Pgp acts as a protective barrier to keep toxic substances out of the body and prevent the accumulation of drugs in sensitive organs. Numerous polymorphisms are reported in drug metabolizing enzymes, transporters and effector systems. The mdr1 2677ga genotype may also play a role in risperidone pharmacokinetics. Mdr1 gene or abcb1 gene or pgp gene and c3435t polymorphism and digoxin which resulted in retrieval of a total of articles in english. The effect of mdr1 c3435t single nucleotide polymorphism snp in exon 26 on digoxin pharmacokinetics has recently been challenged. Further studies are needed to explore the impact of mdr1 2677ga and cyp3a5 polymorphisms on risperidone therapy. However, some mdr1 gene polymorphisms described in human beings have been related with drug pharmacokinetics alteration and also with increased susceptibility to diseases such as parkinsons disease, inflammatory bowel disease, multidrug resistant epilepsy, and renal carcinoma mealey, 2004. Mdr1 gene encodes for p glycoprotein pgp, which plays an important role. Polymorphisms of multidrug resistance gene mdr1 and.
Recent clinical studies suggest the importance of the mdr1 genotype at position 3435 c3435t in terms of pharmacokinetics, but there is still no consensus in reports on the relationship between the genotype and plasmaserum concentrationtime profiles of drugs after conventional oral administration. Mar, 2007 digoxin is a wellknown probe for the activity of pglycoprotein. Role of human mdr1 gene polymorphism in bioavailability. The objective of this work was to apply different methods for covariate selection in nonlinear mixedeffect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the multidrugresistance 1 mdr1 gene coding for pglycoprotein. Studies revealing conflicting results of the functional significance of mdr1 exon 26 c3435t snp on the disposition of digoxin in different ethnic groups led us to perform a metaanalysis on published data investigating the influence of c3435t snp on the pharmacokinetics of digoxin and the expression of mdr1. Objective the atpbinding cassette b1 abcb1 gene encodes pglycoprotein, a transport protein, which plays an important role in the bioavailability of digoxin. Genetic polymorphisms can cause pharmacokinetic variability which may also be responsible for the observed suboptimal response. Abcb1 gene variants, digoxin and risk of sudden cardiac death. An individualized dosage regimen design incorporating such information may improve the efficacy of the drug whilst reducing adverse reactions. Romain bricca, sylvain goutelle, sandrine roux, marieclaude gagnieu, agathe becker, anne conrad, florent valour, frederic laurent, claire triffaultfillit, christian chidiac, tristan ferry, genetic polymorphisms of abcb1 pglycoprotein as a covariate influencing daptomycin pharmacokinetics.
Effect of the c3435t genetic polymorphism in mdr1 on. Mdr1 singlenucleotide polymorphisms snps are involved in the pharmacokinetics of many drugs. Role of human mdr1 gene polymorphism in bioavailability and. To investigate the relationship between c3435t snp and digoxin pharmacokinetics, the following keywords were used.
Each was given a single oral dose of 500 mg azithromycin. Jul 01, 2014 understanding the clinical pharmacokinetics of digoxin will help us to improve in the dosage regimens design and therapeutics drugs monitoring. Three single nucleotide polymorphisms snps in the coding region c3435t, c1236t and g2677ta are the most widely studied snps in mdr1 and have been related to substrate. Metaanalysis of the influence of mdr1 c3435t polymorphism.
