MDR1 C3435T Research Articles

PW01-040 – Definition of polymorphism C3435T MDR1 gene in JIA

Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic disease in children. Brug of choice is methotrexate (MTX) - cytostatic drug from the group of antimetabolites, folic acid antagonists. According to various authors, about 70% of patients receiving therapy with MTX are in remission for the disease. In 1988, MTX was approved FDA (Food and Drug Administration, USA) for the treatment of rheumatoid arthritis. Currently, MTX is the main drug in the treatment of JIA. Preferred therapeutic recommendations on the number of MTX based on a randomized, double-blind, placebo-controlled study conducted in 1992. MDR1-gene product - the P-glycoprotein (P-gp), the protein acts as a trans-membrane pump, and affects the activity of many drugs. Polymorphism in the gene MDR1, may affect the pharmacokinetics of many drugs, including anticancer drugs. According to the authors of Jinwei Chen (2011) in adult patients with rheumatoid arthritis (RA) in the Chinese population C3435T MDR1 gene polymorphism may be associated with susceptibility to RA, but may influence the effectiveness of antirheumatic therapy of RA, and CC genotype may be associated with immune rheumatoid arthritis (RRA).

Is There a Role for MDR1, EPHX1 and Protein Z Gene Variants in Modulation of Warfarin Dosage? A Study on a Cohort of the Egyptian Population

There is considerable inter-individual variability in warfarin dosages necessary to achieve target therapeutic anticoagulation. Polymorphisms in genes, which master warfarin pharmacokinetics and pharmacodynamics, might influence warfarin dose variation. Genes encoding drug transporters, such as human multidrug resistance (MDR1), as well as epoxide hydrolase 1 (EPHX1), which is a putative subunit of the vitamin K epoxide reductase, and Protein Z (PZ), which is a vitamin K-dependent plasma glycoprotein, are among those candidate genes. The purpose of this study was to investigate the contribution of MDR1 C3435T, EPHX1 H139R and PZ A-13G gene polymorphisms in warfarin dose variation in a cohort of the Egyptian population. Eighty-four patients whose international normalized ratio (INR) was in the range of 2-3, 41 males and 43 females, with a mean (±SD) age of 40.9 (13.3) years were recruited into this study. MDR1 C3435T, EPHX1 H139R and PZ A-13G gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism. Primarily, linear regression analysis, including the variables age, gender, MDR1 C3435T, EPHX1 H139R and combined MDR1 C3435T, EPHX1 H139R and PZ A-13G genotypes, was used to assess the effective factors for warfarin maintenance dose. Secondly, the previously examined cytochrome P450 (CYP) 2C9 A1075C and vitamin K epoxide reductase complex subunit 1 (VKORC1) C1173T were added to the regression analysis. Warfarin dose/week was not influenced by each of the MDR1 C3435T, EPHX1 H139R, and PZ A-13G gene polymorphisms when examined separately. However, when these single nucleotide polymorphisms (SNPs) were combined, MDR1 TT/EPHX1 RH,RR/PZ AA subjects showed statistically significant increase in warfarin dose/week when compared with MDR1 CC/EPHX1 RH,RR/PZ AA subjects [median (25th-75th percentiles): 49.0 (42.0-59.5) vs. 35.0 (24.5-42.0)mg/week, respectively] (p=0.014). In contrast, in the presence of wild-type EPHX1 HH, there was a decrease in warfarin dose/week in MDR1 TT subjects when compared with CT and CC subjects [median (25th-75th percentiles): 22.0 (17.5-30.6), 42.0 (35.0-49.0) and 42.0 (28.0-54.3)mg/week, respectively] (p=0.005 and 0.030, respectively). Age had a significant contribution (p=0.048) to the overall variability in warfarin dose. Calculated weekly dose=52.928-(0.289×age)+(9.709×combined genotype). The multivariate linear regression equation of warfarin maintenance dose accounted for about 8% of variation in dose (R (2)=0.079), age accounted for 5% of variation, while combined genotypes added the extra 3%. However, the new regression equation accounted for 20.9% of variation in dose. Age accounted for 5%, while VKORC1 C1173T accounted for an extra 13% of variation and MDR1 C3435T accounted for the remaining 3% of variation. Calculated dose=64.909-(0.282×age)-(13.390×VKORC1)-(7.164×MDR1). Correlation analysis showed a close and significant relationship between the calculated and actual warfarin dose (r=0.457; p<0.0005). Warfarin dose/week was significantly influenced by the combined MDR1 C3435T and EPHX1 H139R gene polymorphism since no polymorphism of PZ A-13G SNP was detected in our studied Egyptian population. Future studies with larger sample size will be needed to confirm our findings before definitive conclusions can be made.

