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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 -
Drug Metabolism and Pharmacokinetics 2010The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development.... (Review)
Review
The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.
Topics: Animals; Cytochrome P-450 Enzyme System; Debrisoquin; Government Regulation; Hepatocytes; Humans; Liver; Metabolic Detoxication, Phase I; Metabolic Detoxication, Phase II; Mice; Models, Animal; Pharmaceutical Preparations; Rats; Transplantation Chimera; Warfarin
PubMed: 20610881
DOI: 10.2133/dmpk.25.223 -
Journal of Pharmaceutical Sciences Oct 2010Drug-drug interactions (DDIs) are a great concern to the selection of new drug candidates. While in vitro screening assays for DDI are a routine procedure in preclinical...
Drug-drug interactions (DDIs) are a great concern to the selection of new drug candidates. While in vitro screening assays for DDI are a routine procedure in preclinical research, their interpretation and relevance for the in vivo situation still represent a major challenge. The objective of the present study was to develop a novel mechanistic modeling approach to quantitatively predict DDI solely based upon in vitro data. The overall strategy consisted of developing a model of the liver with physiological details on three subcompartments: the sinusoidal space, the space of Disse, and the cellular matrix. The substrate and inhibitor concentrations available to the metabolizing enzyme were modeled with respect to time and were used to relate the in vitro inhibition constant (K(i)) to the in vivo situation. The development of the liver model was supported by experimental studies in a stepwise fashion: (i) characterizing the interactions between the three selected drugs (R-bufuralol (BUF), bunitrolol (BUN), and debrisoquine (DBQ)) in microsomal incubations, (ii) modeling DDI based on binary mixtures model for all the possible pairs of interactions (BUF-BUN, BUF-DBQ, BUN-DBQ) describing a mutual competitive inhibition between the compounds, (iii) incorporating in the binary mixtures model the related constants determined in vitro for the inhibition, metabolism, transport, and partition coefficients of each compound, and (iv) validating the overall liver model for the prediction of the perfusate kinetics of each drug determined in isolated perfused rat liver (IPRL) for the single and paired compounds. Results from microsomal coincubations showed that competitive inhibition was the mechanism of interactions between all three compounds, as expected since those compounds are all substrates of rat CYP2D2. For each drug, the K(i) values estimated were similar to their K(m) values for CYP2D2 indicative of a competition for the same substrate-binding site. Comparison of the performance between the novel liver physiologically based pharmacokinetic (PBPK) model and published empirical models in simulating the perfusate concentration-time profile was based on the area under the curve (AUC) and the shape of the curve of the perfusate time course. The present liver PBPK model was able to quantitatively predict the metabolic interactions determined during the perfusions of mixtures of BUF-DBQ and BUN-DBQ. However, a lower degree of accuracy was obtained for the mixtures of BUF-BUN, potentially due to some interindividual variability in the relative proportion of CYP2D1 and CYP2D2 isoenzymes, both involved in BUF metabolism. Overall, in this metabolic interaction prediction exercise, the PBPK model clearly showed to be the best predictor of perfusate kinetics compared to more empirical models. The present study demonstrated the potential of the mechanistic liver model to enable predictions of metabolic DDI under in vivo condition solely from in vitro information.
Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Debrisoquin; Drug Interactions; Ethanolamines; In Vitro Techniques; Liver; Propanolamines; Rats
PubMed: 20310018
DOI: 10.1002/jps.22136 -
Journal of Toxicology and Environmental... 2009Cytochrome P-450 2D6 (CYP2D6) is involved in the metabolism of many therapeutic drugs even though the enzyme represents a small proportion of the total CYP content of... (Review)
Review
Cytochrome P-450 2D6 (CYP2D6) is involved in the metabolism of many therapeutic drugs even though the enzyme represents a small proportion of the total CYP content of human liver. In vivo phenotyping with probe drug substrates such as debrisoquine and dextromethorphan showed a clear separation between poor metabolizers (PM) and extensive metabolizers (EM). This polymorphism may affect susceptibility to environmental disease, as suggested by molecular epidemiologic studies that found an association between CYP2D6 metabolizer phenotype and cancer risk; however, this association is not consistent. There are only a few examples of CYP2D6 involvement in toxicant mechanism of action, but this has not been extensively studied. Gene probe studies documented a number of genetic polymorphisms that underlie CYP2D6 metabolizer phenotypes. The EM group carries the wild-type (*1) or active (*2) variant alleles, while the PM group carries the *3, *4, *5, or *6 alleles, all of which code for a protein that has lower or null CYP2D6 activity. The current analysis characterizes (a) influence of genotype on phenotype based upon in vivo metabolism studies of probe drugs and (b) frequency of the major genotypes in different population groups is also characterized. These data were then incorporated into Monte Carlo modeling to simulate population distributions of CYP2D6 activity. This analysis reproduced the bimodal distributions commonly seen in phenotyping studies of Caucasians and found extensive population variability in enzyme activity, as indicated by the 9- to 56-fold difference between the PM modal median and the total population median CYP2D6 activity. This substantial degree of interindividual variability in CYP function indicates that assessments involving CYP2D6 substrates need to consider the full distribution of enzyme activity in refining estimates of internal dose in health assessments of xenobiotics.
