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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 37 records · Page 2Linked to original sources
PubMed1998

Chloroquine modulation of specific metabolizing enzymes activities: investigation with selective five drug cocktail.

AIMS: The aim of this study was to investigate whether chloroquine can inhibit drug metabolism in humans, if such inhibition is general or selective for certain enzymes and evaluate the potential for and clinical significance of any drug-drug interactions when chloroquine is co-administered with other drugs. METHODS: The study was conducted in fourteen normal non-smoking healthy male volunteers using a cocktail of five drugs consisting of caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone to assess activities of cytochromes P450 (CYP) 1A2, 2C19, 2D6, 2E1 and 3A4 respectively. Dapsone was also used to assess N-acetyltransferase activity. The activities were assessed at baseline, after one and seven daily doses (250 mg daily) of chloroquine and 7 and 14 days after stopping chloroquine dosing. RESULTS: Chloroquine caused a progressive and significant decrease in CYP2D6 activity as measured by debrisoquine metabolism from first to seventh dose and the activity returned to baseline gradually over 14 days after stopping administration. There was no effect on the metabolism of any of the other probe drugs. CONCLUSIONS: Chloroquine has been shown to be capable of inhibiting the activity of CYP2D6 in vivo in humans. This effect is selective as activities of other enzymes investigated were not affected. The effect was modest but suggests a potential for drug-drug interactions when co-administered with other drugs that are substrates for this enzyme. The clinical significance of such an interaction will depend on the therapeutic index of any drug involved.

Adult↗
PubMed1998

The cytochrome P450 suicide inhibitor, 1-aminobenzotriazole, sensitizes rats to zymosan-induced toxicity.

Reduction in whole body cytochrome P450 (CYP 450) activity is evident in humans who develop trauma and sepsis-induced multiple organ failure (MOF). It is not known whether this has any deleterious or protective effect. Intraperitoneal injection of zymosan, the cell wall of Saccharomycoses A, induces dose-dependent inflammation with concomitant MOF in rats. High dose intraperitoneal zymosan (100 mg/100 g body weight) causes mortality and organomegaly in rats; low dose zymosan (20 mg/100 g body weight) does not. To study a role for CYP 450 in zymosan-induced toxicity, we examined the effect of the non-specific CYP 450 suicide inhibitor 1-aminobenzotriazole (1-ABT)(80 mg/kg/d), on rats treated with low dose zymosan. The 90% reduction in CYP 450 content achieved by this dose of 1-ABT was associated with 58% mortality in rats treated with low dose zymosan, in contrast to no mortality in rats treated with low dose zymosan alone (p < 0.01). In survivors, liver and lung organomegaly (p < 0.01), and polymorphonuclear leukocyte accumulation in the liver (p < 0.01) were increased after zymosan administration in rats treated with 1-ABT compared to those without 1-ABT. There was no effect of treatment with 1-ABT on the increased urinary excretion of nitric oxide byproducts observed after zymosan administration. These observations are consistent with the hypothesis that the CYP 450 enzyme system is an endogenous protectant in this experimental model of inflammation-induced MOF.

Animals↗
PubMed1997

Amphotericin B as an intracellular antioxidant: protection against 2,2'-azobis(2,4-dimethylvaleronitrile)-induced peroxidation of membrane phospholipids in rat aortic smooth muscle cells.

The antifungal activity of amphotericin B (AmB) and its side-effects (e.g. nephrotoxicity and hemolytic action) are suggested to be associated with its prooxidant effects in target cells. To test this hypothesis, we have undertaken studies to examine the role of AmB in oxidative stress in cultured rat aortic smooth muscle cells (SMC) incubated in the absence or in the presence of a lipid-soluble azo-initiator of peroxyl radicals, 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN). No changes in the pattern of membrane phospholipids could be detected by two-dimensional high performance thin-layer chromatography (HPTLC) after oxidative stress induced by AMVN in which the cells remained viable, as judged by trypan blue exclusion. To improve the sensitivity of detection of oxidative stress in the cells, cis-parinaric acid (PnA) was incorporated biosynthetically into the membrane phospholipids [using PnA-human serum albumin (hSA) complex]. Incubation of the cells under aerobic conditions in the presence of up to 10 microM AmB showed no significant change in the pattern of PnA-labeled phospholipids, suggesting that AmB was not affecting the oxidative state of the cells. In contrast, treatment with AMVN (0.5 mM, incubation in the dark for 2 hr at 37 degrees--conditions in which the viability of the cells was maintained) caused a significant reduction of all fluorescently labeled phospholipid fractions separated by HPLC. When PnA-labeled cells were subjected to oxidative stress by incubation with 0.5 mM AMVN in the presence of AmB, the loss of fluorescent phospholipids was reduced in a concentration-dependent manner over a concentration range of 0.25 to 10 microM. Thus, AmB does not produce any prooxidant effect but rather acts as an intracellular antioxidant.