Paraquat is a fatal herbicide following acute exposure. They also indicated that a polymorphism in exon 26 at position 3435 c3435t, a silent mutation, affected the expression level of mdr1 protein in duodenum, and thereby the intestinal absorption of digoxin. Likedigoxin,theh 1receptorantagonist fexofenadine, which is used for treatment of seasonal. By its positive inotropic effect, digoxin increases the cardiac muscular force of contraction. Additionally, given its role in the disposition of other chemicals, the abcb1 gene. An integrated pharmacokineticpharmacogenomic analysis of. According to earlier data, homozygous tt of the exon 26 complementary deoxyribonucleic acid cdna 3435ct polymorphism was associated with low p. We investigated the effect of polymorphisms in the pglycoprotein pgp mdr1 gene on steadystate pharmacokinetics of digoxin in caucasians. Jun 21, 2001 the polymorphisms g 2677 t and g 2995 a lead in exon 21 and 24, respectively, and change the protein but do not affect expression levels of mdr1. Heart failure, gene polymorphism, pharmacokinetics, adrenergic antagonists, reninangiotensin system.
With regard to the variability, polymorphisms of the mdr1 gene have recently been reported to be associated with alterations in disposition kinetics and interaction profiles of clinically useful drugs, including digoxin, fexofenadine, ciclosporin and talinolol. According to earlier data, homozygous tt of the exon 26 complementary deoxyribonucleic acid cdna 3435ct polymorphism was associated with low pgp expression in the human intestine. In the present study, we identified genetic polymorphisms in the 5. Given the gaps in knowledge regarding the impact of abcb1 genetics and pgpmediated drugdrug interactions on sitagliptin disposition, the objectives of our study were to. Genotyping may prove an essential tool for individualized treatment by optimizing the drug dosage for an individuals genetic variability. Influence of abcb1 gene polymorphisms on the pharmacokinetics. Functional significance of genetic polymorphisms in pglycoprotein mdr1, abcb1 and breast cancer resistance protein bcrp, abcg2. Results the pharmacokinetics of indinavir were best described by a one. Crohn disease cd and ulcerative colitis uc are overlapping chronic inflammatory bowel diseases ibds. Neither the polymorphisms at exon 26 c3435t and at exon 21 g2677at in mdr1 nor the cyp3a51 allele significantly affected the total body clearance of paclitaxel. Effects of genetic polymorphisms of cyp3a4, cyp3a5 and mdr1 on cyclosporine pharmacokinetics after renal transplantation yong. Pharmacogenomics of heart failure focus on drug disposition. Introduction incorrect dosage of digoxin occurs frequently and is due in most cases to relative over or under dosage 9. Introduction the abc transporter genes represent the largest family of transmembrane proteins.
Functional implications of genetic polymorphisms in the multidrug. Mdr1 gene polymorphism and phenytoin pharmacokinetics in epilepsy adel ali alhazzani, md murali munisamy, phd gauthaman karunakaran, phd background. Significant genetic linkage of mdr1 polymorphisms at positions 3435 and 2677. Pdf modelling the influence of mdr1 polymorphism on digoxin.
Absence of the mdr1a pglycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin. The aim of the present study was to evaluate the effects of abcb1 gene polymorphism and pgp inhibitor coadministration on steadystate digoxin serum concentration in congestive heart failure. Whether this polymorphism is also associated with altered pharmacokinetics of other pglycoprotein substrates has notbeenstudied. To clarify the relationships between mdr1 genetic polymorphisms in exon 26 c3435t and 21 g2677ta and digoxin pharmacokinetics.
View full article html enhanced article html get pdf 146k get pdf 146k. Suggestive evidence for linkage at chromosome 7q has been reported for both cd and uc. Pdf genetic polymorphisms in mdr1, cyp3a4 and cyp3a5. At the same time, digoxin has a negative chronotropic effect that decreases heart rate by its influence on the cardiac electrical conduction pathway. Taken together, we have for the first time demonstrated that polymorphisms of the abcb1 gene may have a considerable impact on the pharmacokinetics of azithromycin among healthy chinese han ethnic subjects. Methods within the rotterdam study, a populationbased cohort study in persons 45 years of age and. Metaanalysis of the influence of mdr1 c3435t polymorphism on. Influence of abcb1 and abcg2 polymorphisms on doxorubicin. Genetic polymorphisms in mdr1, cyp3a4 and cyp3a5 genes.
