MDR1 haplotypes significantly minimize intracellular uptake and transcellular P-gp substrate transport in recombinant LLC-PK1 cells

To date, research on the effect of single nucleotide polymorphisms (SNPs) on P-glycoprotein (P-gp) expression and functionality has rendered inconsistent results. This study systematically evaluates the impact of MDR1 haplotypes (1236/2677, 1236/3435, 2677/3435, 1236/2677/3435) on P-gp functionality compared to individual SNPs (1236, 2677, and 3435) in validated stable recombinant epithelial cells. Recombinant LLC-PK1 cells expressing MDR1wt or its variants were developed and validated for this purpose. Intracellular accumulation and time-dependant efflux of a P-gp substrate, Rhodamine 123 (R123, 5 microM) were evaluated in control and recombinant cells. Additionally, the transepithelial transport of R123 (1 microM) and Vinca alkaloids (5 microM) was evaluated. Except for MDR1(2677T) and MDR1(1236T/2677T/3435T), cells expressing MDR1 variants displayed intermediate R123 intracellular accumulation (1.5-2-fold higher) and lower effluxed R123 (10-20% vs. 52%) compared to those expressing MDR1wt. Efflux ratios across MDR1wt expressing cells were significantly larger for R123 (3.95+/-1.1), Vinblastine (3.75+/-0.26), and Vincristine (2.8+/-0.29). Recombinant cells expressing MDR1 variants displayed 0%-22.7% P-gp activity (approximately 80%-100% efflux loss). Results suggest that MDR1 polymorphisms at the 1236, 2677, and/or 3435 positions significantly minimize P-gp functionality in vitro, the extent of which appears to be substrate dependant.     

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.     

MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer

The genotype frequencies of MDR1 T-129C, C1236T, G2677A,T and C3435T SNPs were compared in 154 healthy Japanese and 100 healthy Caucasians to provide basic information on the inter-ethnic differences of pharmacotherapeutic outcome. The variants were found at allelic frequencies of 5.5%, 65.6%, 16.6%, 40.6% and 40.6%, for T-129C, C1236T, G2677A, G2677T and C3435T, respectively, in Japanese, and at 5.1%, 45.9%, 3.6%, 46.4% and 56.6%, respectively, in Caucasians, with a statistically significant difference for C1236T, G2677A,T and C3435T (p<0.001). G2677A was about 5-fold more frequent in Japanese than Caucasians. These genotype frequencies were also investigated in 95 Japanese patients with colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC), but no significant difference was detected, when compared with healthy Japanese subjects. The haplotype frequency reached a total of about 85% in Japanese with the following 4 major haplotypes; T(-129)-T1236-T2677-T3435 (36.1%), T(-129)-T1236-G2677-C3435 (22.5%), T(-129)-C1236-G2677-C3435 (14.2%) and T(-129)-C1236-A2677-C3435 (13.3%). The second and fourth haplotypes were hardly inferred in Caucasian, whereas T(-129)-C1236-G2677-T3435 (12.8%) was found to be Caucasian-specific. There was a tendency for higher frequencies of the T(-129)/C-(129)-C1236-A2677-C3435 haplotype in Japanese CRC patients and T(-129)-T1236-T2677-T3435 haplotype in Japanese ESCC patients, compared with that in healthy Japanese subjects.     

Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms

The ABC transporter P-glycoprotein is a product of the MDR1 gene and its function in human placenta is to extrude xenobiotics from the tissue thus decreasing fetal exposure. The goal of this investigation was to examine the effect of three polymorphisms in the MDR1 gene on the expression and activity of placental P-gp. In 199 term placentas examined, the C1236T variant was associated with 11% lower P-gp protein expression than wild-type, while the C3435T and G2677T/A variants each were associated with a 16% reduction (p < 0.05). Homozygotes for the C1236T and C3435T variant allele (TT) were associated with 42% and 47% increase in placental P-gp transport activity, respectively (p = 0.04 and p = 0.02) of the prototypic substrate, [³H]-paclitaxel. These findings indicate that the C3435T and G2677T/A SNPs in MDR1 are significantly associated with decreased placental P-gp protein expression, while the C1236T and C3245T homozygous variants are significantly associated with an increase in its efflux activity.     

Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms

OBJECTIVES: Variable expression of the ABC-type multidrug resistance membrane protein P-glycoprotein (P-gp, MDR1, ABCB1) in human heart is a potential modulator of drug effects or drug-induced cardiotoxicity. Expression of P-gp is known to be affected by single nucleotide polymorphisms in the MDR1 gene. Therefore, genotype-dependent expression of P-gp could be an important modulator of action of cardiac drugs. METHODS: Heart tissue (auriculum) from 51 patients undergoing coronary artery bypass graft surgery was screened for genotype-dependent P-gp expression. P-gp was identified by immunoblotting and localized using immunohistochemistry. MDR1 mRNA was quantified by real-time PCR and immunohistochemistry and related to the MDR1 genotypes G2677T/A (Ala893Ser/Thr) and C3435T. RESULTS: MDR1/18S rRNA mRNA copy numbers in heart auriculum were 3.48 +/- 2.25 x 10(-6) compared to 4.56 +/- 0.58 x 10(-6) in non-failing ventricular samples studied before. While the exon 26 C3435T genotype did not influence MDR1 mRNA expression, we found significantly elevated MDR1 mRNA expression in 10 patients carrying the exon 21 2677 AT or TT genotype as compared to 12 patients carrying the GG-variant with intermediate MDR1 mRNA expression in 29 heterozygous samples. P-gp was detected in the endothelial wall. Quantitative immunohistochemistry of protein expression, however, did not reveal significant influence of the studied SNPs. CONCLUSION: The present study based on auricular samples suggests that genetic factors play a rather limited role in modulating P-gp expression in human heart. Therefore, the substantial interindividual variability in cardiac P-gp expression is likely related to environmental or disease related factors.     

江苏地区汉族儿童多药耐药基因3个单核苷酸多态性位点的单倍型研究

目的分析江苏汉族人群多药耐药基因-1（MDR1）的单核甘酸多态（12外显子1236C→T突变、21外显子2677G→T/A突变、26外显子3435C→T突变）及其构成的单倍型分布。方法通过多重单碱基延伸反应（SNaPshotSNP分型技术）对江苏地区170名健康儿童的MDR1C1236T、G2677T/A、C3435T的SNP位点进行基因分型,统计各基因型频率。UNPHASED软件对MDR1的SNPs（C1236T-G2677T/A-C3435T）进行单倍型分析。结果在170例儿童中,等位基因1236T、2677T、2677A、3435T频率分别为63.5%、37.4%、17.0%和35.0%。基因型频率分布符合Hardy-Weinberg平衡（HWE）,差异无统计学意义（P〉0.05）。MDR1的1236、2677、3435三个位点间（C1236T-G2677T/A-C3435T）存在连锁不平衡性,以TTT（31.8%）、TGC（25.3%）、CGC（17.7%）和CAC（16.2%）四种单倍型为主。结论江苏地区汉族人群MDR1的单核甘酸多态及单倍型分布具有自己的特点。在临床应用相关药物时,进行基因型及单倍型检测,将有助于指导临床个体化用药。     

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.     

Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers

Objective The multidrug resistance gene 1 (MDR1) seems to play a role in the carcinogenesis of colorectal tumors. The importance of MDR1 SNPs 2677G > T/A in exon 21 and 3435C > T in exon 26 for cancer susceptibility, however, has not yet been clearly defined. Methods Two hundred and eighty-five colorectal cancer patients and 275 controls from five hospitals in the European part of Russia were genotyped for the polymorphisms −129T > C (rs3213619) in exon 1b, 2677G > T/A (rs2032582), and 3435C > T (rs1045642) in this population-based case-control study. Genotype-phenotype analysis was performed with simultaneous consideration of lifestyle risk factors. Results Our analysis confirmed the preponderate impact of smoking on colorectal cancer development. The risk of heavy smokers (≥60 pack years) to develop colorectal cancer by far exceeded that of lifelong non-smokers (OR = 3.9, 95% CI: 1.4 to 10.6). Smoking is a more potent risk factor than is the genetic influence of MDR1 in our study. However, a smoking and age-stratified analysis, revealed a statistically significant association between MDR1 genotypes and colorectal cancer in life-long non-smokers with an age ≥63 years (the median age in our sample). The association was stronger for rectal cancer than for colon cancer. Patients who carried the genotypes (−129TT; 2677GG; 3435CC) or (−129TT; 2677TT; 3435TT) developed more frequently colorectal cancer than others (OR = 3.9; 95% CI: 2.0 to 7.7). Conclusions Our results show that the interaction of genetic and lifestyle risk factors should be taken into account to elucidate the genetic influence of MDR1 variability on cancer susceptibility.     

