N-acetylation polymorphism of dapsone in a Japanese population.

1. The N-acetylation of dapsone (DDS) was studied in 182 unrelated healthy Japanese subjects. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS, slow acetylators less than 0.30 and rapid acetylators greater than 0.35) at 3 h after an oral dose of DDS (100 mg) was 6.6% (12 of the 182 subjects) with a 95% confidence interval of 3.8 to 11.2%. 2. The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. However, the numbers of heterozygous (n = 105) and homozygous rapid acetylators (n = 65) derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 70, and n = 100) by applying the Hardy-Weinberg Law, when the suggested antimode of 0.85 discriminating these two rapid acetylators was employed. 3. The incidence of slow acetylators was unexpectedly lower in the males (1.4%, 1 of the 69 subjects, with a 95% confidence interval of 0.2 to 7.7%) compared with the incidence in the females (9.7%, 11 of the 113 subjects, with a 95% confidence interval of 5.5 to 16.6%). The difference reached a marginally significant level (Fisher's exact probability test, P = 0.02). 4. The mean plasma concentration of MADDS was significantly (P less than 0.001) lower in the slow compared to the rapid acetylators and there was a highly significant correlation (rs = 0.757, P less than 0.001) between plasma MADDS levels and MADDS/DDS ratios. 5. Slow acetylators showed a significantly (P less than 0.001) lower urinary MADDS/DDS ratio and excreted less (P less than 0.001) MADDS than rapid acetylators.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification and kinetic characterization of acetylator genotype-dependent and -independent arylamine carcinogen N-acetyltransferases in hamster bladder cytosol

Recent studies from our laboratory have shown relatively high levels of polymorphic N-acetyltransferase (NAT)(EC 2.3.1.5) activity toward carcinogenic arylamines in urinary bladder cytosol of humans and in the inbred hamster model of the N-acetylation polymorphism. The expression of this polymorphism is of interest because of the higher incidence of bladder cancer among human slow acetylators with documented exposures to arylamine bladder carcinogens. In this study, arylamine NAT activity was partially purified and characterized in inbred hamster urinary bladder cytosols of defined acetylator genotype. Acetylator gene-dose response relationships were observed for the N-acetylation of p-aminobenzoic acid, p-aminosalicyclic acid, and the arylamine carcinogens 2-aminofluorene, 4-aminobiphenyl, and beta-naphthylamine in hamster bladder cytosol. Partial purification of hamster bladder cytosol by anion-exchange fast protein liquid chromatography yielded two NAT isozymes that catalyzed the N-acetylation of each of the arylamine substrates. The catalytic activity of the first isozyme was acetylator genotype-dependent (polymorphic), whereas the second isozyme appeared to be acetylator genotype-independent (monomorphic). Catalytic activities between homozygous rapid, heterozygous, and homozygous slow acetylator genotypes were compared with respect to both initial rates and apparent maximum velocities. Comparison of homozygous rapid and slow acetylator bladder cytosol showed that the apparent Vmax for 2-aminofluorene NAT activity was significantly higher in rapid than slow acetylators (6-fold in cytosol, 50-fold in the polymorphic NAT isozyme). These results suggest a key role for a polymorphic NAT isozyme, regulated by the acetylator genotype and expressed in urinary bladder cytosol, in the initiation of bladder cancer via arylamine carcinogens.     

N-acetylation phenotyping using dapsone in a Jordanian population.

1. The N-acetylation of dapsone (DDS) was studied in 160 unrelated healthy Jordanian volunteers. 2. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS), was 67.5% with a 95% confidence interval of 59 to 76%. Slow acetylators had an acetylation ratio of less than 0.42. 3. Applying the Hardy-Weinberg Law, the frequency of the recessive allele controlling slow acetylation was found to be 0.82 +/- 0.02. 4. The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. The number of homozygous (n = 16) and heterozygous (n = 36) rapid acetylators derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 5 and n = 47) according to the Hardy-Weinberg Law. The suggested antimode used to discriminate the two groups was 0.82. 5. The mean plasma concentration of MADDS and the mean plasma acetylation ratio were about three times lower in slow than in rapid acetylators. However, there was no difference in mean plasma DDS concentration between slow and rapid acetylators. 6. There was a significant correlation (r = 0.853, P less than 0.001) between plasma MADDS concentration and the acetylation ratio. For DDS such a correlation was absent (r = 0.059, P = 0.23).     