A correlative study of polymorphisms of CYP2C19 and MDR1 C3435T with the pharmacokinetic profiles of lansoprazole and its main metabolites following single oral administration in healthy adult Chinese subjects

Considering that the genotypes of CYP2C19 and MDRI C3435T are two major factors attributed to the inter-individual pharmacokinetic variability of lansoprazole (LSZ), the aim of the study was to simultaneously elucidate the effects of CYP2C19 and MDRI C3435T polymorphisms on the pharmacokinetics difference of LSZ and its metabolites 5'-hydroxy lansoprazole (HLSZ) and lansoprazole sulphone (LSZS) following oral administration of LSZ tablets in healthy Chinese subjects. Plasma concentration of LSZ, HLSZ and LSZS were quantified by a sensitive and specific LC-MS/MS method, while the genotypes of CYP2C19 and MDRI C3435T for each subject were identified by a direct sequencing method. Statistical analysis was performed in the pharmacokinetic parameters including Cmax, t1/2, Tmax, MRTo_-, AUCO-2 and AUCo_r among different genotype groups of CYP2C 19 and MDRI C3435T. Compared to the CYP2Cl9 EMs, the CYP2C 19 PM group showed slower elimination and betteroral bioavailability of LSZ, much higher plasma concentrations of LSZS and lower concentrations of HLSZ with statistically significance. Despite a tendency of more favorable absorption and rapid elimination of LSZ in wild genotype, no significant pharmacokinetics difference was observed between the wild genotype of MDR1 C3435T and its mutant types. In conclusion, the pharmacokinetics of MDRI C3435T.

Multi-drug resistance-1 gene polymorphisms in nephrotic syndrome: Impact on susceptibility and response to steroids

BackgroundRole of multidrug resistance-1 (MDR-1) gene polymorphisms has not been clarified in nephrotic syndrome (NS). Additionally, researchers studied several genetic polymorphisms to explain their influence on different patients' responses to steroid; however the data were inconsistent. Therefore, we aimed to investigate the association of MDR-1 gene polymorphisms [C1236T, G2677T/A, C3435T] and haplotypes with susceptibility to childhood nephrotic syndrome, and whether they influence steroid response. MethodsWe detected MDR-1 gene polymorphisms using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 138 NS patients and 140 age and sex matched healthy children. ResultsThe frequencies of MDR1 G2677T/A GT, GA, TT+AA genotypes or T allele, MDR1 C3435T TT genotype, and T allele genotype frequencies were significantly increased in NS group. While no significant differences were observed in distributions of C1236T genotypes or allele between NS patients and healthy children. Moreover, steroid non-responder NS patients had significantly higher frequencies of MDR1 G2677T/A GT, GA, and TT+AA genotypes than steroid responsive NS patients. We observed also that NS patients with age less than 6years old had increased frequencies of MDR1 G2677T/A GT, GA, TT+AA genotypes or T allele MDR1 C3435T CT, TT genotypes and T allele. Interestingly the frequency of the TGC haplotype of MDR1 was lower in the initial steroid responders than in non-responders NS patients. On the contrary, there were no any association between the MDR1 haplotypes with NS susceptibility and they did not influence renal pathological findings. ConclusionOur data suggested that MDR1 C3435T or G2677T/A gene polymorphisms are risk factors of increased susceptibility, earlier onset of NS, and steroid resistance.