Amphotericin B↗
PubMed1997

A phase II trial of all-trans-retinoic acid in hormone-refractory prostate cancer: a clinical trial with detailed pharmacokinetic analysis.

Retinoids have been shown to have substantial anticancer activity in a number of preclinical and clinical situations. There are considerable epidemiologic, in vitro and in vivo data which indicate that retinoids may have a role in the prevention and therapy of human prostate cancer. Based on anecdotal evidence of response in one patient with hormone-refractory prostate cancer (HRPC), we conducted a phase II trial in HRPC during which we also examined changes in pharmacokinetics of all-trans-retinoic acid (ATRA) which occurred during therapy. Enrolled in the study were 17 patients with HRPC who received 50 mg/m2 ATRA three times daily orally on days 1-14, repeated every 22 days. The pharmacokinetics of ATRA were assessed with the first dose on day 1, again on day 14 and after a 7-day interruption in ATRA therapy on day 22. Patients were evaluable for response if they completed two 14-day courses of ATRA; among 13 such patients no responses were seen. Four patients were considered unevaluable for response owing to rapid disease progression in three and intercurrent illness in one. Apparent clearance of ATRA changed substantially during therapy: day 1 3779 +/- 4215 ml/min, day 14 7179 +/- 3197 ml/min, day 22 3213 +/- 2357 ml/min. Area under the curve was proportionately diminished on day 14 compared with day 1 and had returned to baseline by day 22. We conclude that ATRA is not active in HRPC. Failure of this agent in HRPC may be related to failure of drug delivery associated with enhanced mechanisms of ATRA clearance which occur within a few days of beginning ATRA treatment.

Adult↗
PubMed1997

Mephenytoin disposition and serum bile acids as indices of hepatic function in chronic viral hepatitis.

BACKGROUND AND OBJECTIVES: The effect of chronic viral hepatitis on liver function may vary from none to hepatic failure. Changes in function are usually the result of impaired hepatocyte function or altered vascular flow and architecture. Conventional liver function tests usually cannot distinguish contributions from these mechanisms or indicate degree of hepatic metabolic dysfunction. An alternative approach is to measure the hepatic metabolism of a highly extracted compound whose oral clearance and systemic bioavailability are dependent on both hepatocyte function and degree of portosystemic shunt. METHODS: The stereoselective metabolism of racemic mephenytoin (100 mg oral dose) was investigated in 35 patients with chronic viral hepatitis and compared with 153 healthy subjects. The mephenytoin R/S enantiomeric ratio and cumulative excretion of the 4'-hydroxymephenytoin metabolite in a 0- to 8-hour urine sample were used in addition to serum bile acid levels and pathologic examination of biopsy specimens to assess the severity of hepatic dysfunction and portosystemic shunting. RESULTS: The patients as a group excreted less 4'-hydroxymephenytoin and had a smaller R/S enantiomeric ratio of mephenytoin. The two measures were discriminatory between the patient groups classified by either serum cholylglycine level or pathologic examination of biopsy specimens. Combination of the two measures of mephenytoin metabolism allowed the patients to be classified into three groups: normal hepatocyte function without portosystemic shunt, normal hepatocyte function with portosystemic shunt, and low hepatocyte function with or without portosystemic shunt. CONCLUSION: This study has shown the potential usefulness of mephenytoin metabolism as a sensitive indicator of hepatic pathologic condition with an ability to discriminate between contributory alternative mechanisms.

