C3435T polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with inflammatory bowel disease in a Polish population

BackgroundInflammatory bowel disease (IBD) belongs to the group of chronic diseases of the gastrointestinal tract, prevalence of which is increasing in the Polish population. The two main clinical types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). The expression level of the ABCB1/MDR1 gene which encodes P-glycoprotein seems to be of great prognostic relevance while evaluating patients’ susceptibility to UC or CD. One of the most significant ABCB1/MDR1 gene mutations is the C3435T polymorphism. A decreased expression of the ABCB1/MDR1 gene and lower P-glycoprotein activity has been associated with the 3435T variant. The aim of the study was to evaluate the C3435T polymorphism in the IBD patients and to investigate a possible correlation with disease susceptibility.MethodsThe study was performed on 108 patients with IBD and on 137 healthy individuals. All the participants were of Caucasian origin and came from central Poland. The C3435T polymorphism was analyzed by using the PCR-RFLP method.ResultsOur results showed that ORs for IBD development (including UC and CD) were elevated in individuals both with the 3435CC genotype and the 3435C allele. The differences in genotype and allele frequencies were not significant.ConclusionsThe C3435T polymorphism of the ABCB1/MDR1 gene is not a risk factor for IBD, including UC and CD, in the population coming from central Poland.     

Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson's disease

P-glycoprotein is a membrane protein encoded by the MDR1 gene, which demonstrates functional polymorphism. It is present in endothelial cells of the blood-brain barrier, thus limiting accumulation of its substrates in the central nervous system. Many epidemiological studies suggest an association between pesticides, which are substrates for P-glycoprotein, and Parkinson's disease. It was hypothesized that polymorphism of the MDR1 gene could modulate interindividual susceptibility for the disease in subjects exposed to pesticides. In a pilot case-control study involving 107 Parkinson's disease patients (30 early onset and 77 late onset patients; 59 exposed to pesticides and 48 non-exposed) and 103 controls, C3435T polymorphism of the gene was analysed. No statistically significant correlation between MDR1 gene polymorphism and Parkinson's disease was found. The 3435TT genotype was noted more frequently, but not significantly, in patients with early onset compared to late onset disease (23.3% versus 10.4%, respectively). A significant association between patients with parkinsonism exposed to pesticides and C3435T polymorphism of the MDR1 gene was found. Comparing the exposed and non-exposed patients, a statistically higher frequency of heterozygous subjects was observed (72.9% versus 47.9%, respectively). This genotype was associated with a significant, almost three-fold increased risk of disease. Similarly, a higher frequency of 3435TT subjects was revealed in exposed subjects (15.5%) compared to non-exposed patients (12.5%). In exposed versus non-exposed subjects, patients carrying at least one 3435T allele (i.e. homozygous and heterozygous) had a significant, five-fold higher risk of Parkinson's disease. Thus, it appears that mutation of the MDR1 gene predisposes to damaging effects of pesticides, and possibly other toxic xenobiotics transported by P-glycoprotein, leading to Parkinson's disease.     

The MDR1 3435 polymorphism in patients with rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is a multifactorial disease, the pathogenesis of which involves immunological, genetic and environmental factors. P-glycoprotein (P-gp) encoded by the MDR1 gene, is an important transporter for many drugs, xenobiotics and cytokines and may be associated with many immunological processes and apoptosis. The activity of P-gp is genetically determined. Naturally occurring MDR1 polymorphisms have been described and correlated with potential clinical effects. Several mutations in the MDR1 gene have been recognized, but only some of them are associated with P-gp expression. The C3435T polymorphism was found to correlate with the activity of P-glycoprotein. The aim of the study was to evaluate the C3435T MDR1 polymorphism in patients with rheumatoid arthritis and to investigate a possible correlation with disease susceptibility, activity and severity. METHODS: The study was carried out in 92 patients with rheumatoid arthritis and 97 healthy subjects as a control group. The C3435T polymorphism was determined using the PCR-RFLP method. RESULTS: The distribution of C3435TT MDR1 genotypes in RA patients did not differ significantly from that in a control group and was as follows: 3435CC in 25 (26.9%) subjects, 3435CT in 50 (53.8%) and 3435TT in 17 (18.3%). The probability of remission of RA symptoms after therapy with methotrexate and glucocorticosteroids however, was 2.89-fold greater in patients with the 3435TT genotype compared to patients with the genotypes 3435CC and 3435CT. The risk of having an active form of rheumatoid arthritis resistant to therapy with disease-modifying antirheumatic drugs in patients with 3435CC and 3435CT genotypes was 2.89 times greater than in homozygous 3435TT subjects. CONCLUSION: We suggest that the C3435T MDR1 polymorphism is not an important genetic risk factor for RA susceptibility, but that this polymorphism may have an influence on the activity of the disease and its response to therapy with disease-modifying antirheumatic drugs.     