The association of MDR1 C3435T and G2677T/A polymorphisms with plasma platelet-activating factor levels and coronary artery disease risk in Turkish population

Increased levels of peripheral proinflammatory mediators can contribute to the development of coronary artery disease (CAD). Platelet activating factor (PAF) is an important proinflammatory mediator and plasma levels of PAF correlate with transmembrane transporter multidrug resistant 1 P-glycoprotein (MDR1 Pgp) expression and activity. MDR1 polymorphisms can affect the expression and activity of Pgp and plasma PAF levels. Therefore, we investigated the possible relationship between MDR1 C3435T and G2677T/A polymorphisms and plasma PAF levels and the risk of CAD. The study population consisted of 198 patients angiographically documented CAD, including 113 cases with at least 1 coronary artery with ≥50% luminal diameter stenosis and 85 control subjects with strictly normal coronary angiograms. Genotypes of the MDR1 C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Plasma PAF levels were detected by enzyme-linked immunosorbent assay (ELISA). There were no significant differences among plasma PAF levels in regard to MDR1 C3435T and G2677T polymorphisms in CAD patients and controls. No statistically significant difference was found for the genotypic and allelic distributions of the polymorphisms in the MDR1 gene between the patients and the control subjects. Furthermore, analysis of MDR1 haplotypes did not show any associations with increased plasma PAF levels and risk of CAD. Our results suggest that plasma PAF levels are not associated with MDR1 gene polymorphisms. There is no association between MDR1 C3435T and G2677T/A polymorphisms and the risk of CAD in Turkish patients.

The Role of MDR1 C3435T Gene Polymorphism on Gingival Hyperplasia in Turkish Renal Transplant Patients Treated With Cyclosporine in the Absence of Calcium Channel Blockers

ObjectiveTo investigate the occurrence of MDR1 C3435T gene polymorphisms in the Turkish renal transplant patients treated with cyclosporine (CsA), and correlate these findings with prevalence and degree of gingival hyperplasia (GH). MethodsBefore to renal transplantation, dental treatment and oral hygiene education of 300 renal disease patients was completed. Peripheral blood samples were collected from 154 renal transplant recipients on CsA treatment without calcium channel blockers. MDR1 C3435T gene polymorphism and GH were analyzed at posttransplant month 6. ResultsNo difference was detected among groups for age, posttransplant period, creatine levels, serum concentration of CsA, or plaque and bleeding indices (P > .05). Out of all transplanted patients, 42.8% were found to have the heterozygote genotype. This was reduced to 37.5% when individuals with GH were taken into account. However, when degree of GH was analyzed, those with severe GH were found to have the heterozygote genotype significantly more often (P < .05). ConclusionsThe MDR1 gene polymorphism is not associated with GH frequency, but may be associated with GH severity.

Association between theMDR1gene variant C3435T and risk of leukaemia: a meta-analysis

Although a number of genetic studies have attempted to link the multidrug resistance (MDR1) C3435T polymorphism to risk of leukaemia, the results were often inconsistent. The present study aimed at investigating the pooled association using a meta-analysis on the published studies. 1933 cases and 2215 controls of 11 published studies in English before June 2012 were involved in the updated meta-analysis. Furthermore, subgroup analysis was performed in different ethnic and leukaemia subtype groups. This meta-analysis suggests that the MDR1 C3435T polymorphism associate with risk of leukaemia. The effect of the variant on the expression levels and the possible functional role of the variant in leukaemia should be addressed in further studies.

MDR-1 and GST polymorphisms are involved in myelodysplasia progression

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by abnormal hematopoietic differentiation and maturation, which progress toward acute leukemia in approximately 30% of the cases. Drug metabolism polymorphisms in Cytochrome P450 2B6 (CYP2B6), Glutathione S-transferase (GST) and Dehydrogenase Quinone 1 (NQO1) enzymes and P-glycoprotein (MDR-1) could modify enzyme activity. Thus, the aim of this study was to identify the influence of CYP2B6 G15631T, GSTT1, GSTM1, NQO1 C609T and MDR-1 C3435T polymorphisms on MDS progression. We analyzed 78 MDS patients using the PCR-RFLP and multiplex method. The frequency of GST deletions and MDR-1 CC genotype was lower in progression-free patients compared to patients with progression; GST: 17% vs. 35% (P=0.018); MDR-1 gene: 19% vs. 48% (P=0.012). We also verified the influence of GST deletions and MDR-1 C3435T on patient overall survival and found no significant difference (RR=0.75; P=0.599 and RR=0.79; P=0.594 respectively). We concluded that GSTM1 deletion may contribute toward MDS progression probably due to toxic metabolite accumulation which generates cell toxicity and DNA damage. Moreover, MDR-1 C3435T may have a protective effect against MDS progression because the expected lower expression of P-glycoprotein would lead to a higher degree of cell death. To the best of our knowledge, this is the first study showing the relationship of these polymorphisms with MDS progression.

