozygotes for functional and defective alleles. CONCLUSIONS: CYP2D6*5 and CYP2D6*14 are the major defective alleles found in Japanese subjects. In addition, CYP2D6*10 may play a more important role than previously thought for the treatment of Japanese patients with drugs metabolized by CYP2D6.     

No evidence of increased adverse drug reactions in cytochrome P450 CYP2D6 poor metabolizers treated with fluoxetine or nortriptyline

The polymorphic enzyme cytochrome P450 CYP2D6 is involved in the metabolism of many antidepressants, including nortriptyline and fluoxetine. Some 7%-10% Caucasians have inactivating mutations in both alleles of the CYP2D6 gene, and are referred to as poor metabolizers (PMs). Several case reports and clinical studies suggest that CYP2D6 PMs are at a greater risk of developing adverse drug reactions (ADRs) on antidepressant medication than extensive metabolizers (EMs). However, few clinical trials have investigated whether CYP2D6 PM genotype is predictive of ADRs during antidepressant treatment. This paper explores the link between CYP2D6 genotype and antidepressant-associated ADRs in outpatients being treated for major depression with either nortriptyline or fluoxetine. Patients were randomized to fluoxetine (n=65) or nortriptyline (n=60) for the 6 week trial. CYP2D6 genotypes predicted that of these patients 115 were EM and the remaining 10 were PMs. ADRs attributed to antidepressant usage were recorded over the 6-week trial. Although the type of ADR was, as expected, different between drugs, the frequency of ADRs experienced did not differ significantly between the two antidepressants or between CYP2D6 PMs and EMs. In addition, the frequency at which PMs discontinued antidepressant medication was not noticeably different from EMs, although with only 10 PMs the study is under powered to detect moderate or small differences. These findings suggest that inability to efficiently metabolize antidepressants that are CYP2D6 substrates does not necessarily lead to increased occurrence of antidepressant-associated ADRs. Thus, for clinicians prescribing antidepressant monotherapy, CYP2D6 polymorphisms are probably not of relevance to antidepressant side effects and therapy.     

Genetic polymorphism of debrisoquine (CYP2D6) and proguanil (CYP2C19) in South Pacific Polynesian populations

Objective: Genetic oxidation polymorphisms of debrisoquine (CYP2D6) and proguanil (CYP2C19) were studied in unrelated healthy South Pacific Polynesian volunteers recruited in the South Island of New Zealand. Methods: Phenotyping for CYP2D6 and CYP2C19 activities was determined using debrisoquine and proguanil, respectively, as probe drugs by measuring the urinary metabolic ratio of parent drug and its␣metabolite. Results: Of 100 Polynesian subjects phenotyped, the metabolic ratio of debrisoquine ranged from 0.01 to 9.94. Therefore, all South Pacific Polynesians were classified as extensive metabolizers of debrisoquine according to previously established criteria of the antimode. The prevalence of poor metabolizers of debrisoquine (CYP2D6) in this Polynesian population is 0% (95% confidence interval of 0–3.6%). Oxidation polymorphism of CYP2C19 using proguanil as a probe was also studied in 59 Polynesian volunteers. The frequency distribution of the proguanil/cycloguanil ratio was bimodal. The proguanil/cycloguanil ratios for these subjects ranged from 0.09 to 34.4. Using a recommended proguanil/cycloguanil ratio cut-off point of 10 established in Caucasian populations, eight Polynesian subjects were identified as poor metabolizers of proguanil (CYP2C19), which corresponds to a poor metabolizer phenotype frequency of 13.6% (a 95% confidence interval of 5.9–24.6%). Conclusion: The incidence of poor metabolizer phenotypes for debrisoquine (CYP2D6) in South Pacific Polynesians appears to lower than in Caucasian populations, while the prevalence of poor metabolizers for proguanil (CYP2C19) in this ethnic population is higher. The frequencies of the poor metabolizer phenotype for debrisoquine and also for proguanil in South Pacific Polynesians are similar to those reported in Asian populations. Received: 18 December 1997 / Accepted in revised form: 30 April 1998     

Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects

AIMS: Short-term disulfiram administration has been shown to selectively inhibit CYP2E1 activity but the effects of chronic disulfiram administration on the activities of drug metabolizing enzymes is unclear. The purpose of this study was to evaluate the effects of disulfiram given for 11 days on selected drug metabolizing enzyme activities. METHODS: Seven healthy volunteers were given disulfiram 250 mg daily for 11 days. Activities of the drug metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, CYP2E1 and N-acetyltransferase were determined using the probe drugs caffeine, mephenytoin, debrisoquine, chlorzoxazone, and dapsone, respectively. Chlorzoxazone was administered before disulfiram administration and after the second and eleventh doses of disulfiram, while the other probe drugs were given before disulfiram administration and after the eleventh disulfiram dose. RESULTS: Disulfiram administration markedly inhibited chlorzoxazone 6-hydroxylation by more than 95%, but did not affect metabolism of debrisoquine or mephenytoin. Caffeine N3-demethylation was decreased by 34% (P < 0.05). Monoacetyldapsone concentrations were markedly elevated by disulfiram administration resulting in a nearly 16-fold increase in the dapsone acetylation index, calculated as the plasma concentration ratio of monoacetyldapsone to dapsone. CYP-mediated dapsone N-hydroxylation was not significantly altered. CONCLUSIONS: These data suggest that disulfiram-mediated inhibition is predominantly selective for CYP2E1. The magnitude of CYP2E1 inhibition was similar after both acute and chronic disulfiram administration. The effects on caffeine N3-demethylation (CYP1A2) and dapsone metabolism suggest that chronic disulfiram administration may affect multiple drug metabolizing enzymes, which could potentially complicate the use of chronically administered disulfiram as a diagnostic inhibitor of CYP2E1.     

Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers

AIMS: The study was carried out in order to assess the effects of gender and the use of oral contraceptives (OCs) on CYP2D6 and CYP2C19 activities in healthy volunteers. METHODS: Six hundred and eleven Caucasian volunteers (330 males and 281 females; age range 18-49 years) were phenotyped with respect to CYP2D6 and CYP2C19 by means of the probe drugs dextromethorphan and mephenytoin, respectively. Extensive metabolisers were selected for this study. RESULTS: The median dextromethorphan/dextrorphan metabolic ratio in non-OC using females was significantly lower than in males (0.067 vs 0.080; P = 0.033) (mean difference in ln dextromethorphan/dextrorphan metabolic ratio 0.023, 95% CI 0.03-0.43). For the mephenytoin S/R ratio, no such difference was observed. However, OC using females had a significantly higher median mephenytoin S/R ratio than non-OC using females (0.230 vs 0.090; P < 0.001) (mean difference in ln mephenytoin S/R ratio 0.082, 95% CI 0.60-1.04). Moreover, females using combined OCs had a significantly higher median ratio than females using OCs with progestins only (median 0.258 vs 0.135; P = 0.008) (mean difference in ln mephenytoin S/R ratio 0.82, 95% CI 0.21-1.34). CONCLUSIONS: Given certain assumptions, the study indicates that females in the fertile age have a slightly higher CYP2D6 activity compared with males. There was no evidence of a gender difference in CYP2C19 activity. The use of combined OCs reduces the activity of CYP2C19, an effect that seems to be related to the ethinyloestradiol component.