Genotype-dependent down-regulation of gene expression and function of MDR1 in human peripheral blood mononuclear cells under acute inflammation

Recent advances in pharmacogenomics have suggested the association of clinical outcome of glucocorticoid-based anti-inflammatory therapy with a single nucleotide polymorphism at position 3435 in exon 26 (C3435T) of the MDR1 gene. In the present study, the effects of the MDR1 C3435T genotype on the time-dependent profiles of gene expression and function of MDR1/P-glycoprotein were evaluated in peripheral blood mononuclear cells (PBMCs) under lipopolysaccharide (LPS)-induced experimental acute inflammation. LPS treatment resulted in the rapid elevation of IL-1beta and TNF-alpha mRNA levels relative to beta-actin mRNA at 1 h, with a subsequent slight decrease at 3 h after the treatment, while the down-regulation of the relative concentration of MDR1 mRNA was found at 3 h, not at 1 h, after LPS treatment. Here, the C3435T genotype-dependent down-regulations of MDR1 mRNA level were found for CC(3435) and CT(3435), but not for TT(3435), and were 64.1+/-10.1%, 71.4+/-5.9% and 100.0+/-22.5% (+/-S.D.), respectively, of their respective baseline levels, which were independent of C3435T (0.010+/-0.005, 0.011+/-0.013 and 0.009+/-0.006 (+/-S.D.), respectively). The C3435T genotype-dependent down-regulation was supported by the increase of the intracellular accumulation of calcein in PBMCs treated with LPS for 72 h, and the increase was more predominant for CC(3435) than TT(3435). These data suggested that glucocorticoid-based anti-inflammatory therapy might be more effective for C(3435)-allele carriers than non-carriers.     

Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn’s disease

Background The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear. Aims To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour. Patients and methods Three hundred eighty-eight German IBD patients [244 with Crohn’s disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T. Genotype–phenotype analysis was performed with respect to disease susceptibility stratified by age at diagnosis as well as disease localisation and behaviour. Results Genotype distribution did not differ between all UC or CD patients and controls. Between UC and CD patients, however, we observed a trend of different distribution of the combined genotypes derived from SNPs 2677 and 3435 (χ² = 15.997, df = 8, p = 0.054). In subgroup analysis, genotype frequencies between UC patients with early onset of disease and controls showed significant difference for combined positions 2677 and 3435 (χ² = 16.054, df = 8, p = 0.034 for age at diagnosis ≥25, lower quartile). Herein the rare genotype 2677GG/3435TT was more frequently observed (odds ratio = 7.0, 95% confidence interval 2.5 – 19.7). In this group severe course of disease behaviour depended on the combined MDR1 SNPs (χ² = 16.101, df = 6, p = 0.017 for age at diagnosis ≥25). No association of MDR1 genotypes with disease subgroups in CD was observed. Conclusions While overall genotype distribution did not differ, combined MDR1 genotypes derived from positions 2677 and 3435 are possibly associated with young age onset of UC and severe course of disease in this patient group.     

Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression

AIMS: 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-analysis on published data investigating the influence of C3435T SNP on the pharmacokinetics of digoxin and the expression of MDR1. METHODS: Meta-analysis was performed on data from published studies investigating the influence of MDR1 C3435T SNP on digoxin pharmacokinetics, as well as MDR1 expression in Caucasian and Japanese populations. The following outcomes were included: exposures to digoxin measured by area under the concentration-time curve and maximum concentration, the mean intestinal MDR1 mRNA expression and P-gp expression in the absence of digoxin administration. RESULTS: The overall results of the meta-analysis in Caucasian and Japanese subjects suggested no major influence of the C3435T SNP on exposure levels of digoxin as determined by AUC(0-4 h) or AUC(0-24 h) although C(max) values for digoxin were lower in wild-type (CC) subjects compared with subjects harbouring TT genotypes. Subgroup analysis by ethnic populations showed the oral availability of digoxin to be lower in wild-type Caucasian populations compared with wild-type Japanese subjects. No causal relationships were detected between the C3435T SNP and MDR1 mRNA or protein expression. CONCLUSIONS: Our meta-analysis of available studies indicates that the synonymous MDR1 C3435T SNP does not affect the pharmacokinetics of digoxin and the expression of MDR1 mRNA. Future studies should focus on the impact of MDR1 haplotypes on the pharmacokinetics of MDR1 substrates rather than the C3435T SNP alone.     

