Role of human <i>MDR1</i> gene polymorphism in bioavailability and interaction of digoxin, a substrate of P‐glycoprotein

Kurata, Yasuo; Ieiri, Ichiro; Kimura, Miyuki; Morita, Toshihiro; Irie, Shin; Urae, Akinori; Ohdo, Shigehiro; Ohtani, Hisakazu; Sawada, Yasufumi; Higuchi, Shun; Otsubo, Kenji

doi:10.1067/mcp.2002.126177

Cited by 250 publications

(165 citation statements)

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“…The 1236C>T and 2677G>T/A/C polymorphisms have also been linked to several diseases such as pharmacoresistant epilepsy and Parkinsons disease [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Studies on these polymorphisms have yielded contradictory results, possibly due to small sample sizes and the isolated nature of the study populations.…”

Section: Discussionmentioning

confidence: 99%

Ethnicity-related polymorphisms and haplotypes in the humanABCB1gene

et al. 2007

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Introduction-The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related.

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Section: Discussionmentioning

confidence: 99%

Ethnicity-related polymorphisms and haplotypes in the humanABCB1gene

et al. 2007

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“…27 Haplotype analysis has revealed equally inconsistent results, with the G2677/T3435 haplotype being associated ABCB1 genotype and therapeutic drug response GD Leschziner et al with a higher AUC, 37 no association with transport or efflux in LLC-PK1 transfected cells, 29 and an association between homozygosity for the G2677/C3435 haplotype and decreased C max , decreased oral bioavailability and increased renal clearance. 41 …”

Section: Digoxinmentioning

confidence: 99%

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

et al. 2006

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The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

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“…Additional studies involving larger samples sizes and stratification according to haplotype are required for a complete understanding of the contribution of genetic variability in ABCB1 and related proteins to drug disposition, www.TheOncologist.com therapeutic response, and toxicity [21,39]. To reduce the risk of a spurious association between MDR1 genotypes and in vivo phenotypes, demographic data of subjects selected for the various MDR1 SNPs as well as sample size and environmental factors should also be considered carefully.…”

Section: Impact Of Genetic Polymorphism In the Abcb1 Gene On Functionmentioning

confidence: 99%

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

et al. 2007

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Key Words. P-glycoprotein • Drug interaction • Complementary and alternative medicine • CAM • Pharmacokinetics Pharmacodynamics LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Identify important sources of variability in drug exposure caused by drug interactions mediated by P-glycoprotein.2. Describe how unwanted drug-drug interactions may lead to unexpected serious toxicity or undertreatment.3. Prevent these interactions by individualizing pharmacotherapy; this means selecting noninteracting drugs or adapting the dose of (the) interacting drug(s).Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTThe importance of P-glycoprotein (P-gp) in drug-drug interactions is increasingly being identified. P-gp has been reported to affect the pharmacokinetics of numerous structurally and pharmacologically diverse substrate drugs. Furthermore, genetic variability in the multidrug resistance 1 gene influences absorption and tissue distribution of drugs transported. Inhibition or induction of P-gp by coadministered drugs or food as well as herbal constituents may result in pharmacokinetic interactions leading to unexpected toxicities or undertreatment. On the other hand, modulation of P-gp expression and/or activity may be a useful strategy to improve the pharmacological profile of anticancer P-gp substrate drugs. In recent years, the use of complementary and alternative medicine (CAM), like herbs, food, and vitamins, by cancer patients has increased significantly. CAM use substantially increases the risk for interactions with anticancer drugs, especially because of the narrow therapeutic window of these compounds. However, for most CAMs, it is unknown whether they affect metabolizing enzymes and/or drug transporter activity. Clinically relevant interactions are reported between St John's wort or grapefruit juice and anticancer as well as nonanticancer drugs. CAM-drug interactions could explain, at least in part, the large interindividual variation in efficacy and toxicity associated with drug therapy in both cancer and noncancer patients.

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Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P‐glycoprotein

Abstract: The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P-glycoprotein-mediated drug interaction

Cited by 250 publications

References 42 publications

Ethnicity-related polymorphisms and haplotypes in the humanABCB1gene

Ethnicity-related polymorphisms and haplotypes in the humanABCB1gene

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

Concise Review: Clinical Relevance of Drug–Drug and Herb–Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein)

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