Adult↗
PubMed1997

Validation of the five-drug "Pittsburgh cocktail" approach for assessment of selective regulation of drug-metabolizing enzymes.

OBJECTIVES: To determine whether the probe drugs caffeine, chlorzoxazone, dapsone, debrisoquin (INN, debrisoquine), and mephenytoin can be simultaneously administered as a metabolic cocktail to estimate in vivo cytochrome P450 (CYP) and N-acetyltransferase enzyme activities. METHODS: Fourteen healthy nonsmoking male volunteers (mean age +/- SD, 21.6 +/- 2.2 years) received 100 mg caffeine, 250 mg chlorzoxazone, 100 mg dapsone, 10 mg debrisoquin, and 100 mg mephenytoin individually and in four and five-drug combinations in a randomized manner using a 7 x 7 Latin square. Each drug or drug combination was given orally after an overnight fast, with a minimum 1-week washout between administrations. In each session, urine was collected from 0 to 8 hours and plasma was obtained at 4 and 8 hours after drug administration. Plasma and metabolite concentrations were used to estimate phenotypic trait measures for the efficiency of each drug's metabolism. RESULTS: The phenotypic indexes determined for caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin were not significantly different when given alone than when given in combination. The median percentage change of the trait measures observed during administration of all five compounds compared with individual administration ranged from -10.7% for the 6-hydroxychlorzoxazone to chlorzoxazone plasma ratio to +2.2% for the debrisoquin recovery ratio. CONCLUSIONS: The results of this study show that caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin in low doses can be simultaneously administered without metabolic interaction. This cocktail approach can thus simultaneously provide independent in vivo phenotypic measures for multiple CYP enzymes and N-acetyltransferase.

Adult↗
PubMed1997

Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies.

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.

Amphotericin B↗
PubMed1997

Amphotericin B protects cis-parinaric acid against peroxyl radical-induced oxidation: amphotericin B as an antioxidant.

The antifungal effects of amphotericin B are believed to be due to two possibly interrelated mechanisms: an increase in permeation by binding to sterols in cellular membranes and a prooxidant effect causing oxidative damage in target cells. However, the seven conjugated double bonds in amphotericin B raise the possibility that it could be highly susceptible to autoxidation, causing an antioxidant effect. In the present study, we investigated the prooxidant and antioxidant properties of amphotericin B in a model system in which oxidation of a reporter molecule, cis-parinaric acid, was induced by azo initiators of peroxyl radicals. Since interactions of amphotericin B with sterols are essential for its pharmacological and toxic actions, we also studied the effects of cholesterol on the prooxidant and antioxidant properties of amphotericin B. Amphotericin B caused a noncollisional quenching of a characteristic fluorescence of cholesteryl cis-parinarate integrated in liposomes, suggesting the formation of amphotericin B-cholesteryl cis-parinarate complex. This effect of amphotericin B was ablated by increasing concentrations of cholesterol. We found that amphotericin B inhibited oxidation of cis-parinaric acid complexed with human serum albumin [using a water-soluble azo initiator, 2,2'-azobis(2aminopropane)dihydrochloride] and in liposomes [using a lipid-soluble azo initiator, 2,2'-azobis(2,4-dimethylvaleronitrile)]. The inhibitory effect of amphotericin B on 2,2'-azobis(2,4-dimethylvaleronitrile)-induced peroxidation of cis-parinaric acid in liposomes was also diminished by cholesterol. The antioxidant effect of amphotericin B in this model system suggests that amphotericin B does not exert its pharmacological and toxicological responses through a prooxidant effect to cause damage in target cells.

Amphotericin B↗
PubMed1996

Improved high-performance liquid chromatographic determination of debrisoquine and 4-hydroxydebrisoquine in human urine following direct injection.