Thalidomide-induced neuropathy and genetic differences in drug metabolism

A pharmacogenetic predisposition to thalidomide-induced neuropathy has been investigated. Differences of drug metabolism were examined in 16 patients with severe orogenital ulceration, who were treated with thalidomide (200 mg/day) for 0.3–5.0 years. Eight had evidence of early peripheral neuropathy according to nerve conduction studies. Rates of C-hydroxylation, N-acetylation, and conjugation reactions with sulphate, glucuronide and glycine, were tested with the probe compounds debrisoquine, sulphadimidine, paracetamol and aspirin, respectively. Urinary drug metabolites were analysed by high pressure liquid chromatography. Results were compared with 16 healthy age- and sex-matched volunteers.Of the patients 6.25% and 13.3% of the controls had a poor Debrisoquine Hydroxylator Ratio (DMR); none of the patients with neuropathy had a poor DMR as compared to 12.5% without neuropathy. Of the patients 40.0% and 35.7% of the controls were slow acetylators; 28.6% with neuropathy were slow acetylators as opposed to 50% without neuropathy. Similarly, there were no significant differences in rates of conjugation between groups. All unaffected patients were active smokers, whereas only two of those with neuropathy smoked. Cumulative dose or duration of therapy were unrelated to risk of neuropathy.In conclusion, changes of nerve conductivity are a frequent and unpredictable adverse effect of thalidomide (200 mg/day), although smoking may have a protective action against their development. Nerve conduction studies are required before and during treatment, irrespective of the prescribed dose.     

N-acetylation and debrisoquine hydroxylation polymorphisms in patients with Gilbert's syndrome.

1. N-acetylation and debrisoquine hydroxylation phenotypes were determined in 54 patients with Gilbert's syndrome and in 247 (sulphamethazine) and 76 (debrisoquine) non-related healthy volunteers. 2. Forty (74.1%) of the patients and 135 (54.7%) of the healthy volunteers were slow acetylators (chi 2 = 6.87). In the patients, the cumulative urinary excretion of sulphamethazine up to 6 h (Ae(0,6)) was significantly lower. No differences in the frequency of debrisoquine poor metabolizers were observed: Gilbert's syndrome 5/54 (9.3%), healthy volunteers 5/76 (6.6%). The metabolic ratios were similar in both groups as well as the urinary recoveries of debrisoquine and its 4-hydroxy metabolite. 3. Gilbert's syndrome seems to be related in some way to N-acetylation but not to the debrisoquine hydroxylation polymorphism.     

N-acetylation phenotyping with dapsone in a mainland Chinese population.

1 The N-acetylation of dapsone (DDS) was studied in 108 unrelated Chinese subjects residing in the mainland of China. 2 The frequency of slow acetylators determined using the plasma monoacetyldapsone to DDS ratio (MADDS/DDS, slow acetylators less than 0.30 and rapid acetylators greater than 0.35) at 3 h after an oral dose of DDS (100 mg) was 13.0% (14 of the 108 subjects) with a 95% confidence interval of 7.9 to 20.6%. 3 The mean plasma concentration of MADDS was about three times lower in the slow than in the rapid acetylators and there was a highly significant correlation (rs = 0.886, P less than 0.001) between plasma MADDS concentration and acetylation ratio. 4 Urinary acetylation ratios (MADDS/DDS) and cumulative urinary excretion of MADDS were significantly (P less than 0.001) lower in slow acetylators compared with rapid acetylators. In addition, there was a significant relationship (rs = 0.510 to 0.718, P less than 0.001) between plasma and urinary acetylation ratios. However, the distribution of the urinary acetylation ratio was not bimodal. 5 The urinary acetylation ratio after an oral dose of DDS is not a discriminative index for determining acetylation phenotype.     