MDR1polymorphisms are associated with inflammatory bowel disease in a cohort of Croatian IBD patients

BackgroundInflammatory bowel diseases (IBD) are chronic diseases of unknown etiology and pathogenesis in which genetic factors contribute to development of disease. MDR1/ABCB1 is an interesting candidate gene for IBD. The role of two single nucleotide polymorphisms, C3435T and G2677T remains unclear due to contradictory results of current studies. Thus, the aims of this research were to investigate the association of MDR1 polymorphisms, C3435T and G2677T, and IBD.MethodsA total of 310 IBD patients, 199 Crohn's disease (CD) patients and 109 ulcerative colitis (UC) patients, and 120 healthy controls were included in the study. All subjects were genotyped for G2677T/A and C3435T polymorphism using RT-PCR. In IBD patients, review of medical records was performed and patients were phenotyped according to the Montreal classification.ResultsSignificantly higher frequency of 2677T allele (p = 0.05; OR 1.46, 95% CI (1.0-2.14)) and of the 3435TT genotype was observed among UC patients compared to controls (p = 0.02; OR 2.12; 95% CI (1.11-4.03). Heterozygous carriers for C3435T were significantly less likely to have CD (p = 0.02; OR 0.58, 95% CI (0.36-0.91)). Haplotype analysis revealed that carriers of 3435T/2677T haplotype had a significantly higher risk of having UC (p = 0.02; OR 1.55; 95% CI (1.06-2.28)).ConclusionMDR1 polymorphisms are associated with both CD and UC with a stronger association with UC.

Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children

BackgroundVariability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children. MethodsGenotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (Ctrough) and between 1 and 2h after (Cpost-dose) the administration of the next dose of drug. CD4+ T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r. ResultsMDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV Cpost-dose than homozygotes 1236TT (median Cpost-dose=3.04μg/ml and 6.50μg/ml, respectively; p=0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes=−0.50log10 copies/ml and −2.08log10 copies/ml, respectively; p=0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR. ConclusionsOur results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4+ T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression.

The role of mdr1 gene polymorphisms in type 2 Diabetes Mellitus

Objective: The ABCB1/MDR1 is a 170-kDa transporter protein called P-glycoprotein (Pgp) which has been associated with the transport of cellular lipids and drugs. Recent studies focused on MDR1, and its effects on lipid transport, show that the constitutive expression of P-gp transporter in normal tissues plays an important role in drug disposition and response. In addition, it is known that some polymorphisms on the MDR1 gene alter the expression of the P-gp. This study aims to investigate the effects of the MDR1 C3435T and the C1236T gene polymorphisms on the dyslipidemia of diabetic patients. Material and methods: The PCR-RFLP method has been used on 77 patients and 75 controls in order to determine the MDR1 genotype. Results: There are no statistical differences for the MDR1 C3435T and the C1236T genotype ranges among between our inspected groups. However, the C1236T mutant type T allele ratio increases statistically in the patient group (p = 0.026 OR: 1.679 % 95 CI: 1.062 – 2.652 ). A weak connection has been observed between the MDR1 C3435T C and the C1236T C alleles, according to the linkage disequilibrium analysis. Conclusion: This study is one of the preceding studies, which examines the relationship between MDR1 polymorphisms and type 2 diabetes. Studies on MDR1 genotypes, and their effects on lipid levels are new in literature, hence our study proves to be unique when it comes to both the C3435T and the C1236T polymorphisms in type 2 diabetes patients; however, further research is still needed for the confirmation of our findings.