MDR1 (ABCB1) gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia

Functional single nucleotide polymorphism (SNP) C3435T in exon 26 of the MDR1 ( ABCB1 ) gene encoding the xenobiotic transporter P-glycoprotein (P-gp, MDR1, ABCB1) may influence susceptibility to several diseases as well as clinical outcome of treatment with P-gp substrates. Exposure to environmental chemicals is thought to be involved in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) and P-gp-transported drugs are used in its treatment; however, little is known about the impact of the C3435T MDR1 SNP in B-CLL. In this study, 110 Caucasian B-CLL patients and 201 healthy controls were genotyped for the MDR1 C3435T SNP. Additionally, P-gp activity was assessed in malignant lymphocytes of 22 untreated B-CLL patients. We observed a higher frequency of carriers of at least one 3435T allele (3435CT and 3435TT genotypes) among B-CLL patients as compared to normal individuals (76% vs . 63%, p=0.027). The genotypes 3435CT and 3435TT were associated with B-CLL, (odds ratio=1.8, 95% confidence interval = 1.1-3.0). Moreover, P-gp activity in B-CLL cells depended on MDR1 genotype, with the highest P-gp activity in 3435CC homozygotes, intermediate in 3435CT heterozygotes and the lowest in 3435TT homozygotes (p=0.042). P-gp activity was also significantly lower in carriers of the T-allele (3435CT/TT genotype) as compared to the non-carriers (3435CC genotype), (p=0.029). Taken together, these data indicate that the MDR1 C3435T SNP may carry an increased risk of developing B-CLL, possibly by virtue of decreased protection against P-gp-substrate carcinogens. The differences in P-gp activity in B-CLL tumor cells related to MDR1 genotype may have implications to the response to chemotherapy with P-gp transported anticancer agents.     

MDR1基因C3435T多态性对替米沙坦血药浓度与药动学的影响

目的：探讨健康志愿者和高血压患者的多药耐药基因26（exon26）C3435T基因多态性对替米沙坦的血药浓度和药动学的影响。方法：采用聚合酶链反应（PCR）和限制性内切片段多态性（RFLP）的方法对19例健康志愿者和66例高血压患者进行MDR1基因分型。使用HPLC-MS法测定健康志愿者单剂量口服40mg替米沙坦48h内血药浓度和高血压患者的稳态血药浓度。比较不同基因型之间替米沙坦在健康志愿者的药物动力学的差异,和高血压患者的稳态血药浓度差异。结果：C3435T发生率在健康人群和高血压患者之间没有明显的差异,C3435T的3个不同基因型健康志愿者的Cmax,tmax,AUC0-48,AUC0-∞,CL差异无统计学意义（P〉0．05）。3个基因型的高血压患者的稳态血药浓度差异无统计学意义（P〉0．05）。结论：MDR1C3435T基因多态性对替米沙坦的血药浓度和药动学无影响。     

C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation

The bioavailability of structurally unrelated drugs is limited by active secretion via the multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) from enterocyte into lumen as well as intestinal metabolism by cytochrome P450 IIIA4 (CYP3A4). In the present study, we analyzed whether genetic polymorphism of the MDR1 had some influence on the intestinal expression levels of Pgp and CYP3A4 and the tacrolimus concentration/dose ratio over the first postoperative days in recipients of living-donor liver transplantation (LDLT). Genotyping assays were performed for the major 10 polymorphisms in the MDR1 gene by the polymerase chain reaction-restriction enzyme length polymorphism method. The allele frequencies of variations at five positions were almost comparable with those in the former studies in Caucasians and Japanese, but there was no variation at the other five positions. Although no polymorphism correlated with the intestinal expression of MDR1 mRNA or the tacrolimus concentration/dose ratio in the LDLT recipients, the C3435T polymorphism significantly affected the intestinal expression level of CYP3A4 mRNA as follows; 3435C/C>3435C/T (P < 0.05 vs. 3435C/C)>3435T/T (P < 0.01 vs. 3435C/C). Therefore, the identified polymorphisms including C3435T in the MDR1 gene were indicated to have no influence on the intestinal expression level of Pgp or the tacrolimus concentration/dose ratio in the recipients of LDLT. On the other hand, the C3435T polymorphism of MDR1 was suggested to correlate with the enterocyte expression of CYP3A4 rather than Pgp linking unknown genetic variation in CYP3A4 gene.     

