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Therapeutic Advances in Urology Jul 2017The objective of this study was to examine the inhibitory potential of darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride...
BACKGROUND
The objective of this study was to examine the inhibitory potential of darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium chloride on the seven major human cytochrome P450 enzymes (CYP) by using a standardized and validated seven-in-one cytochrome P450 cocktail inhibition assay.
METHODS
An cocktail of seven highly selective probe substrates was incubated with human liver microsomes and varying concentrations of the seven test compounds. The major metabolites of the probe substrates were simultaneously analysed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Enzyme kinetics were estimated by determining IC and values nonlinear regression. Obtained values were used for predictions of potential clinical impact of the inhibition using a static mechanistic prediction model.
RESULTS
In this study, 49 IC experiments were conducted. In six cases, IC values lower than the calculated threshold for drug-drug interactions (DDIs) in the gut wall were observed. In these cases, no increase in inhibition was determined after a 30 min preincubation. Considering a typical dosing regimen and applying the obtained values of 0.72 µM (darifenacin, 15 mg daily) and 7.2 µM [propiverine, 30 mg daily, immediate release (IR)] for the inhibition of CYP2D6 yielded a predicted 1.9-fold and 1.4-fold increase in the area under the curve (AUC) of debrisoquine (CYP2D6 substrate), respectively. Due to the inhibition of the particular intestinal CYP3A4, the obtained values of 14 µM of propiverine (30 mg daily, IR) resulted in a predicted doubling of the AUC for midazolam (CYP3A4 substrate).
CONCLUSIONS
/ extrapolation based on pharmacokinetic data and the conducted screening experiments yielded similar effects of darifenacin on CYP2D6 and propiverine on CYP3A4 as obtained in separately conducted DDI studies. As a novel finding, propiverine was identified to potentially inhibit CYP2D6 at clinically occurring concentrations.
PubMed: 28747995
DOI: 10.1177/1756287217708951 -
BMJ (Clinical Research Ed.) Jul 1988Patients with well defined reactions to foods were examined for their ability to carry out both sulphur and carbon oxidation reactions by using carbocisteine and... (Clinical Trial)
Clinical Trial
Patients with well defined reactions to foods were examined for their ability to carry out both sulphur and carbon oxidation reactions by using carbocisteine and debrisoquine as probe compounds. The proportion of poor sulphoxidisers (58 of 74) was significantly greater than that of a previously determined normal control population (67 of 200; p less than 0.005). The proportion of poor carbon oxidisers was not significantly different from the controls. Metabolic defects may play a part in the pathogenesis of adverse reactions to foods.
Topics: Adult; Aged; Carbocysteine; Carbon; Debrisoquin; Female; Food Hypersensitivity; Humans; Male; Middle Aged; Sulfur
PubMed: 3408928
DOI: 10.1136/bmj.297.6641.105 -
Environmental Health Perspectives Oct 1993Genetic polymorphisms of drug-metabolizing enzymes, principally CYP2D6 (debrisoquine 4-hydroxylase), have long been considered influential on host responsiveness to... (Review)
Review
Genetic polymorphisms of drug-metabolizing enzymes, principally CYP2D6 (debrisoquine 4-hydroxylase), have long been considered influential on host responsiveness to environmental carcinogens. In several independent studies, lung cancer cases are more frequently associated with the extensive metabolizer phenotype of CYP2D6. However, assignment of phenotype has traditionally involved administration of debrisoquine and analysis of drug and metabolite concentrations in patient urine and is thus potentially confounded by concomitant drug therapy and the presence of the tumor itself. The development of molecular genotyping methods offers unique opportunities to obviate these problems and to ascertain the relationship between the presence of individual alleles and disease risk. Preliminary data are presented that indicate that the CYP2D6 wild-type allele may be a predisposing factor in lung cancer.