MDR1 polymorphisms associated with risk and survival in diffuse large B-cell lymphoma

MDR1 encodes an adenosine triphosphate (ATP)-dependent efflux transporter that protects the body from environmental xenobiotics to maintain optimal health. Five single nucleotide polymorphisms (SNPs) of MDR1, T-2410C, T-129C, C1236T, G2677T/A and C3435T, were identified in our previous study. To investigate further the biological significance of these SNPs, we genotyped the SNPs in 135 patients with diffuse large B-cell lymphoma (DLBCL) and 376 age- and sex-matched controls. Statistical analysis indicated that the MDR1-129TC genotype was associated with an increased risk of DLBCL (p = 0.040) compared with the TT genotype, and the increased risk was more pronounced in older patients (> 50 years, p = 0.011). Patients with MDR1 2677TT displayed worse survival rates compared with those carrying MDR1 2677G/A alleles (p = 0.036). Multivariate Cox analysis revealed that the G2677T/A polymorphism was an independent prognostic factor for overall survival (OS). Further, we found a combined effect of MDR1 G2677T/A and C3435T on OS of patients with DLBCL. These results suggest that the MDR1 T-129C, G2677T/A and C3435T polymorphisms are associated with risk of and survival in DLBCL, although the p-values are not as strong after Bonferroni correction. Further investigations with a relatively larger number of patients and longer follow-up periods should be undertaken to confirm our results.

RNA Expression and Polymorphisms in Imatinib Influx and Efflux Transporters Influence Molecular Response to Imatinib Therapy in Newly Diagnosed Patients with Chronic Myeloid Leukemia.

AbstractAbstract 2785Targeted therapy in CML with tyrosine kinase inhibitor (TKI) imatinib has resulted in significant improvement in outcome. However, resistance and intolerance to imatinib have seriously limited the success of this therapy, with only a proportion of patients achieving major molecular response (MMR). It is important to identify predictors of response to imatinib, since early switch to second generation TKI has been shown to improve outcome in non-responders. Overexpression of efflux transporters, decreased expression of influx transporters and polymorphisms in these transporters and drug metabolizing enzymes have been shown to influence imatinib therapy. We evaluated the role of RNA expression and polymorphisms in imatinib influx and efflux transporters in 86 newly diagnosed patients with CML at our centre receiving imatinib from December 2009 till April 2012. Total RNA was extracted and RNA expression of the transporter genes ABCA3 (sequesters imatinib; increased expression shown to decrease imatinib exposure), ABCB1, ABCG2 (both efflux transporters) and SLC22A1 (influx transporter) were analyzed with GAPDH as housekeeping gene using Taqman based gene expression assays. The dCT values (where dCT = CT value of target gene – CT value of housekeeping gene; lower dCT corresponds to higher expression and vice versa) were used for comparing expression between groups. Polymorphisms in ABCB1 (T1236C, T2677A, and C3435T), ABCG2 (Ex2 G34A and Ex5 C421A, promoter SNP -15994C->T), SLC22A1 (all coding exons) that were associated with the expression of these transporters were analyzed from genomic DNA samples by PCR followed by direct sequencing or RFLP. BCR-ABL transcript levels were monitored at diagnosis, 3, 6, 9, 12, 18, 24 and 30 months after start of imatinib. Molecular response to imatinib after a minimum of 12 months was calculated using the ratio of BCR-ABL to ABL transcript expressed in International scale. Patients were classified to have MMR (BCR-ABL/ABL <0.01) or no MMR (BCR-ABL/ABL >0.01; but complete or partial cytogenetic response [CCR or PCR] based on FISH analysis at around 12 months from the start of imatinib therapy), and resistant (BCR-ABL/ABL >10; no cytogenetic response even after imatinib dose was increased), or intolerant (severe cytopenia or skin toxicity requiring frequent dose reductions). The RNA expression was compared between different groups by ANOVA and the effect of SNPs on outcome was compared by Fisher’s test.Out of the 86 patients, 34 achieved MMR, 22 did not achieve MMR; 14 were resistant and 12 were intolerant to imatinib; 4 patients progressed. RNA expression of ABCB1, ABCG2, ABCA3 and SLC22A1 showed wide variation among CML patients. RNA expression of SLC22A1 was significantly higher in those with MMR compared to no MMR; but not significantly different from resistance or intolerant groups (Fig 1a). ABCA3, ABCG2 and ABCB1 expression, though lower in the MMR group compared to no MMR, did not reach statistical significance. We then compared the ratio of influx to efflux transporters: dCThOCT1/dCTABCB1*dCTABCG2, referred to as resistance index (RI), in these groups; patients with MMR had significantly lower RI compared to those who did not achieve MMR (Fig 1b).We then compared the influence of SNPs in candidate genes with molecular response to imatinib. There was significantly increased frequency of variant alleles of MDR1 C3435T and T1236C in those who achieved MMR compared to those who did not achieve MMR/ resistant (p=0.03 and 0.01 respectively). We identified nine coding nonsynonymous variants including a novel exon2 variant Gly-165-Cys and 2 intronic variants in SLC22A1 upon sequencing. Among these SNPs, Pro341Leu in exon6 (p=0.015) and –TGA del polymorphism resulting in frame shift in exon 7 (p value=0.02) were significantly associated with decreased molecular response. None of the screened SNPs were particularly different in the intolerant patients.In conclusion, we show for the first time a predictive model with RNA expression pattern and genotype that could identify CML patients who would achieve MMR on imatinib therapy. The group that did not achieve MMR, but partial or complete cytogenetic response, could be made to achieve MMR by increasing the dose of imatinib or modulating the candidate ABC transporter expression. However, this model could not differentiate patients who develop therapy resistance or intolerance, which needs to be evaluated further. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Is the MDR1 C3435T Polymorphism Responsible for Oral Mucositis in Children with Acute Lymphoblastic Leukemia?