A sensitive and specific reversed-phase high-performance liquid chromatographic assay was developed for the determination of debrisoquine and 4-hydroxydebrisoquine in urine. The urine samples were directly injected following an ether clean-up step which eliminated interference. Separation of the analytes was achieved using a mobile phase consisting of acetonitrile-methanol-0.02 M heptane sulfonic acid (pH 3.0) (6:37:57) and a mu Bondapak C18 analytical column. The assay utilizes fluorescence detection at 208 nm (ex) and 562 (em). The within-day and between-day coefficients of variation were < or = 10% for both components and accuracy was within 12%. The method is suitable of pharmacogenetic studies utilizing debrisoquine.

Calibration↗
PubMed1996

Adenosine does not mediate renal sodium retention and peripheral vasodilation elicited by partial portal vein ligation in rats.

This study was conducted to assess the role of adenosine in the peripheral vasodilation and sodium retention that occurs after partial portal vein ligation (PVL) in the rat. The experiment was performed on day 1 after surgery when transient maximal sodium retention developed and day 7 when rats returned to sodium balance. Hemodynamic studies were conducted under anesthesia in portal hypertensive rats with sodium retention and in sham-operated controls. Measurements were obtained before and after administration of a nonselective A1 and A2 adenosine receptor antagonist 1,3-dipropyl-8-p-sulfophenylxanthine (DPSPX) (10 mg/kg intravenously followed by 150 micrograms/min). Under baseline conditions, portal hypertensive rats with sodium retention were hypotensive, with decreases in total peripheral resistance and filtration fraction on day 1 in comparison with the control group. Although hyperdynamic circulation was still maintained by day 7, there was a return to sodium balance. The adenosine receptor antagonist had a modest vasoconstrictor effect on systemic and renal vasculature in both groups, but less in portal hypertensive rats. However, no change in glomerular filtration rate was observed. DPSPX induced a natriuresis in control rats (from 0.40 +/- 0.11 to 5.97 +/- 0.61 mEq/min on day 1, from 0.48 +/- 0.20 to 6.34 +/- 0.45 mEq/min on day 7). This response was attenuated in portal hypertensive rats on day 1 (from 0.14 +/- 0.04 to 1.67 +/- 0.57 mEq/min). but not on day 7 (from 0.20 +/- 0.06 to 5.11 +/- 0.55 mEq/min). These results suggest that in portal hypertensive rats (1) adenosine is not responsible for vasodilation and sodium retention, (2) a sodium-retaining factor acting directly on the renal tubule is responsible for sodium retention.

Adenosine↗
PubMed1996

Association of low CYP3A activity with p53 mutation and CYP2D6 activity with Rb mutation in human bladder cancer.

p53 and Rb gene mutations are intermediate biomarkers useful for the prediction of neoplastic progression in bladder cancers. Previously, we have shown that low CYP3A activity, measured by dapsone N-hydroxylation, and high CYP2D6 activity, assessed by debrisoquine 4-hydroxylation, were significant susceptibility risk factors in developing aggressive bladder cancer. However, no information is available about the relationship between drug/xenobiotic metabolizing enzyme activities and p53/Rb mutations that may suggest mechanisms of bladder carcinogenesis. We evaluated in vivo CYP3A activity by the dapsone recovery ratio (DPRR), CYP2D6 activity by the debrisoquine recovery ratio (DBRR), CYP2C19 activity by the mephenytoin R/S ratio (RSR), N-acetyltransferase activity by the monoacetyl dapsone to dapsone ratio and glutathione-S-transferase M1 (GSTM1) genotype by PCR. In immunohistochemical studies of bladder tumor tissue, over expression of p53 protein was detected with antibody pAb1801 and loss of Rb protein expression was evaluated with antibody PMG3-245 in patients with transitional cell carcinoma of the bladder. Low CYP3A activity was significantly associated with over expression of or mutated p53 protein (P < 0.05). High CYP2D6 activity (within the extensive metabolizer group) was significantly associated with loss of expression of or mutated Rb protein (P < 0.05). Positive p53 staining also predicted aggressive bladder cancer histopathology (P < 0.05, odds ratio 2.9), and the lowest tertile of DPRR predicted p53 positivity (P < 0.01, odds ratio 3.9 comparing means of lower tertile versus upper tertile of DPRR). These selective associations are consistent with the hypothesis that an environmental pro-carcinogen fails to be detoxified by CYP3A which may preferentially induce p53 mutations, whereas, an alternative pro-carcinogen that may be activated by CYP2D6, may selectively induce Rb mutations.