MDR1 genotypes related to pharmacokinetics and MDR1 expression

The multidrug-resistant transporter encoded by the MDR1 gene belongs to the ATP-binding cassette superfamily of membrane transporters. It is involved not only in the acquisition of multidrug-resistance phenotypes in cancer cells but also in normal tissues such as the brain, kidneys, liver, and intestines. This transporter has the potential to export unnecessary or toxic exogenous substances or metabolites, and in the intestine it is thought to play a role in limiting the oral absorption of a number of structurally unrelated drugs. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and suggested that a single-nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene (C3435T) was associated with a lower level of intestinal MDR1 expression, and thereby with lower plasma concentrations of digoxin after oral administration. At present, over 20 SNPs have been found in the MDR1 gene. Clinical studies on the effects of C3435T on MDR1 expression and function in the tissues, and consequently on the pharmacokinetics, have been performed worldwide. In this review, the latest reports concerning the relationship of MDR1 genotypes with pharmacokinetics and MDR1 expression are summarized. Our experimental results demonstrate the importance of genetic polymorphisms at positions 3435 and 2677 in the MDR1 gene on pharmacokinetics and intestinal MDR1 expression. In the future, haplotype analysis of the MDR1 gene and subsequent classification of subjects are needed for individualized pharmacotherapy based on MDR1 genotyping.     

Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities

The two most frequently observed single nucleotide polymorphisms (SNPs) of the human multidrug resistance 1 (MDR1) gene are 2677G/T/A (893Ala/Ser/Thr) and 3435C/T (no amino acid substitution). In this study, six forms of MDR1 cDNAs with the SNPs were expressed in LLC-PK1 cells and their transport activities were determined. Nearly identical amounts of the recombinant MDR1 proteins were expressed in the established cell lines using the Flp recombinase, which integrates a gene of interest at a specific genomic location. Four structurally diverse compounds: verapamil, digoxin, vinblastine and cyclosporin A, were examined for transcellular transport activities and intracellular accumulation. No significant differences were observed between cells expressing five polymorphic types of the MDR1 cDNAs (2677G/3435T, 2677A/3435C, 2677A/3435T, 2677T/3435C, 2677T/3435T) and cells expressing the wild-type (2677G/3435C). These results suggested that the two frequently observed MDR1 SNPs had no effect on the transport activities of MDR1 proteins expressed in LLC-PK1 cells in vitro, and other genetic or environmental factors might control the expression of MDR1 and the in vivo activity of MDR1.     

Effect of MDR1 gene polymorphism on progression of end-stage renal disease

AIM: P-glycoprotein is localized at the apical brush-border membrane of the proximal renal tubule and functions as extruding toxins and xenobiotics out of cells. The difference of P-glycoproteinos function resulted from single nucleotide polymorphisms in MDR1 (multidrug resistance gene encoding for P-gp) and may be the cause of interindividual differences in susceptibility to end-stage renal disease (ESRD). The purpose of this study is to compare the genotype frequency of C3435T and G1199A polymorphisms in MDR1 between ESRD patients and healthy controls in the Chinese population to determine whether the alteration of the P-gp function is associated with ESRD. METHODS: Two hundred and eighty-four healthy Chinese controls and 244 Chinese patients with ESRD were involved in this study. Allele specific PCR and polymerase chain reaction-restriction fragment length polymorphism assay were used to determine the genotype MDR1 G1199A and C3435T, respectively. RESULTS: The genotype distribution of 3435CC, 3435CT, and 3435TT were 0.35, 0.50, and 0.15, respectively, in the control group and 0.38, 0.47, and 0.15 in the group with the ESRD patients. No variant allele 1199G>A was found in any of the patients. The value of serum creatinine for genotypes 3435CC, 3435CT, and 3435TT in the ESRD patients were 753.8+/-276.0 mumol/L, 849.6+/-342.2 micromol/L, and 987.0+/-512.0 micromol/L, respectively. The difference between 3435TT and 3435CC reached statistical significance (P<0.05). CONCLUSION: The low expression of P-glycoprotein was not the etiological factor for the kidney disease, but it may contribute to the progression of ESRD and affect the severity. Chinese people do not carry the 1199G>A variant allele. More studies are needed to clarify the cause and interindividual differences in the susceptibility for the risk of ESRD.     