Correlations among the metabolic ratios of three test probes (metoprolol, debrisoquine and sparteine) for genetically determined oxidation polymorphism in a Japanese population

The study was aimed at defining the relationships among the oxidative capacities for three prototype drugs, metoprolol, debrisoquine and sparteine, used for assessing genetically determined polymorphism of drug oxidation in a Japanese population. Among 292 unrelated healthy Japanese subjects who had been defined as extensive (EMs, n = 291) or poor (PM, n = 1) metabolisers of metoprolol oxidation, 55 subjects (EMs = 54 and PM = 1) were selected. One PM of metoprolol oxidation was also identified as a PM not only of debrisoquine but also of sparteine, and no misclassification by the three phenotypic methods was observed. All three correlations among the metabolic ratios of the three test probes assessed by Spearman's rank test were highly significant (P less than 0.001). These findings indicate that in Japanese subjects the oxidation capacities of metoprolol, debrisoquine, and sparteine are closely related. It appears that in Japanese the polymorphic oxidation of the three drugs is co-regulated, either by the same enzyme or gene-controlling system.     

Pharmacokinetics of hydralazine and its acid-labile hydrazone metabolites in relation to acetylator phenotype

The pharmacokinetics of hydralazine (H) and its acid-labile hydrazone metabolites were compared in rapid and slow acetylators. Following a 20-mg intravenous infusion, the elimination half-life (t_1/2) and the apparent volume of distribution of H did not differ between the two groups. Plasma clearance estimates approached hepatic blood flow. When a single 100-mg dose of H was given-orally, the area under the plasma concentration-time curve (AUC) and systemic availability () in slow acetylators were, on the average, twice as high as in the rapid acetylators, indicating a difference in the extent of first-pass metabolism of the drug. Furthermore, the observed in the slow individuals exceeded theoretical predictions. Hence saturation of first-pass metabolism of H is suggested, and a nonlinear relationship between AUC and oral dose of H was indeed observed in the three subjects studied with two doses. The half-life of decline of the acidlabile metabolites was similar to the t_1/2 of H. The AUCs for metabolites were 4–12 times larger than for the parentdrug. However, the ratio between the metabolite AUC and drug AUC did not differ irrespective ofroutes of administration or the acetylator status.This study was supported in part by Grant RR 828 from United States Public Health Service and a Research Starter grant from the Pharmaceutical Manufacturers Association Foundation, Inc. (D. D. S.).     

Influence of acetylator phenotype on the pharmacokinetics of a new vasodilator antihypertensive,endralazine

Summary Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30±1.08 h for the 5 mg dose and 4.25±1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC ₀ ) was 18.2% lower (p<0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p>0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC ₀ of the acetylation metabolite (methyltriazoloendralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p<0.01).     

Should the acetylator phenotype be determined when prescribing hydralazine for hypertension?

Summary The role of acetylator phenotype in determining the response to hydralazine when it was added to diuretic and -blocker at doses not exceeding 200 mg daily was examined in 57 hypertensive patients. 81% of rapid acetylators needed 200 mg hydralazine daily compared to 38% of slow acetylators (p<0.01). Despite higher doses of hydralazine the blood pressure was controlled in only 27% of rapid acetylators compared to 65% of slow acetylators (p<0.02). The relation of acetylator phenotype to blood pressure response was statistically independent of initial blood pressure, age, sex, body weight and serum creatinine (p<0.005). Current recommendations on hydralazine dosage are unsatisfactory for the 40% of hypertensive patients who are rapid acetylators. We suggest measurement of the acetylator phenotype in patients who respond incompletely to 200 mg hydralazine daily. About 70% of these patients will be rapid acetylators in whom the dose of hydralazine can be increased safely.     

