Functional Impact of ABCB1 Variants on Interactions between P-Glycoprotein and Methadone

Hung, Chin‐Chuan; Chiou, Mu-Han; Teng, Yu‐Ning; Hsieh, Ying‐Hen; Huang, Chieh-Liang; Lane, Hsien‐Yuan

doi:10.1371/journal.pone.0059419

Cited by 38 publications

(34 citation statements)

References 48 publications

(65 reference statements)

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“…There was no significant difference among the mRNA and protein expression levels of wild type ABCB1 and the two variant types as showed in our previous studies [16], [17]. After 72 hours treatment of 5 µg/mL EEAC, the ABCB1 mRNA and protein expression remained unchanged in wild type ABCB1 and the two variant types (Fig.…”

Section: Resultssupporting

confidence: 58%

The Functional Influences of Common ABCB1 Genetic Variants on the Inhibition of P-glycoprotein by Antrodia cinnamomea Extracts

et al. 2014

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Antrodia cinnamomea is a traditional healthy food that has been demonstrated to possess anti-inflammatory, antioxidative, and anticacer effects. The purpose of this study was to evaluate whether the ethanolic extract of A. cinnamomea (EEAC) can affect the efflux function of P-glycoprotein (P-gp) and the effect of ABCB1 genetic variants on the interaction between EEAC and P-gp. To investigate the mechanism of this interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established and the expression of P-gp was confirmed by Western blot. The results of the rhodamine 123 efflux assay demonstrated that EEAC efficiently inhibited wild-type P-gp function at an IC50 concentration of 1.51±0.08 µg/mL through non-competitive inhibition. The IC50 concentrations for variant-type 1236T-2677T-3435T P-gp and variant-type 1236T-2677A-3435T P-gp were 5.56±0.49 µg/mL and 3.33±0.67 µg/mL, respectively. In addition, the inhibition kinetics of EEAC also changed to uncompetitive inhibition in variant-type 1236T-2677A-3435T P-gp. The ATPase assay revealed that EEAC was an ATPase stimulator and was capable of reducing verapamil-induced ATPase levels. These results indicate that EEAC may be a potent P-gp inhibitor and higher dosages may be required in subjects carrying variant-types P-gp. Further studies are required to translate this basic knowledge into clinical applications.

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Section: Resultssupporting

confidence: 58%

The Functional Influences of Common ABCB1 Genetic Variants on the Inhibition of P-glycoprotein by Antrodia cinnamomea Extracts

et al. 2014

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“…A more recent in vitro study utilizing cells stably transfected with various genotypes of ABCB1 (P-gp) found that methadone most potently inhibited wild-type P-gp (IC 50 =2.17 μM), while the genotypes 1236T-2677T-3435T (IC 50 = 2.97 μM) and 1236T-2677A-3435T (IC 50 =4.43 μM) exhibited much less inhibition. The study also confirmed that methadone stimulated P-gp ATPase activity and inhibited verapamil (145).…”

Section: Methadonesupporting

confidence: 72%

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

et al. 2015

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Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

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“…However, recent research suggests that the large inter-individual variability in methadone dose may be influenced by an interactions between ABCB1 polymorphisms and p-glycoproteins [53]. Most recent investigations into this area are limited by the lack of available clinical populations; further evidence is required to examine this interaction.…”

Section: Discussionmentioning

confidence: 99%

Impact of ABCB1 and CYP2B6 Genetic Polymorphisms on Methadone Metabolism, Dose and Treatment Response in Patients with Opioid Addiction: A Systematic Review and Meta-Analysis

et al. 2014

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BackgroundGenetic variability may influence methadone metabolism, dose requirements, and risk of relapse.ObjectivesTo determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment).MethodsTwo independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms.ResultsWe screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05–1.00, p = 0.03) with minimal heterogeneity (I2 = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27–2.61, p = 0.02) however significant heterogeneity was observed (I2 = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response.ConclusionAlthough the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.

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Functional Impact of ABCB1 Variants on Interactions between P-Glycoprotein and Methadone

Cited by 38 publications

References 48 publications

The Functional Influences of Common ABCB1 Genetic Variants on the Inhibition of P-glycoprotein by Antrodia cinnamomea Extracts

The Functional Influences of Common ABCB1 Genetic Variants on the Inhibition of P-glycoprotein by Antrodia cinnamomea Extracts

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

Impact of ABCB1 and CYP2B6 Genetic Polymorphisms on Methadone Metabolism, Dose and Treatment Response in Patients with Opioid Addiction: A Systematic Review and Meta-Analysis

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