Although the functional consequences of MDR-1 polymorphisms have been the subject of numerous studies, to the best to our knowledge, associations with clinical side effects of anticancer drugs have yet to be assessed. Our aim was to clarify any role of the C3435T polymorphism of the MDR1 gene in oral mucositis and its relation with elevated reactive oxygen species (ROS) levels, in children with acute lymphoblastic leukemia (ALL). The distribution of the MDR-1 C3435T polymorphism in 47 patients with ALL was determined by RFLP and compared with that of 68 healthy controls. There were no association in distribution of genotypes of MDR-1 C3435T polymorphism and the risk of ALL. Oral mucositis were detected in 78.7% (n=37) of the patients and significantly related to the MDR-1 CT genotype (p=0.042), as confirmed by logistic regression analysis. Our preliminary data suggest that children carrying the CT genotype are more prone to develop oral mucositis, which might mean that the heterozygous genotype leads to accumulation of more reactive oxygen species. Since a limited number of patients was investigated, further studies are needed to confirm these findings.

CYP2C9*3(1075A&gt;C), MDR1 G2677T/A and MDR1 C3435T are Determinants of Inter-subject Variability in Fluvastatin Pharmacokinetics in Healthy Chinese Volunteers

To evaluate the impact of single-nucleotide polymorphisms (SNPs) in CYP2C9, MDR1, SLCO1B1 and ABCG2 on the pharmacokinetics of fluvastatin in Chinese participants.A pharmacokinetic study of fluvastatin (single dose 40 mg) was conducted in 12 healthy Chinese volunteers. Plasma concentrations of fluvastatin were determined by a high-performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by non-compartmental method. The SNPs were determined by TaqMan®(MGB) genotyping assay.Effect of CYP2C9*3 (c.1075A>C) on area under the plasma concentration-time curve (AUC) of fluvastatin was statistically significant. Heterozygous variant (C/A) carriers had higher AUC values compared to homozygous wild type (A/A) carriers (922.03±148.17 µg · h · L - 1 vs. 496.00±168.93 µg · h · L - 1, P=0.003092). The elimination half-life (T 1/2) values of fluvastatin were longer in MDR1 2677non-G carriers than in MDR1 2677G carriers (2.21±0.47 h vs. 1.25±0.62 h, P=0.02319), and also they were longer in MDR1 1236T-2677non-G-3435T carriers than in MDR1 1236C-2677G-3435C carriers (2.31±0.51 h vs. 1.32±0.62 h, P=0.03320). MDR1 C3435T polymorphism had a significant effect on maximal plasma concentrations (C max) of fluvastatin. Mutation gene T (TT+CT) carriers had higher C max values compared to homozygous wild type (C/C) carriers (688.54±142.67 µg · L - 1 vs. . 413.78±177.83 µg · L - 1, P=0.01448). Some SNPs such as MDR1 C1236T, ABCG2 c.34G>A, ABCG2 c.421C>A, SLCO1B1 c.388 A>G, SLCO1B1 c.521 T>C, SLCO1B1 c.571 T>C and SLCO1B1 c.597 C>T have no significant effects on fluvastatin pharmacokinetics.CYP2C9*3(1075A>C), MDR1 C3435T and MDR1 G2677T/A were determinants of inter-subject variability in fluvastatin pharmacokinetics in healthy Chinese volunteers.