Topics: Cytochrome P-450 CYP2D6; Genetic Predisposition to Disease; Genetic Variation; Genetics, Population; Humans; Molecular Epidemiology; Monte Carlo Method; Pharmaceutical Preparations; Phenotype; Polymorphism, Genetic; Racial Groups
PubMed: 20183526
DOI: 10.1080/10937400903158342 -
Drugs 2009The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular... (Review)
Review
The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and conventional drugs. Literature searches were performed using MEDLINE, Cochrane Library and EMBASE and we identified 128 case reports or case series, and 80 clinical trials. Clinical trials indicate that St John's wort (Hypericum perforatum), via cytochrome P450 (CYP) and/or P-glycoprotein induction, reduces the plasma concentrations (and/or increases the clearance) of alprazolam, amitriptyline, atorvastatin, chlorzoxazone, ciclosporin, debrisoquine, digoxin, erythromycin, fexofenadine, gliclazide, imatinib, indinavir, irinotecan, ivabradine, mephenytoin, methadone, midazolam, nifedipine, omeprazole, oral contraceptives, quazepam, simvastatin, tacrolimus, talinolol, verapamil, voriconazole and warfarin. Case reports or case series suggest interactions of St John's wort with adrenergic vasopressors, anaesthetics, bupropion, buspirone, ciclosporin, eletriptan, loperamide, nefazodone, nevirapine, oral contraceptives, paroxetine, phenprocoumon, prednisone, sertraline, tacrolimus, theophylline, tibolone, tryptophan, venlafaxine and warfarin. Ginkgo (Ginkgo biloba) decreases the plasma concentrations of omeprazole, ritonavir and tolbutamide. Clinical cases indicate interactions of ginkgo with antiepileptics, aspirin (acetylsalicylic acid), diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin. Ginseng (Panax ginseng) may interact with phenelzine and warfarin. Kava (Piper methysticum) increases the clearance of chlorzoxazone (a CYP2E1 substrate) and may interact with alprazolam, levodopa and paroxetine. Garlic (Allium sativum) interacts with chlorpropamide, fluindione, ritonavir and warfarin; it also reduces plasma concentrations of chlorzoxazone (a CYP2E1 probe). Echinacea might affect the clearance of caffeine (a CYP1A2 probe) and midazolam (a CYP3A4 probe). No interactions have been reported for saw palmetto (Serenoa repens). Numerous interactions between herbal medicines and conventional drugs have been documented. While the significance of many interactions is uncertain, several interactions, particularly those with St John's wort, may have serious clinical consequences.
Topics: Clinical Trials as Topic; Cytochrome P-450 Enzyme System; Herb-Drug Interactions; Humans
PubMed: 19719333
DOI: 10.2165/11317010-000000000-00000 -
Expert Opinion on Drug Metabolism &... Nov 2009Rats are an important tool in pharmacology and toxicology. The authors focus on rat P450s in relation to diazepam metabolism. In particular, considerable attention is... (Review)
Review
Rats are an important tool in pharmacology and toxicology. The authors focus on rat P450s in relation to diazepam metabolism. In particular, considerable attention is devoted to the CYP2D subfamily, which is a group of highly polymorphic enzymes. First, the metabolic profiles of diazepam of humans and other animals are compared. In this review, the authors describe a novel genetic polymorphism of diazepam observed in commonly used rat strains and compare it to human genetic polymorphisms. The genetic basis underlying diazepam polymorphism in rats is also discussed. The authors conclude that the metabolic capacities and major metabolic pathways of diazepam are quite different among rat strains and in the Wistar strain due to CYP2D3 genetic polymorphism, which is independent of the debrisoquine polymorphism catalyzed by CYP2D2. The situation, in which major metabolites differ depending on animal strain, will be highly problematic not only in pharmacokinetic studies of test compounds, but also in pharmacological or toxicological tests. This may provide researchers who use experimental animals insights into important aspects of the genetic background of experimental animals. Thus, great caution must be taken in the choice of rat strains for studies of drug metabolism.
Topics: Animals; Cytochrome P-450 Enzyme System; Diazepam; Humans; Hydroxylation; Hypnotics and Sedatives; Polymorphism, Genetic; Rats; Species Specificity
PubMed: 19689220
DOI: 10.1517/17425250903207002 -
Environmental and Molecular Mutagenesis Jan 2010Polymorphic variations of several genes associated with dietary effects and exposure to environmental carcinogens may influence susceptibility to leukemia development....