Topics: DNA, Neoplasm; Genotype; Humans; Neoplasms; Phenotype; Polymerase Chain Reaction; Risk Factors
PubMed: 8143602
DOI: 10.1289/ehp.93101s3117 -
British Journal of Clinical Pharmacology Aug 1997To investigate the kinetics of the (+)RS- and (-)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers. (Clinical Trial)
Clinical Trial
AIMS
To investigate the kinetics of the (+)RS- and (-)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers.
METHODS
Ten subjects of which three were poor metabolizers of debrisoquine received racemic MQ 250 mg once weekly for 16 weeks. The kinetics were followed in plasma and urine and evaluated by individual kinetic modelling as well as by a nonparametric population kinetic method.
RESULTS
A two-compartment model adequately described the disposition of (+)RS-MQ. CL/F was 6.5 +/- 1.8 l h(-1), V(ss)/F 815 +/- 165 l, and k 0.0081 +/- 0.0023 h(-1). The kinetics of (-)SR-MQ were time- and/or concentration dependent with a lower oral clearance (0.92 +/- 0.25 vs 2.14 +/- 0.63 l h(-1), 95% CI for the difference 0.86-1.60 l h(-1)) and a longer half-life (345 vs 185 h, 95% CI for the difference 47-291 h) after the last dose compared with the first dose. Clearance of (+)RS-MQ and (-)SR-MQ was significantly correlated within subjects (r = 0.69, P < 0.05). Urinary recovery of unchanged substance was 8.7% for (+)RS-MQ and 12.3% for (-)SR-MQ. The elimination of MMQ was disposition rate-limited and not determined by its rate of formation. Poor metabolizers of debrisoquine did not differ from extensive metabolizers in the kinetics of any compound.
CONCLUSIONS
The MQ enantiomers differ extensively in their disposition both with regard to parameter values and the kinetic stability over time during repeated dosing with racemic MQ. Kinetic modelling of racemic MQ is therefore inadequate.
Topics: Adult; Antimalarials; Female; Half-Life; Humans; Kidney; Male; Mefloquine; Middle Aged; Models, Chemical; Reference Values; Stereoisomerism
PubMed: 9278194
DOI: 10.1046/j.1365-2125.1997.00633.x -
Drug Metabolism and Pharmacokinetics 2010Cytochrome P450 2D6 (CYP2D6) is an enzyme with a large interindividual variability in its metabolic activity due to genetic polymorphisms. In the present study, both its...
Cytochrome P450 2D6 (CYP2D6) is an enzyme with a large interindividual variability in its metabolic activity due to genetic polymorphisms. In the present study, both its intrinsic metabolic activity (CL(int,CYP2D6,app)) relative to extensive metabolizers (EM) and its variability were estimated by analyzing the urinary metabolic ratios (MR) based on the well-stirred model. Sparteine and debrisoquine were considered to be appropriate probes for our methodology, whereas dextromethorphan was not appropriate since the formation of its metabolite of interest is not described by the well-stirred model. From the analysis of MRs of sparteine and debrisoquine for Caucasian subjects in the literature, CL(int,CYP2D6,app) for intermediate metabolizers (IM) was estimated to be approximately 15% of that for EM. The coefficient of variability (CV) of CL(int,CYP2D6,app) was estimated to be approximately 60% for both EM and IM and 100% for the combined population of ultrarapid metabolizer, EM and IM [i.e., the non-poor metabolizer (non-PM) population]. Simulation of exposure in the non-PM population showed that the CV of exposure was 140% for dextromethorphan and 71% for metoprolol, which reflected the reported values of 110% and 53% for dextromethorphan and metoprolol, respectively. The present study should be useful for predicting the interindividual variability in exposure to investigational drugs that are metabolized by CYP2D6.
Topics: Cytochrome P-450 CYP2D6; Dextromethorphan; Humans; Metabolic Clearance Rate; Models, Biological; Monte Carlo Method; Pharmaceutical Preparations; Phenotype; Sparteine; Urine
PubMed: 20610883
DOI: 10.2133/dmpk.25.243 -
British Journal of Clinical Pharmacology Oct 1996Studies were performed in eight healthy extensive metabolizers of mephenytoin and debrisoquine to determine the effect of fluvoxamine on the activities of S-mephenytoin...