MDR1 polymorphisms (G2677T and C3435T) in B-chronic lymphocytic leukemia

The human multidrug resistance (MDR1) gene encodes P-glycoprotein, which affects the pharmacokinetics of many drugs. We investigated whether common MDR1 single-nucleotide polymorphisms (C3435T and G2677T) affect predisposition to B-chronic lymphocytic leukemia (B-CLL). Genotyping was performed in 65 patients with CLL and in 70 controls using polymerase chain reaction—restriction fragment length polymorphism. We observed a higher frequency of carriers of 3435CT gene among B-CLL patients as compared to normal individuals (58.5 vs. 22.9 %, p = <0.001). The genotype 3435CT was associated with B-CLL [odds ratio = 4.8, 95 % confidence interval = 2.3–10.0]. Moreover, patient and control groups did not differ significantly regarding the MDR1 genotype (G2677T). Furthermore, no correlation was shown between the MDR1 (3435 or 2677) genotypes and clinical and laboratory data of patient group. These data indicate that MDR1 C3435T single-nucleotide polymorphism may carry an increased risk of developing B-CLL.

MDR1 single nucleotide polymorphism C3435T in Turkish patients with non-small-cell lung cancer

We assessed whether single nucleotide polymorphisms (SNPs) in MDR1 gene C3435T predicted the outcome of platinum-based chemotherapies and survival in our non small cell lung cancer (NSCLC) patients. A total of 79 non-small cell lung cancer patients were enrolled to study. We determined the MDR1 C3435T single nucleotide gene polymorphisms. Median age was 60years: 91.7% male, 8.9% female. We found that CC, CT, TT genotype and T, C allele frequencies in lung cancer patients as 24.1%, 62%, 13.9% and 44.3%, 55.7%, respectively. Patients with CT genotype had a higher response rate (11.4%) than the other genotypes. However, this difference is not statistically significant (p=0.743). Cox regression analysis for overall survival showed that ECOG PS status 0 (HR PS 1 vs. 0, 5.68 p=0.002; HR of PS 2 vs. 0 is 21.579, p=0.001; HR of PS 3 vs. 0 is 35.35, p=0.001), stage ≤II (HR of stage III vs. I+II is 17.77; p=0.016, HR of stage IV vs. I+II is 26.97, p=0.006), and albumin level ≥3g/dl (HR of albumin <3g/dl vs. ≥3g/dl is 2.46, p=0.044) were the most important prognostic factors (also, time to progression was related to these factors). There was no significant association between the genotypes and clinicopathologic parameters; however, good performance status, early stage and ≥3g/dl albumin level were found to be the most important prognostic factors for overall survival and progression-free survival.