Polymorphic CYP2C19 and N-acetylation: human variability in kinetics and pathway-related uncertainty factors.

CYP2C19-mediated oxidation and N-acetylation constitute major phase I and phase II polymorphic pathways of xenobiotic metabolism in humans. Analysis of human variability in kinetics for these pathways has been carried out for compounds metabolised extensively (>60%) by these routes. Data for minor substrates for CYP2C19 metabolism (10-60%) have also been analysed. Published pharmacokinetic studies (after oral and intravenous dosing) in CYP2C19 non-phenotyped healthy adults (NPs), and phenotyped extensive (EMs), slow-extensive (SEMs) and poor metabolisers (PMs) have been analysed using data for parameters that relate primarily to chronic exposure (metabolic and total clearances, area under the plasma concentration-time curve) and primarily to acute exposure (peak concentration). Similar analyses were performed for the N-acetylation pathway using data for fast acetylators (FA) and slow acetylators (SA). Interindividual variability in the kinetics of CYP2C19 substrates after oral dosage was greater in EMs than in NPs (60 vs 43% for clearances and 54 vs 45% for Cmax). Lower variability was found for N-acetylation for both phenotypes (32 and 22% for FA and SA, respectively). The internal dose of CYP2C19 substrates in PM subjects would be 31-fold higher than in EMs, while for N-acetylated substrates there was a three-fold difference between SA and FA subjects. Pathway-related uncertainty factors were above the default safety factor of 3.16 for most subgroups and values of 52 and 5.2 would be necessary to cover to the 99th centile of the poor metaboliser phenotype for CYP2C19 and N-acetylation, respectively. An exponential relationship (R(2)=0.86) was found between the extent of CYP2C19 metabolism and the difference in internal dose between EMs and PMs. The kinetic default factor (3.16) would cover PMs for substrates for which CYP2C19 was responsible for up to 20-30% of the metabolism in EMs.     

Correlation between N-acetyltransferase activities in uroepithelia and in vivo acetylator phenotype.

The relationship between in vivo acetylator phenotype of individuals and N-acetyltransferase (NAT) activity in the cytosol of their cultured uroepithelia was examined in four urology patients. In vivo acetylator phenotypes were assigned by determining the ratio of N-acetyl vs. total [N-acetyl+free] sulfamethazine in urine and blood following a single oral dose (1 gm) of sulfamethazine. From the same patients, a surgical specimen of the ureter was obtained, uroepithelial cells were cultured in vitro, and the cytosols prepared. NAT activities were determined by measuring the amount of 4-acetylaminobiphenyl formed from incubation of uroepithelial cytosol with the substrate, 4-aminobiphenyl, and the cofactor [14C]acetyl coenzyme A. The two individuals phenotyped as "slow acetylators" by the in vivo method had NAT activities of 8.3 and 16.2 pmol 4-acetylaminobiphenyl/mg protein/min. In contrast, the two individuals phenotyped as "rapid acetylators" showed activities of 50.9 and 109.5 pmol 4-acetylaminobiphenyl/mg protein/min. The rapid acetylators exhibit about 6-fold greater uroepithelial NAT activities than slow acetylators, thus showing a direct correlation between the NAT activity in the uroepithelium, the target tissue of the human bladder carcinogen 4-aminobiphenyl, and the in vivo acetylator phenotype. These results imply that susceptibility of individuals to arylamine-induced bladder cancer might be associated with NAT activities in their target cells and that in vivo acetylator phenotyping could serve as a useful and relevant biochemical screening marker to assess the risk of developing bladder cancer.     

Acetylator phenotyping: the effect of ethanol on the dapsone test

In twelve healthy drug-free subjects (six slow acetylators), administration of alcohol (to achieve an ethanol concentration between 650 and 1180 mg 1(-1) ) did not significantly affect the ratio of monoacetyl dapsone (MADS) to dapsone (DDS) 3 h after oral dapsone (100 mg). We conclude that moderate acute ethanol consumption is unlikely to alter the acetylator phenotype measured by the dapsone test.     