MDR1基因C3435T多态性对重症肌无力患者环孢素血药浓度的影响

目的 :研究MDR1基因C3435T多态性与重症肌无力患者环孢素药物动力学的关系。方法 :采用荧光PCR的方法检测 96名重症肌无力 (MG)患者MDR1C3435T基因型 ,其中临床资料较全的 73名 ,对其环孢素用药的血药检测结果与基因型结果分析。结果 :重症肌无力患者MDR1C3435T的分布频率接近 1:1;野生型 3435CC患者的环孢素全血谷浓度高于杂合型和突变型 (P <0 .0 5 ) ,杂合型与突变型之间无明显差异。结论 :药物遗传学研究对环孢素治疗重症肌无力患者的临床合理用药有指导意义。     

Polymorphism in the P-glycoprotein drug transporter MDR1 gene in renal transplant patients treated with cyclosporin A in a Polish population

P-glycoprotein (P-gp), the product of MDR1 gene, is a protein which mediates transmembrane transport of a great number of xenobiotics including cyclosporin A used as an immunosuppressive drug in patients with allogenic kidney grafts. The P-gp activity and expression is dependent on the MDR1 gene polymorphism in position C3435T of exon 26. In this study, C3435T polymorphism was analyzed in 116 patients with allogenic kidney graft treated with cyclosporin Aand 144 randomly selected healthy individuals. The prevalence of MDR1 gene genotypes 3435CC, 3435CT, 3435TT were also compared in patients after allogenic kidney graft with both acute and chronic graft rejection (48 patients with acute and 76 with chronic graft rejection) and control groups (respectively 139 and 112). The results of the study demonstrated that the allelic frequency and MDR1 genotype distribution were similar in all evaluated groups. It was revealed that MDR1 gene polymorphism was not a predisposing factor for terminal kidney failure leading to renal transplantation. Moreover, evaluation of C3435T polymorphism of MDR1 gene will probably not be useful for characterization of groups of patients at increased risk of acute and chronic kidney graft rejection.     

Expression polymorphism of the blood-brain barrier component P-glycoprotein (MDR1) in relation to Parkinson's disease

Because drug transporters such as P-glycoprotein, the product of the multidrug resistance (MDR1 ) gene, contribute to the function of the blood-brain barrier, we hypothesized that differences in their expression could affect the uptake of neurotoxic xenobiotics, thereby modulating interindividual susceptibility for neurological disorders such as Parkinson's disease. In a pilot case-control study comprising 95 Parkinson's disease patients (25 early-onset patients with onset age < or = 45 years) and 106 controls we analysed the three common polymorphisms, 3435C >T in exon 26, 2677G > T,A in exon 21, and -129T > C in exon 1b. There were no statistically significant associations between any of these polymorphisms and Parkinson's disease. However, a distribution pattern consistent with our hypothesis was observed in that the frequency of the 3435T/T genotype, which had previously been associated with decreased P-glycoprotein expression and function, was highest in the early-onset Parkinson's disease group (36.0%), second-highest in the late-onset Parkinson's disease group (22.9%), and lowest in the control group (18.9%). Furthermore, we confirmed that the MDR1 exon 21 and exon 26 polymorphisms are in significant linkage disequilibrium since the [2677G, 3435C] and [2677T, 3435T] haplotypes were far more frequently observed than expected. In conclusion, MDR1 and other drug transporters represent plausible candidates as Parkinson's disease risk genes. Larger studies are required to confirm this role in the etiology of Parkinson's disease.     

Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs

The multi-drug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette (ABC) superfamily of membrane transporters. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multi-drug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of various types of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and indicated that a single nucleotide polymorphism (SNP), C3435T in exon 26, which caused no amino acid change, was associated with the duodenal expression of MDR1 and thereby the plasma concentrations of digoxin after oral administration. Interethnic differences in genotype frequencies of C3435T have been clarified, and, at present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on the effects of C3435T on MDR1 expression and function in the tissues, and also on the pharmacokinetics and pharmacodynamics have been performed around the world; however, there are still discrepancies in the results, suggesting that the haplotype analysis of the gene should be included instead of SNP detection, and the design of clinical trials must be carefully planned to avoid misinterpretations. A polymorphism of C3435T is also reported to be a risk factor for a certain class of diseases such as the inflammatory bowel diseases, Parkinson's disease and renal epithelial tumor, and this might also be explained by the effects on MDR1 expression and function. In this review, the latest reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping.     