Meta-Analysis on Pharmacogenetics of Platinum-Based Chemotherapy in Non Small Cell Lung Cancer (NSCLC) Patients

AimTo determine the pharmacogenetics of platinum-based chemotherapy in Non Small Cell Lung Cancer (NSCLC) patients.MethodsPublications were selected from PubMed, Cochrane Library and ISI Web of Knowledge. A meta-analysis was conducted to determine the association between genetic polymorphisms and platinum-based chemotherapy by checking odds ratio (OR) and 95% confidence interval (CI).ResultsData were extracted from 24 publications, which included 11 polymorphisms in 8 genes for meta-analysis. MDR1 C3435T (OR = 1.97, 95% CI: 1.11–3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44–4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17–0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients.ConclusionAttention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future.

The Influence of MDR1 G2677T/A Genetic Polymorphisms on the Pharmacokinetics of Repaglinide in Healthy Chinese Volunteers

Aims: The aim of this study was to evaluate the pharmacogenetic variability in the disposition of repaglinide in healthy Chinese subjects. Methods: A single dose of 2 mg repaglinide was orally administered to 24 healthy Chinese subjects. The serum concentrations of repaglinide were measured by using liquid chromatography/tandem mass spectrometry. We determined the polymorphic alleles of MDR1 C1236T, MDR1 G2677T/A, MDR1 C3435T, CYP3A4*18, OATP1B1 G388A, and OATP1B1 T521C in each subject. Results: The area under the plasma concentration-time curve from time 0 to infinity (AUC_(0–inf)) of repaglinide was significantly higher in subjects possessing the MDR1 2677GT and 2677TT alleles than in those with the MDR1 2677GG and 2677TA alleles (p = 0.007). The mean AUCs and peak plasma concentration were higher in subjects with the 521TC allele than in those with the OATP1B1 521TT allele, and the OATP1B1 388A allele is associated with a reduced trend of pharmacokinetic exposure; however, these trends were not statistically significant. The pharmacokinetics of repaglinide was not associated with MDR1 C1236T, MDR1 C3435T, and CYP3A4*18. Conclusion: This study shows that the genetic polymorphisms of MDR1 G2677T/A might explain the variability in the pharmacokinetics of repaglinide in the Chinese population.

MDR1 gene C3435T polymorphism and cancer risk: a meta-analysis of 34 case–control studies

P-glycoprotein, the product of the MDR1 gene, is a transmembrane active efflux pump for a variety of environmental toxins and xenobiotics. Epidemiological studies have evaluated the association between MDR1 C3435T polymorphism and cancer susceptibility. However, published data are still inconclusive. To derive a more precise assessment of this relevance, we performed a meta-analysis, up to September 2010, of 5,196 cases with different cancer types and 6,827 controls from 34 published case-control studies. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for MDR1 C3435T polymorphism and cancer were estimated using fixed- and random-effects models when appropriate. The overall results suggested that the variant was associated with a moderately increased cancer risk in all comparison models tested (OR = 1.26, 95% CI: 1.06-1.50 for TT vs. CC; OR = 1.19, 95% CI: 1.04-1.37 for CT vs. CC; OR = 1.15, 95% CI: 1.01-1.32 for recessive model; OR = 1.21, 95% CI: 1.06-1.38 for domain model, and OR = 1.14, 95% CI: 1.04-1.26 for allele contrast). In the subgroup analysis by cancer types, significant associations were found in breast cancer (OR = 1.66, 95% CI: 1.24-2.21 for TT vs. CC; OR = 1.44, 95% CI: 1.14-1.82 for recessive model; OR = 1.41, 95% CI: 1.10-1.81 for domain model; and OR = 1.31, 95% CI: 1.13-1.52 for allele contrast) and renal cancer (OR = 1.99, 95% CI: 1.37-2.90 for TT vs. CC; OR = 1.74, 95% CI: 1.25-2.42 for domain model; OR = 1.43, 95% CI: 1.09-1.88 for recessive model; and OR = 1.40, 95% CI: 1.17-1.68 for allele contrast). However, no significant associations were found in colorectal cancer, gastric cancer, and acute lymphoblastic leukemia for all genetic models. In the ethnicity subgroup analysis, a significant association with cancer among Caucasians was found under the dominant model, homozygote comparison, CT versus CC comparison, and allele comparison. In summary, this meta-analysis suggests that the MDR1 C3435T polymorphism is associated with cancer susceptibility, increasing the risk of breast and renal cancer.