The effect of acetylator phenotype on the disposition of aminoglutethimide.

Aminoglutethimide (AG) 500 mg was administered orally to four normal volunteers and eight patients undergoing treatment for metastatic breast cancer. In each subject the acetylator phenotype was established from the monoacetyldapsone (MADDS)/dapsone (DDS) ratio. Acetylaminoglutethimide (acetylAG) rapidly appeared in the plasma and its disposition paralleled that of AG. A close relationship (P less than 0.01) was observed between the acetyl AG/AG and MADDS/DDS ratio suggesting that AG may undergo polymorphic acetylation like DDS. AG half-life was 19.5 +/- 7.7 h in seven fast acetylators of DDS and 12.6 +/- 2.3 h in five slow acetylators and its apparent metabolic clearance was significantly (P less than 0.01) related to the acetylAG/AG ratio. Over 48 h the fast acetylators excreted 7.7 +/- 4.4% of the administered AG dose in the urine as unchanged AG as compared to 12.4 +/- 2.8% in slow acetylators. A much smaller fraction of the dose was excreted as acetylAG: 3.6 +/- 1.5% by fast and 1.9 +/- 1.0% by slow acetylators respectively. After 7 days treatment with AG at an accepted clinical dose regimen to the eight patients there were significant reductions in the half-lives of AG (P less than 0.01) and acetylAG (P less than 0.01) and a trend (0.1 greater than P greater than 0.05) towards reduction of the acetylAG/AG ratio which became significant (P less than 0.05) if the one patient on a known enzyme inducer was omitted. The mean apparent volume of distribution was not significantly (P greater than 0.1) altered but the mean apparent systemic clearance of AG was increased (P less than 0.05). These changes are attributed to auto-induction of oxidative enzymes involved in AG metabolism.     

N-acetyltransferase polymorphism in patients with Behçet's disease

OBJECTIVES: The objective of our study was to investigate the possible role of human arylamine N-acetyltransferase 2 (NAT2) polymorphism in susceptibility to Beh?et's disease. METHODS: Eighty-five patients with Beh?et's disease gave their written informed consent to participate in the study. Seven point mutations (G191A, C282T, T341C, C481T, A803G, G590A, G857A) in the NAT2 gene were analysed using polymerase chain reaction/restriction fragment length polymorphism techniques. In addition, each patient received 100 mg dapsone orally to determine their NAT2 phenotype. Dapsone and its metabolite monoacetyl-dapsone were measured in 3-h plasma samples using high-performance liquid chromatography. Subjects with an acetylation ratio (monoacetyl-dapsone/dapsone) less than 0.4 were defined as slow acetylators. RESULTS: Of 85 patients with Beh?et's disease, 54 (63.5%) were identified as genotypically slow acetylators. However, 60% (51 of 85) of patients were diagnosed as slow acetylators according to monoacetyl-dapsone/dapsone ratio. Thus, a low incidence of genotype/phenotype discrepancy (3.5%) was observed in Turkish patients with Behcet's disease. When we compared our results with previous phenotyping and genotyping studies in the Turkish population, frequencies of slow and rapid acetylators were not statistically different in patients with Beh?et's disease. The frequency of the *5B allele was found to be slightly higher in patients with Beh?et's disease than historic controls (44.7 vs 35.6%, P = 0.039). However, there was no significant difference in the frequency of the overall genotypes and alleles of NAT2 between patients and controls. CONCLUSION: Although the frequency of the NAT2*5B allele, responsible for slow acetylation, was slightly higher in patients than historic controls, our results failed to show an association between NAT2-acetylator status and risk for developing Beh?et's disease.     