MDR1基因多态性对替米沙坦血药浓度和药动力学影响研究

目的:探讨健康志愿者和高血压患者的多药耐药基因(Multidrug resistance 1 gene,MDR1) C3435T基因多态性对替米沙坦血药浓度和药动学的影响.方法:采用聚合酶链反应(Polymerase chain reaction,PCR)和限制性内切片段多态性(Restriction fragment length polymorphism,RFLP)的方法对19名健康志愿者和61例高血压患者进行MDR1基因分型;使用HPLC-MS法测定志愿者单剂量口服40 mg替米沙坦48 h内血药浓度和高血压患者的稳态血药浓度.比较替米沙坦在不同基因型的健康志愿者单剂量药动学及高血压患者稳态血药浓度的差异.结果:在61例高血压患者中,MDRlCC型纯合子频率39.34％,TT型纯合子频率11.48％,CT型杂合子频率49.18％,C3435T发生率在健康人群和高血压患者之间没有明显的差异,C3435T的三个不同基因型志愿者Cmax、tmax、t1/2、AUC0-48、AUC0-∞和CL差异无统计学意义(P＞0.05).三个基因型高血压患者的稳态血药浓度差异无统计学意义(P＞0.05).结论:MDR1C3435T基因多态性对替米沙坦的血药浓度和药动学无影响.     

MDR1 genotype-related pharmacokinetics and pharmacodynamics

The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). 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. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.     

Digoxin pharmacokinetics and MDR1 genetic polymorphisms

BACKGROUND: The effect of MDR1 C3435T single nucleotide polymorphism (SNP) in exon 26 on digoxin pharmacokinetics has recently been challenged. OBJECTIVE. To clarify the relationships between MDR1 genetic polymorphisms in exon 26 (C3435T) and 21 (G2677T/A) and digoxin pharmacokinetics. MATERIALS AND METHODS: MDR1 genotypes for C3435T and G2677T/A SNPs were determined in 32 healthy subjects whose single oral dose digoxin pharmacokinetics had been measured over 48 h. RESULTS: A significant relationship was observed between C3435T SNP and digoxin AUCs ( p<0,05). Homozygous TT subjects had 20% higher digoxin plasma concentrations than CT and CC subjects and a trend for higher 48 h digoxin urinary recoveries (TT>CT>CC). Similar results, although not statistically significant, were observed from the MDR1 G2677T/A SNP. CONCLUSIONS: Our results confirm that the MDR1 C3435T single nucleotide polymorphism (SNP) significantly affects digoxin disposition kinetics, with homozygous TT subjects presenting the highest plasma concentrations.     

Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1)

The MDR1 gene product P-glycoprotein in the human placenta is important for protecting the fetus from unintended, harmful drug exposure, but also for limiting the access of therapeutic drugs to the fetus after maternal drug intake. A polymorphism in exon 26 of the MDR1 gene (C3435T) has previously been shown to be associated with reduced P-glycoprotein expression in the small intestine, kidney and lymphocytes. In the present study, we examined systematically whether MDR1 polymorphisms also have an impact on P-glycoprotein expression in the human placenta. MDR1 mRNA and P-glycoprotein were analysed in 73 full-term human placentas of Caucasians, as well as respective MDR1 genotypes/haplotypes, for the C3435T and G2677T/A polymorphisms of mothers and infants. MDR1 mRNA levels were not different between these genotype groups. However, P-glycoprotein expression was significantly lower when both mother and infant were homozygous for the 3435T allele (TT/tt) compared to maternal and fetal homozygotes for the C-allele (0.40 +/- 0.18 a.u. for TT/tt versus 0.66 +/- 0.30 a.u. for CC/cc, P = 0.01). Moreover, placentas from mothers carrying both polymorphisms (3435T and 2677T; TT/TT) also had a significantly lower P-glycoprotein expression (0.31 +/- 0.12 a.u.) compared to placentas of wild-type individuals (CC/GG, 0.71 +/- 0.31 a.u., P = 0.02). Taken together, the MDR1 polymorphisms C3435T and G2677T are associated with altered P-glycoprotein expression in the human placenta, and may have clinical consequences due to genetically determined, variable drug exposure of the fetus.