Aged↗
PubMed1996

Reduced liver function is the trigger for renal sodium retention following portal vein ligation in the rat.

Sodium retention along with peripheral vasodilation are features of prehepatic portal hypertension. In several models of experimental liver damage, sodium retention occurs only when hepatic function, measured by the aminopyrine breath test (ABT-k), falls below a critical threshold. The relationship between renal sodium handling, ABT-k and systemic and renal haemodynamics in partial portal vein ligated (PVL) rats was examined to test hypothesis that peripheral vasodilation was responsible for initiating sodium retention. Haemodynamic measurements were conducted early after surgery in portal hypertensive rats with and without sodium retention and in sham-operated controls. Compared with control, both PVL groups of rats had elevated portal pressure and lower peripheral vascular resistance (P < 0.05). Sodium retaining-PVL rats had both lower ABT-k (0.95 +/- 0.05 vs 1.38 +/- 0.06 x 10(-2)/min; P < 0.05) and higher sodium balance (1.38 +/- 0.09 vs 0.43 +/- 0.09 mmol/day; P < 0.05) than non-sodium retaining PVL rats. No differences in plasma renin activity or noradrenaline concentrations were observed. In a separate group of rats, hydralazine-induced pheripheral vasodilation did not induce sodium retention. These results suggest that the presence of peripheral vasodilation alone is not sufficient to trigger a sodium-retaining status. A factor, probably liver function-dependent, acting directly on renal tubules may be necessary for changes in renal sodium handling in this model.

Animals↗
PubMed1996

Metabolic interactions of putative cytochrome P4503A substrates with alternative pathways of dapsone metabolism in human liver microsomes.

The cytochrome P4503A (CYP3A) subfamily of enzymes are responsible for the metabolism of a large number of endogenous and exogenous compounds, and activation of some procarcinogens; but the activity is not well understood. N-Hydroxylation of dapsone in human liver microsomes has been shown to be mediated largely by CYP3A4. We have also observed the formation of an as yet unidentified metabolite of dapsone, whose formation is inhibited by antibody to CYP3A4, by these microsomes. This study investigated the influence of various (22) CYP3A putative substrates on the formation of both metabolites of dapsone in human liver microsomes. The compounds fall into four different categories on the basis of the pattern of their inhibitory interaction with the formation of both metabolites: those that inhibited both metabolites; those that inhibited N-hydroxylamine alone; those that inhibited the unidentified metabolite alone; and those with no significant effect on either metabolite. Some others were stimulatory. These results are consistent with two alternative but not mutually exclusive hypotheses: 1) different isoforms of CYP3A are involved in the formation of the alternative metabolites and the pattern of interaction observed was caused by the particular isoform(s) that each compound interacted with; or 2) formation of the alternative metabolites is a result of dapsone's interaction with and orientation at the enzyme's active site and the pattern of interaction observed is a consequence of changes in orientation caused by these compounds. This study provides relevant observations that must be considered in understanding mechanisms of CYP3A-mediated metabolism.

Catalysis↗
PubMed1996

CYP2D6 mRNA expression in circulating peripheral blood mononuclear cells correlates with in vivo debrisoquine hydroxylase activity in extensive metabolizers.

Extensive metabolizers of drugs which are oxidized by cytochrome P450s show wide interindividual variability in drug metabolism. Elucidation of the relationship between specific P450 isozyme mRNA expression and variability in metabolism of specific drugs could improve understanding of the molecular mechanism involved. In this study, a novel non-radiometric reverse transcription polymerase chain reaction based assay was used to quantify CYP2D6 mRNA levels in peripheral blood mononuclear cells in twelve human volunteers who were phenotyped as extensive metabolizers of debrisoquine. We report a significant correlation (r=0.724, p= 0.008) between CYP2D6 mRNA levels in circulating peripheral blood mononuclear cells and the in vivo debrisoquine recovery ratio. This suggests that interindividual variability in extensive metabolizers could be related, in part, to differences in gene expression. Circulating peripheral blood mononuclear cells can provide an accessible ex vivo measure of this phenomenon.