Polymorphic variations of several genes associated with dietary effects and exposure to environmental carcinogens may influence susceptibility to leukemia development. The objective of the present study was to evaluate the effect of the polymorphisms of debrisoquine hydroxylase (CYP2D6), epoxide hydrolase (EPHX1), myeloperoxidase (MPO), and quinone-oxoreductase (NQO1), which have been implicated in xenobiotic metabolism, on the risk of childhood acute lymphoblastic leukemia (ALL). We evaluated the frequency of polymorphisms in the CYP2D6 (*3 and *4), EPHX1 (*2 and *3), MPO (*2), and NQO1 (*2) genes in 206 patients with childhood ALL and in 364 healthy individuals matched for age and gender from a Brazilian population separated by ethnicity (European ancestry and African ancestry), using the PCR-RFLP method. The CYP2D6 polymorphism variants were associated with an increased risk of ALL. The EPHX1, NQO1, and MPO variant genotypes were significantly associated with a reduced risk of childhood ALL. A significantly stronger protective effect is observed when the EPHX1, NQO1, and MPO variant genotypes are combined suggesting that, CYP2D6 polymorphisms may play a role in the susceptibility to pediatric ALL, whereas the EPHX1, NQO1, and MPO polymorphisms might have a protective function against leukemogenesis.
Topics: Adolescent; Brazil; Cytochrome P-450 CYP2D6; Epoxide Hydrolases; Female; Genetic Predisposition to Disease; Granulocyte Colony-Stimulating Factor; Humans; Infant; Interleukin-3; Male; NAD(P)H Dehydrogenase (Quinone); Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Fusion Proteins; Recombinant Proteins
PubMed: 19593802
DOI: 10.1002/em.20510 -
Pharmacogenomics Jan 2009Debrisoquine hydroxylation polymorphism is by far the most thoroughly studied genetic polymorphism of the CYP2D6 drug-metabolizing enzyme. Debrisoquine hydroxylation... (Review)
Review
Debrisoquine hydroxylation polymorphism is by far the most thoroughly studied genetic polymorphism of the CYP2D6 drug-metabolizing enzyme. Debrisoquine hydroxylation phenotype has been the most used test in humans to evaluate CYP2D6 activity. Two debrisoquine hydroxylation phenotypes have been described: poor and extensive metabolizers. A group with a very low debrisoquine metabolic ratio within the extensive metabolizers, named ultrarapid metabolizers, has also been distinguished. This CYP2D6 variability can be for a large part alternatively determined by genotyping, which appears to be of clinical importance given CYP2D6 involvement in the metabolism of a large number of commonly prescribed drugs. CYP2D6 pharmacogenetics may then become a useful tool to predict drug-related side effects, interactions or therapeutic failures. However, a number of reasons appear to have made research into this field lag behind. The present review focuses on the relevance of genetics and environmental factors for determining debrisoquine hydroxylation phenotype, as well as the relevance of CYP2D6 genetic polymorphism in psychiatric patients treated with antipsychotic drugs.
Topics: Antipsychotic Agents; Biomarkers; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Debrisoquin; Drug Monitoring; Humans; Hydroxylation; Mental Disorders; Pharmacogenetics; Polymorphism, Genetic
PubMed: 19102711
DOI: 10.2217/14622416.10.1.17 -
Lijecnicki Vjesnik 2002Cytochrome P450 enzyme debrisoquine 4-hydroxylase, responsible for the metabolism of different classes of drugs and other chemical substances, exhibits genetic...
Cytochrome P450 enzyme debrisoquine 4-hydroxylase, responsible for the metabolism of different classes of drugs and other chemical substances, exhibits genetic polymorphism with great interindividual and interethnic differences in metabolic capacity. The activity of enzyme ranges from very expressed, rapid, to total absence of activity. Up to 7% of Caucasians may demonstrate ultrarapid metabolism--UEM of debrisoquine and other drugs, substrates of debrisoquin hydroxylase, due to inheritance of multiplicate functional CYP2D6 gene, causing an increased amount of enzyme to be expressed. Identification of subjects with ultrarapid metabolism is of potential clinical value for optimization of therapy and avoidance of therapeutic failure due to inadequate dosage. In our study we wanted to determine the prevalence of UEM genotype in Croatian population applying long-PCR method. We found a 4% prevalence of ultrarapid metabolizers with multiplicated CYP2D6 gene.
Topics: Adult; Croatia; Cytochrome P-450 CYP2D6; Debrisoquin; Female; Gene Amplification; Genetics, Population; Genotype; Humans; Male; Pharmacogenetics; Polymerase Chain Reaction; Polymorphism, Genetic
PubMed: 18958918
DOI: No ID Found -
Journal of the American Society of... May 2009The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial... (Review)
Review
The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial role of sympathetic activation for both progression of renal failure and the high rate of cardiovascular events in patients with chronic kidney disease. The contribution of sympathetic neural mechanisms to the occurrence of cardiac arrhythmias, the development of hypertension, and the progression of heart failure are well established; however, the exact mechanisms contributing to heightened sympathetic tone in patients with chronic kidney disease are unclear. This review analyses potential mechanisms underlying sympathetic activation in chronic kidney disease, the range of adverse consequences associated with this activation, and potential therapeutic implications resulting from this relationship.
Topics: Animals; Cardiovascular Diseases; Catecholamines; Clonidine; Debrisoquin; Disease Models, Animal; Efferent Pathways; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Monoamine Oxidase; Nerve Fibers; Nitric Oxide; Norepinephrine; Sympathetic Nervous System
PubMed: 18799718
DOI: 10.1681/ASN.2008040402