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      Contribution of Cytochrome P450 and ABCB1 Genetic Variability on Methadone Pharmacokinetics, Dose Requirements, and Response

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          Abstract

          Although the efficacy of methadone maintenance treatment (MMT) in opioid dependence disorder has been well established, the influence of methadone pharmacokinetics in dose requirement and clinical outcome remains controversial. The aim of this study is to analyze methadone dosage in responder and nonresponder patients considering pharmacogenetic and pharmacokinetic factors that may contribute to dosage adequacy. Opioid dependence patients (meeting Diagnostic and Statistical Manual of Mental Disorders, [4 th Edition] criteria) from a MMT community program were recruited. Patients were clinically assessed and blood samples were obtained to determine plasma concentrations of (R,S)-, (R) and (S)- methadone and to study allelic variants of genes encoding CYP3A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. Responders and nonresponders were defined by illicit opioid consumption detected in random urinalysis. The final sample consisted in 105 opioid dependent patients of Caucasian origin. Responder patients received higher doses of methadone and have been included into treatment for a longer period. No differences were found in terms of genotype frequencies between groups. Only CYP2D6 metabolizing phenotype differences were found in outcome status, methadone dose requirements, and plasma concentrations, being higher in the ultrarapid metabolizers. No other differences were found between phenotype and responder status, methadone dose requirements, neither in methadone plasma concentrations. Pharmacokinetic factors could explain some but not all differences in MMT outcome and methadone dose requirements.

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          Most cited references 68

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          Pharmacogenomics--drug disposition, drug targets, and side effects.

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            Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

            To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.
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              An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index.

              The Addiction Severity Index (ASI) is a structured clinical interview developed to fill the need for a reliable, valid, and standardized diagnostic and evaluative instrument in the field of alcohol and drug abuse. The ASI may be administered by a technician in 20 to 30 minutes producing 10-point problem severity ratings in each of six areas commonly affected by addiction. Analyses of these problem severity ratings on 524 male veteran alcoholics and drug addicts showed them to be highly reliable and valid. Correlational analyses using the severity ratings indicated considerable independence between the problem areas, suggesting that the treatment problems of patients are not necessarily related to the severity of their chemical abuse. Cluster analyses using these ratings revealed the presence of six subgroups having distinctly different patterns of treatment problems. The authors suggest the use of the ASI to match patients with treatments and to promote greater comparability of research findings.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                12 May 2011
                : 6
                : 5
                Affiliations
                [1 ]Institut de Neuropsiquiatria i Addiccions - Parc de Salut Mar, Barcelona, Spain
                [2 ]Universitat Pompeu Fabra (CEXS-UPF), Barcelona, Spain
                [3 ]Disorders by Use of Substances Research Group, Neuropsychopharmacology Research Program, Institut Municipal d'Investigació Mèdica (IMIM-Hospital del Mar Research Institute), Barcelona, Spain
                [4 ]Human Pharmacology and Clinical Neurosciences Research Group, Neuropsychopharmacology Research Program, Institut Municipal d'Investigació Mèdica (IMIM-Hospital del Mar Research Institute), Barcelona, Spain
                [5 ]CIBER de Fisiopatología de la Obesidad y Nutrición (CB06/03), Hospital Clínico Universitario Santiago de Compostela, Santiago de Compostela, Spain
                [6 ]Pharmacology Department, Autonomous University of Barcelona, Barcelona, Spain
                [7 ]Psychiatric Department, Autonomous University of Barcelona, Barcelona, Spain
                Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Germany
                Author notes

                Conceived and designed the experiments: RdT MF MT. Performed the experiments: FF LD AP NP EC OK. Analyzed the data: FF RdT AP EC NP OK. Contributed reagents/materials/analysis tools: AP EC NP OK. Wrote the paper: FF RdT EC NP OK MT. Subject inclusion and interviews: LD. Critical review of the manuscript: MF.

                Article
                PONE-D-10-05589
                10.1371/journal.pone.0019527
                3093392
                21589866
                Fonseca et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 10
                Categories
                Research Article
                Biology
                Biochemistry
                Blood Chemistry
                Metabolism
                Medicine
                Drugs and Devices
                Behavioral Pharmacology
                Drug Dependence
                Pharmacokinetics
                Drug Metabolism
                Pharmacogenetics
                Mental Health
                Psychiatry
                Substance Abuse
                Psychology
                Behavior

                Uncategorized

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