The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups n 5 each on the basis of genotyping for. Read digoxin pharmacokinetics and mdr1 genetic polymorphisms, european journal of clinical pharmacology on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Snp does not affect the pharmacokinetics of digoxin and the expression of mdr1 mrna. A prospective analysis, clinical therapeutics on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. May 22, 2007 the genetic heterogeneity of cyp3a and mdr1 genes has recently become a major concern as a potential cause of variability in drug disposition 15, 16. A cardiac glycoside extracted from the foxglove plant, digitalis lanata, it is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation, but the margin between toxic and therapeutic doses is small. The host and the parasite do have mdr1 and cyp3a genes and some workers have postulated that parasite mdr1 gene may be contributing towards drug inefficacy 28. Mdr1 genotyperelated duodenal absorption rate of digoxin.
Results grapefruit juice had no significant effect on the maximum plasma drug concentration c max of digoxin or the area under the plasma concentration. Clinical pharmacokinetics of digitoxin university of arizona. A plausible explanation for altered metabolism of ivermectin in humans. Absence of association between mdr1 genetic polymorphisms, i. Mdr1 gene polymorphism and phenytoin pharmacokinetics in epilepsy. The objective of this study is to apply machine learning techniques to predict the appropriateness of initial digoxin dosage. Pharmacogenomics of heart failure focus on drug disposition and. Genetic influences on the pharmacokinetics of orally and intravenously administered digoxin as exhibited by monozygotic twins. We modelled the pharmacokinetics of digoxin using nonlinear.
The multidrug resistant mdr1 gene, which encodes a pglycoprotein pgp adenosine triphosphate atpdependent drug efflux pump, influences drug pharmacokinetics by extruding csa out of the gut wall into the intestinal lumen thereby limiting csa bioavailability. Genetic polymorphisms of the cyp3a4, cyp3a5, and mdr. Minimal effect of mdr1 and cyp3a5 genetic polymorphisms on the pharmacokinetics of indinavir in hivinfected patients caroline solas, 1, 3 nicolas simon, 1 mariepierre drogoul, 2 sylvie quaranta, 3 veronique frixonmarin, 2 veronique bourgarelrey, 3 corinne brunet, 4 jeanalbert gastaut, 2 alain durand, 1 bruno lacarelle, 1, 3 and. Read modelling the influence of mdr1 polymorphism on digoxin pharmacokinetic parameters, european journal of clinical pharmacology on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Read abcb1 c3435t genetic polymorphism on population pharmacokinetics of methotrexate after hematopoietic stem cell transplantation in korean patients. Functional relevance to pharmacokinetics of digoxin. View the article pdf and any associated supplements and. Role of snp and digoxin response in atrial fibrillation. Also, genetic variability in the mdr1 gene affects absorption and tissue distribution of p. Pharmacogenomics and pharmacogenetics studies have revealed that genetic polymorphisms of mdr1 are. Absence of association between mdr1 genetic polymorphisms, indinavir pharmacokinetics and response to highly active antiretroviral therapy. Mdr1 gene polymorphisms and disposition of the pglycoprotein. Studies revealing conflicting results of the functional significance of mdr1 exon 26 c3435t snp on the disposition of digoxin in different ethnic groups led us to perform a meta. Variation in the expression of the abcb1 mdr1 gene is likely to be an important source of interindividual variability in pharmacokinetics and pharmacodynamics of many drugs 1, 2.
Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by abcb1 genetic polymorphism, those. Metaanalysis of the influence of mdr1 c3435t polymorphism on digoxin pharmacokinetics and mdr1 gene expression article in british journal of clinical pharmacology 602. Polymorphisms in the abc drug transporter gene mdr1 nature. Mdr1 gene encodes for p glycoprotein pgp, which plays an important role in bioavailability and celltoxicity limitation of a wide range of drugs and xenobiotics. Genetic polymorphisms in mdr1, cyp3a4 and cyp3a5 genes in a. This study tested the hypothesis that response to digoxin is modulated by single nucleotid polymorphism snp. A systematic screen of the entire mdr1 gene for polymorphisms was performed by hoffmeyer et al, in which all 28 exons as well as the core promoter region. Several single nucleotide polymorphisms snps of mdr1, cyp3a4 and cyp3a5 genes have been described. Pglycoprotein 1 permeability glycoprotein, abbreviated as pgp or pgp also known as multidrug resistance protein 1 mdr1 or atpbinding cassette subfamily b member 1 abcb1 or cluster of differentiation 243 cd243 is an important protein of the cell membrane that pumps many foreign substances out of cells. In vivo and in vitro studies have demonstrated that pglycoprotein pgp plays a very significant role in the adme processes absorption, distribution, metabolism, excretion and drugdrug interaction ddi of drugs in humans. Our results do not support an association between mdr1 genetic polymorphisms and modelled idv clearance or clinical.
Digoxin is a highalert medication because of its narrow therapeutic range and high drugtodrug interactions ddis. Modulation of steadystate kinetics of digoxin by haplotypes. The objective of the present study was to determine the association between mdr1 genetic polymorphisms in exons 21 g2677ta and 26 c3435t, and indinavir idv pharmacokinetics and response to haart. Thus, it remains unclear whether this substitution alters pgp expression level directly. We investigated the effect of polymorphisms in the p.
Mdr1 gene polymorphisms and clinical relevance sciencedirect. Investigation of polymorphism in the mdr1 gene and. Responses to different drugs can vary widely among different individuals as a result of genetic variations in drugmetabolizing enzymes, transporters, receptors, and or other cofactors. Genetic polymorphisms in mdr1, cyp3a4 and cyp3a5 genes in a ghanaian population. Potential impact of genetic polymorphisms on the outcome of heart failure patients. Aug 22, 2002 the pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups n 5 each on the basis of genotyping for the mdr1 gene, in a 4. Population pharmacokinetics of gabapentin in healthy korean. The concentrationtime profile of digoxin was established using 12 to 16 blood samples taken 15 minutes to 72 hours after administration. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailabilily. Multi drug resistance mdr1 gene haplotypes and solute carrier organic anion transporter family member 1b3 slco1b3 gene polymorphism and their role in the response to treatement. We aimed to investigate the interaction between variants within the abcb1 gene and digoxin on the risk of sudden cardiac death scd.
The use of pharmacokinetics to adjust the dosing regimen can reduce the incidence of digoxin toxicity. Modelling the influence of mdr1 polymorphism on digoxin pharmacokinetic parameters. Mdr1 genotypes for c3435t and g2677ta snps were determined in 32 healthy subjects whose single oral dose digoxin pharmacokinetics. Mdr1 is a highly polymorphic gene with many single nucleotide polymorphisms snps. Association of the multidrug resistance1 gene single. Minimal effect of mdr1 and cyp3a5 genetic polymorphisms on.
Effect of grapefruit juice on digoxin pharmacokinetics in. Previous studies have suggested that multidrug resistance protein 1 mdr1 might help remove paraquat from the lungs and the kidney. We modelled the pharmacokinetics of digoxin using nonlinear mixed effect models. Therefore, the influence of pgp on pharmacokinetics is gaining attention. Of mdr1 gene mutations8,16,18 breed approximate frequency collie 70%. Zuruck zum zitat horinouchi m, sakaeda t, nakamura t, morita y, tamura t, aoyama n, kasuga m, okumura k. Digoxin is a cardenolide glycoside that is digitoxin betahydroxylated at c12. Our study showed for the first time that verapamil pharmacokinetics may be influenced by particular genetic polymorphisms of the abcb1 gene among healthy chinese han ethnic subjects. Pdf digoxin is a wellknown probe for the activity of pglycoprotein. Digoxin is a wellknown probe for the activity of pglycoprotein. Investigation of polymorphism in the mdr1 gene and antidepressantinduced mania.