Studies were performed in eight healthy extensive metabolizers of mephenytoin and debrisoquine to determine the effect of fluvoxamine on the activities of S-mephenytoin 4'-hydroxylase (CYP2C19) and metoprolol alpha-hydroxylase (CYP2D6). Therapeutic dosing with fluvoxamine (100 mg day-1) for 2 weeks caused a significant increase in the 0-8 h urinary S/R ratio of mephenytoin from 0.16 to 0.55 (95% confidence interval for difference between means: 0.28-0.50; P < 0.01), accompanied by a 54% reduction in the 0-8 h urinary recovery of 4'-hydroxymephenytoin (95% confidence interval for difference between means: 3.64-16.24 mg; P < 0.05). However, this did not alter the assigned phenotype of any of the subjects based on the established antimode of 0.95 (S/R-mephenytoin ratio). Two weeks after fluvoxamine was discontinued, both metabolic indices returned to their pre-study values. By contrast, fluvoxamine had no effect on either 0-8 h urinary metoprolol/alpha-hydroxymetoprolol ratio (95% confidence interval for difference between means: -0.38-0.46; P > 0.05) or the 0-8 h urinary recovery of alpha-hydroxymetoprolol (95% confidence interval for difference between means: -0.61-0.70 mg; P > 0.05). These results indicated fluvoxamine has a modest inhibitory effect on the activity of CYP2C19, but no effect on that of CYP2D6 in vivo.
Topics: Adult; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors; Fluvoxamine; Humans; Male; Mephenytoin; Metoprolol; Mixed Function Oxygenases; Reference Values
PubMed: 8904628
DOI: 10.1046/j.1365-2125.1996.45319.x -
British Journal of Clinical Pharmacology May 19821 A method for the assay of debrisoquine 4-hydroxylase activity in vitro by microsomal fractions of human liver is described. The assay utilises gas chromatography-mass...
1 A method for the assay of debrisoquine 4-hydroxylase activity in vitro by microsomal fractions of human liver is described. The assay utilises gas chromatography-mass spectrometry with d9-4-hydroxydebrisoquine as internal standard. 2 The limit of detection of 4-hydroxydebrisoquine was 2 ng ml -1 and the coefficient of variation was 4.4%. 3 Debrisoquine 4-hydroxylase activity was linear with protein to concentrations above 2.1 mg ml -1 and with incubation times of at least 15 min. 4 Debrisoquine 4-hydroxylase is a microsomal enzyme with a requirement for NADPH. Activity was inhibited by carbon monoxide. It is concluded that the activity is catalysed by cytochrome P-450. 5 In three samples of human liver the mean value for Vmax of debrisoquine 4-hydroxylase activity was 69.9 +/- 14.3 pmol mg -1 min -1 and for Km it was 130 +/- 24 microM. 6 The only variable from smoking status, alcohol ingestion, sex of the patients, source of liver sample and presence of liver disease that had a significant effect on 4-hydroxylation of debrisoquine was the presence of liver disease. This was associated with a decrease in enzyme activity.
Topics: Cytochrome P-450 CYP2D6; Debrisoquin; Humans; Kinetics; Microsomes, Liver; Mixed Function Oxygenases
PubMed: 7082530
DOI: 10.1111/j.1365-2125.1982.tb01430.x -
British Medical Journal Mar 1975A cross-over trail of debrisoquine and guanethidine in 32 patients showed that both drugs were equally effective in lowering both systolic and diastolic blood pressure.... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A cross-over trail of debrisoquine and guanethidine in 32 patients showed that both drugs were equally effective in lowering both systolic and diastolic blood pressure. The degree to which they were tolerated by the patients, however, differed greatly. After three months on each drug 18 patients preferred debrisoquine, nine preferred guanethidine, and five showed no particular preference. At current prices the cost of daily treatment to the patient was cheaper with debrisoquine than with guanethidine.