Influence of the N-acetylation polymorphism on the metabolism of talampanel: an investigation in fasted and fed subjects genotyped for NAT2 variants

Talampanel is a 2,3-benzodiazepine-type allosteric (noncompetitive) AMPA-antagonist currently being developed as an orally active, broad-spectrum anticonvulsant. Here, a detailed study of its N-acetylation in humans is presented using plasma concentration data of both TLP and its N-acetyl metabolite obtained from healthy volunteers (n = 28) genotyped for N-acetyltansferase NAT2 isozymes. Plasma samples were obtained for up to 48 h after a single oral dose of 75 mg TLP both in fasted and in fed subjects. A perfect correspondence could be established between the phenotype inferred before the study from genotyping and that determined after the study by using plasma metabolite-to-parent molar ratios confirming that this route of metabolism is indeed mediated by NAT2. Analysis of the data has been performed using both noncompartmental analysis and a custom-built, unified parent-metabolite PK model, which incorporates three different acetylation rates according to the genotype-based classification of each subject as slow, intermediate, or fast acetylator to simultaneously fit plasma levels for both TLP and its metabolite. This suggest that for TLP in humans, (i) N-acetylation represents only a relatively small fraction of its total elimination (about one-fourth in fast acetylators and much less in slow acetylators), (ii) acetylation is about eight-twelve times faster in fast and three-six times faster in intermediate acetylators than in slow acetylators, and (iii) the N-acetyl metabolite is eliminated faster than the parent TLP.     

N-Acetylation and hydroxylation polymorphisms in type II diabetics with microvascular disturbances

The N-acetylation and hydroxylation (CYP2D6) genetic polymorphisms were assessed in 43 healthy subjects and in 84 type II (non-insulin-dependent) diabetics. The proportions of slow and fast acetylators as well as poor and extensive metabolisers in a group of diabetics suffering from microvascular disturbances (nephropathy, retinopathy and neuropathy) were compared with the ocntrol group and with diabetics without such ocmplications. Sulphadimidine was used as a probe for polymorphic acetylation and debrisoqine for CYP2D6. Debrisoquine and its 4-OH metabolite were assayed by means of HPLC, and sulphadimidine using a modified Bratton-Marshall proceedure. The frequency of the slow phenotype (63%) was significantly higher in diabetics with microvascular disturbances than in patiens without diabetic complica tions (P < 0.005). In patients with type II diabetes (84), only the extensive phenotype of hydroxylation was observed. Received: 18 March 1996 / Accepted in revised form: 11 July 1996     

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

Objective

This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis.

Methods

In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week.

Results

One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen.

Conclusion

Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.     

The ability to 4-hydroxylate debrisoquine is related to recurrence of bladder cancer.

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)     

Metoprolol oxidation polymorphism in a Korean population: comparison with native Japanese and Chinese populations.

We examined metoprolol oxidation capacity in 218 unrelated, healthy Korean subjects using the 8 h urinary metabolic ratio (MR) of metoprolol to alpha-hydroxymetoprolol after an oral dose of 100 mg metoprolol tartrate. The results were compared with those from 295 Japanese and 107 mainland Chinese whose metoprolol oxidation capacities were assessed in a similar manner. The frequency of occurrence of poor metabolisers (PMs) was 0.5% (1/218) in the Korean, 0.7% (2/295) in the Japanese and 0% in the Chinese population. However, the respective mean (+/- s.d.) MRs (0.84 +/- 1.14 and 0.87 +/- 0.90) in the Korean and Japanese extensive metabolisers (EMs) were significantly (P less than 0.001) less than that in the Chinese EMs (2.81 +/- 2.35), and the mode of the distribution histogram and the probit plot of data for Chinese EMs were shifted to the right compared with those for Korean and Japanese EMs. The results indicate that Koreans, like Japanese and mainland Chinese, have a much lower frequency of the PM phenotype of debrisoquine/sparteine-type oxidation compared with that reported for Caucasian populations. Chinese EMs appear to have a lower capacity to metabolise metoprolol to alpha-hydroxymetoprolol compared with Korean or Japanese EMs.