Actins↗
PubMed1996

Clonal analysis of human recurrent superficial bladder cancer by immunohistochemistry of P53 and retinoblastoma proteins.

PURPOSE: To investigate the clonal origin of malignant cells in recurrent superficial bladder cancer. MATERIALS AND METHODS: We compared the protein expression of p53 and retinoblastoma (Rb) by immunohistochemistry using antibody P1801 and PMG3-245, respectively, in 13 patients at the time of primary superficial bladder cancer resection (6 Ta and 7 T1) and their 15 corresponding recurrences of disease. Mutations in p53 and Rb were inferred on the basis of immunoperoxidase staining. RESULTS: At the time of initial tumor resection, a p53 mutation was observed in 5 patients (39%) and an Rb mutation was observed in 3 (23%). The p53/Rb mutation status of recurrent bladder cancers completely matched their corresponding primary bladder cancer. CONCLUSIONS: The chance that recurrent bladder cancer originated from independent clones in this study was extremely small (p < 10(-6)). This result strongly supports the monoclonal origin of recurrent superficial bladder cancer.

Carcinoma, Transitional Cell↗
PubMed1995

The influence of clinical study design on cost-effectiveness projections for the treatment of gram-negative sepsis with human anti-endotoxin antibody.

PURPOSE: This study was performed to compare the effect of entry criteria, patient population, and study design on outcome and projected cost-effectiveness of human anti-endotoxin antibody (HA-1A). MATERIALS AND METHODS: Patients with suspected or documented gram-negative bacteremia (GNB) with sepsis syndrome or shock received HA-1A during an open-label protocol. The patient characteristics and outcome measures of this series were compared with those of a placebo-controlled randomized clinical trial (RCT) of HA-1A. Both data sets were subjected to three published cost-effectiveness models of anti-endotoxin therapy, which were derived from RCT data. RESULTS: One hundred thirty-one patients (43 with gram-negative bacteremia) received HA-1A during a 19-month open-label protocol. Comparison with the RCT results demonstrated greater severity of illness and higher 28-day mortality in the open-label protocol. When projected for open-label recipients, HA-1A was considerably less cost-effective than in the original projections based on RCT-derived data. This reduction in cost-effectiveness was consistent across all three models and their respective sensitivity analyses. CONCLUSIONS: Extrapolating cost-effectiveness from RCT-derived analyses to open-label usage may yield widely inaccurate projections because of only small differences in patient population and the drug administration protocol.

Aged↗
PubMed1995

The procarcinogen hypothesis for bladder cancer: activities of individual drug metabolizing enzymes as risk factors.

Bladder cancer provides the most definitive example for an association between environmental agents and cancer. However, in the absence of industrial occupational exposure, the primary carcinogen is rarely identified, and the mechanisms involved in cancer formation are poorly understood. The environmental procarcinogen hypothesis of tumour pathogenesis proposes that many carcinogens require metabolic activation by drug metabolizing enzymes to form the proximate carcinogen. A balance of exposure to the carcinogen, the activity of the enzymes involved in either formation of proximate carcinogen, or production of non-toxic metabolites, will determine tumour risk. We have used mephenytoin, debrisoquine and dapsone as selective probes for the phenotypic measures of activity of CYP2C19, CYP2D6, and CYP3A4, respectively. Within subject reproducibility of phenotypic measures, and the lack of cross-inhibition when the three drugs are given in a concurrent cocktail, have been confirmed. We have applied the cocktail drug approach in two, non-overlapping series of cases with bladder cancer and matched controls. In both series, patients with aggressive bladder cancer (GIII histopathology) had a history of excess alcohol intake, an under-representation of poor metabolizers of debrisoquine, a significant mean reduction in dapsone recovery ratio, but no difference in mephenytoin phenotype. Collectively, these observations involving multiple routes of drug metabolism support the procarcinogen environmental hypothesis for bladder cancer and suggest that measurement of activity of selected individual drug metabolizing enzymes involved in the pathogenesis of this tumour can be used to identify subjects at high risk of developing bladder cancer.

Aryl Hydrocarbon Hydroxylases↗