Topics: Administration, Oral; Adult; Body Weight; Chronic Disease; Debrisoquin; Economics, Medical; Ejaculation; Female; Guanethidine; Humans; Hypertension; Isoquinolines; Libido; Male; Middle Aged; Surveys and Questionnaires; Time Factors
PubMed: 1125586
DOI: 10.1136/bmj.1.5956.482 -
The Journal of Biological Chemistry May 2012Purification and Characterization of the Human Liver Cytochromes P-450 Involved in Debrisoquine 4-Hydroxylation and Phenacetin -Deethylation, Two Prototypes for Genetic...
Purification and Characterization of the Human Liver Cytochromes P-450 Involved in Debrisoquine 4-Hydroxylation and Phenacetin -Deethylation, Two Prototypes for Genetic Polymorphism in Oxidative Drug Metabolism (Distlerath, L. M., Reilly, P. E. B., Martin, M. V., Davis, G. G., Wilkinson, G. R., and Guengerich, F. P. (1985) 260, 9057–9067) Human Liver Microsomal Cytochrome P-450 Mephenytoin 4-Hydroxylase, a Prototype of Genetic Polymorphism in Oxidative Drug Metabolism. Purification and Characterization of Two Similar Forms Involved in the Reaction (Shimada, T., Misono, K. S., and Guengerich, F. P. (1986) 261, 909–921) Characterization of Rat and Human Liver Microsomal Cytochrome P-450 Forms Involved in Nifedipine Oxidation, a Prototype for Genetic Polymorphism in Oxidative Drug Metabolism (Guengerich, F. P., Martin, M. V., Beaune, P. H., Kremers, P., Wolff, T., and Waxman, D. J. (1986) 261, 5051–5060)
Topics: Cytochrome P-450 Enzyme System; Drug Industry; History, 20th Century; History, 21st Century; Humans; Isoenzymes; Microsomes, Liver; Pharmaceutical Preparations; United States
PubMed: 22563099
DOI: 10.1074/jbc.O112.000003 -
British Journal of Clinical Pharmacology Sep 1997To evaluate the use of different graphical methods and statistical tests in the detection of interindividual and interethnic variations in codeine metabolism. Various... (Comparative Study)
Comparative Study
AIMS
To evaluate the use of different graphical methods and statistical tests in the detection of interindividual and interethnic variations in codeine metabolism. Various urinary metabolic ratios (MR) for codeine O-demethylation were also compared for their ability to determine phenotype.
METHODS
Frequency histograms, normal test variable (NTV) plots and admixture analysis were used to examine the distributions of the urinary MRs for codeine O-demethylation, N-demethylation and glucuronidation in 132 Caucasian and 222 Chinese subjects.
RESULTS
In the Caucasian population, apparent bimodality was shown in both a frequency histogram and NTV plot of the log MR of codeine O-demethylation (codeine/(morphine (M) + M-3 and M-6-glucuronide (M3G and M6G) + normorphine (NM)). Admixture analysis confirmed the co-segregation of codeine O-demethylation and debrisoquine hydroxylation. The antimode for the codeine O-demethylation MR between extensive and poor metabolisers was located between 5.5 and 8.3. A simplified MR for codeine O-demethylation (codeine/M3G) demonstrated a similar correlation with the debrisoquine MR to the more complex MR, allowing a simplification of the analytical method for phenotyping. The Chinese population had significantly higher median MRs for codeine N-demethylation, O-demethylation and glucuronidation, which was shown clearly in the frequency histograms, but not in the NTV plots.
CONCLUSION
A histogram seems preferable over a NTV plot for assigning phenotype using the codeine O-demethylation MR, because it is clear and simple. Interethnic difference in the metabolism of codeine are also better visualised from the histograms.
Topics: Adult; Asian People; China; Codeine; Drug Monitoring; Humans; Oxidoreductases, N-Demethylating; Oxidoreductases, O-Demethylating; Phenotype; Statistics as Topic; Sweden; White People
PubMed: 9296317
DOI: 10.1046/j.1365-2125.1997.t01-1-00571.x