Strother and others published effect of the c3435t genetic polymorphism in mdr1 on etoposide pharmacokinetics find, read and cite all the research you need. Future studies should focus on the impact of mdr1 haplotypes on the pharmacokinetics of mdr1 substrates rather than the c3435t snp alone. Effect of cyp2d6, cyp3a5, and mdr1 genetic polymorphisms. Modelling the influence of mdr1 polymorphism on digoxin. Pharmacokinetics is a widely used antiepileptic drug phenytoin, which exhibits noticeable interindividual variations in efficacy.
Some of the positions corresponding to the polymorphisms in the mdr1 gene are indicated. Methods kidney transplant recipients receiving cyclosporine n 110 or tacrolimus n 64 were genotyped for cyp3a41b and 3, cyp3a53 and 6, and mdr. All subjects were genotyped for the mdr1 c3435t and g2677ta genotypes. Mdr1 ala893 polymorphism is associated with inflammatory. The aim of this study was to evaluate the effects of abcb1 gene polymorphisms on azithromycin pharmacokinetics in chinese han ethnic subjects.
Recently, functional genetic polymorphisms in the mdr1 gene have been identified. Contained within this region is the gene for mdr1 multidrug resistance, a membrane transport protein for which human polymorphisms have been reported in ala893serthr and c3435t that alter. Metaanalysis of the influence of mdr1 c3435t polymorphism on digoxin pharmacokinetics and mdr1 gene expression. Effect of grapefruit juice on digoxin pharmacokinetics in humans. Our objective was to determine the role of genetic polymorphisms in cyp3a4, cyp3a5, and mdr. Mar, 2007 read modelling the influence of mdr1 polymorphism on digoxin pharmacokinetic parameters, european journal of clinical pharmacology on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Digoxin is used in several cardiac pathologies such as atrial fibrillation and heart failure. Significant genetic linkage of mdr1 polymorphisms at. This study was performed to elucidate the effects of c3435t on the rate of duodenal.
Mdr1 genetic polymorphisms and tacrolimus pharmacokinetics. Mar 01, 2003 read digoxin pharmacokinetics and mdr1 genetic polymorphisms, european journal of clinical pharmacology on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. In total, 20 healthy volunteers with various abcb1 genotypes 6 with 2677gg3435cc, 8 with 2677gt3435ct, 6 with 2677tt3435tt were enrolled. Pgp is the product of multidrug resistance gene mdr1abcb1. Relationship between the c3435t and g2677ta polymorphisms. Effect of mdr1 gene polymorphisms on mortality in paraquat. Polymorphisms in the abc drug transporter gene mdr1 the. The multidrug resistance 1 mdr1 transporter, a wellcharacterized member of the atpbinding cassette superfamily, was shown to efflux a wide variety of structurally and functionally unrelated drugs, including. The dose of digoxin was reduced during the clarithromycin phase 0. Pdf human intestinal pglycoprotein activity estimated. The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Functional significance of genetic polymorphisms in pglycoprotein. Mdr1 genotypes for c3435t and g2677ta snps were determined in. Several studies have identified genetic polymorphisms within the mdr1 gene with altered pgp expression levels and functionality in tissues as well as effects on drug response and clinical outcomes 6, 7.
Patients were genotyped for two mdr1 polymorphisms, c3435t. Additionally, given its role in the disposition of other chemicals, the abcb1 gene may also act as a susceptibility factor for cancer. The aim of this study was to examine pgp activity in relation to age, gender, medical treatment rifampicin or ketoconazole and the multidrug resistance mdr1 gene single nucleotide polymorphisms snps g2677t and c3435t using the model drug digoxin. The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups n 5 each on the basis of genotyping for the mdr1 gene, in a 4.
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