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.     

Frequency of common MDR1 gene variants in a Polish population

P-glycoprotein (P-gp) is a transmembrane transporter playing an important role in drug efflux. There is growing evidence that P-gp activity may be related to haplotypes of MDR1 gene. In the current study, the frequencies of common functional polymorphisms in MDR1 gene (2677G > A,T and 3435C > T) were evaluated using PCR-RFLP and allele-specific amplification, in a group of 204 healthy individuals of Caucasian origin from Poland. It was found that the frequencies of the studied single nucleotide polymorphisms were similar to those reported for other Caucasian populations, and were as follows: 2677G-3435C--0.453, 2677G-3435T--0.143, 2677T-3435C--0.015, 2677T-3435T--0.370, 2677A-3435C--0.008, 2677A-3435T--0.011. The results of our study may give the basis for predicting pharmacokinetic and pharmacodynamic effects of many commonly used drugs in the Polish population.     

Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver

AIMS: The aim of the study was to determine whether a correlation exists between MDR1 (ABCB1) gene polymorphisms at positions 3435 (C3435T) and 2677 (G2677T(A)) and the expression of human hepatic P-glycoprotein (P-gp). METHODS: P-gp protein expression in 26 human livers was assessed by Western blotting and ABCB1 mRNA expression was determined by real time RT-PCR. The C3435T and G2677T(A) polymorphisms were identified by RFLP and direct sequence analysis, respectively. RESULTS: The C and G allele frequencies for the C3435T and G2677T(A) polymorphisms were 0.48 and 0.79, respectively, and the genotypes were in Hardy-Weinberg equilibrium. There was a 200- and 20-fold variation in the expression of ABCB1 mRNA and Pgp protein expression, respectively. There were no differences in mRNA and protein expression identified amongst the different genotypes attributable to the C3435T and G2677T(A) polymorphisms in the ABCB1 gene. Exposure to a PXR ligand prior to death did not influence mRNA or protein expression. CONCLUSIONS: There is substantial variability in the expression of Pgp in human liver, but this is not due to the presence of C3435T and G2677T(A) polymorphisms in the ABCB1 gene, although our study is limited by a small sample size.     

ABCB1 C3435T and G2677T/A polymorphism decreased the risk for steroid-induced osteonecrosis of the femoral head after kidney transplantation

Advances in transplantation technology have brought about great benefits to patients suffering from organ failure, but the problem still remains of complications induced by steroids used for post-transplant immunosuppression. Among the side-effects caused by steroids, non-traumatic osteonecrosis of the femoral head (ONF) constitutes a serious problem. The same protocol for steroid administration induces ONF in some patients, but not in others, indicating the presence of individual difference in steroid sensitivity. We hypothesized that this difference might be mediated by the drug-transport protein, P-glycoprotein (P-gp), and investigated the relationship between single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1, MDR1) encoding P-gp and ONF. Subjects comprised 136 patients receiving kidney transplantation. Thirty patients developed post-transplant ONF. Genomic DNA was extracted from peripheral blood, and genotypes of ABCB1 C3435T (exon 26) and G2677T/A (exon 21) were determined by direct sequencing. Multivariate analyses based on clinical information were performed to determine the relationship between ABCB1 genotypes and ONF. The dose/concentration (D/C) ratios of tacrolimus were also determined to estimate the activity of P-gp in patients with different genotypes of ABCB1 C3435T (CC, CT, TT), and in those who did and did not develop ONF. The ABCB1 3435TT genotype showed a significantly lower incidence of ONF (adjusted odds ratio = 0.10, P = 0.034). The D/C ratio in the 3435TT genotype was significantly higher than that in the 3435CC genotype. The D/C ratio in patients developing ONF was significantly higher than in those patients who did not develop ONF. The results suggest increased activity of P-gp in patients with the 3435TT genotype and in those who did not develop ONF. The ABCB1 2677 homozygous variant type also showed a lower incidence of ONF (adjusted odds ratio = 0.26, P = 0.056). The 3435T and 3435C alleles were in linkage disequilibrium with the 2677T and the 2677G alleles, respectively, in the study population. An assessment of C3435T and G2677T/A polymorphisms preceding steroid treatment could be useful for predicting the resistance to ONF development.     

MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients

This retrospective study investigated the impact of MDR1 haplotypes derived from the single-nucleotide polymorphisms (SNPs) 2677G>T (exon 21) and 3435C>T (exon 26) on the pharmacokinetics of cyclosporine in 98 renal transplant patients. Based on SNPs 2677 and 3435, four different haplotypes and nine different genotypes were identified in the study sample. Frequencies of SNPs, genotypes, and haplotypes were in agreement with previously reported values. Cyclosporine pharmacokinetics were characterized using a 2-hour AUC (AUC0-12), trough concentrations (C0), and blood concentrations 2 hours after cyclosporine administration (C2). No significant differences in dose-corrected AUC0-12, C0, or C2 values were observed between carriers of different SNP variants and genotypes (Kruskal-Wallis test), as well as between carriers and noncarriers of each haplotype (Mann-Whitney U test). Carriers of haplotype 12 (2677G and 3435T), which has previously been associated with increased digoxin AUC values, had a median AUC0-12 of 18.9 micro g*h*L-1 (range: 9.0-35.2) compared to 17.5 micro g*h*L-1 (range: 7.5-37.1) in the noncarrier group. It was concluded that MDR1 haplotypes derived from the SNPs 2677G>T (exon 21) and 3435C>T (exon 26) are not associated with cyclosporine pharmacokinetics in renal transplant patients.     

Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects

In the present study, we examined whether polymorphisms in the ATP-binding cassette (ABC) transporter genes, MDR1, MRP1 and MRP2, were associated with their respective mRNA expression levels in duodenal enterocytes of 13 healthy Japanese volunteers. MDR1 genotypes of T-129C, G2677(A,T) and C3435T, MRP1 genotypes of G128C, C218T, G2168A and G3173A, and MRP2 genotypes of C-24T, G1249A, C2302T, C2366T and G4348A were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or direct sequencing. Mutations T-129C, G2677(A,T) and C3435T of MDRI gene were found at allele frequencies of 2/26, 16/26 and 12/26, respectively. Mutations G2168A of the MRPI gene and C-24T of the MRP2 gene were also found at allele frequencies of 1/26 and 6/26, respectively, whereas other mutations were not detected in MRP1 and MRP2 genes. The relative concentrations (mean +/- S.E.) of MDR1 mRNA to villin mRNA were 0.38 +/- 0.15, 0.56 +/- 0.14 and 1.13 +/- 0.42 in the subjects with C/C3435, C/T(3435) and T/T(3435), respectively, which supported the lower serum concentrations of digoxin after single oral administration in the subjects with the mutant T-allele at position 3435. Genetic collaboration between positions 3435 and 2677 was suggested, and those in G/G2677, G/(A,T)(2677) and T/(A,T)(2677) were 0.16 +/- 0.05, 1.10 +/- 0.40, and 0.63 +/- 0.16, respectively (p = 0.107). However, there was no remarkable effect of the G2168A of the MRP1 gene or of C-24T of the MRP2 gene on the relative MRP1 or MRP2 mRNA concentrations, respectively.     

Analyses of single nucleotide polymorphisms and haplotype linkage of the humanABCB1 (MDR1) gene in Korean

Single nucleotide polymorphisms (SNPs) in theMDR1 gene that are responsible for drug efflux can cause toxicity. Therefore, this study determined the SNPs of the KoreanMDR1 gene, and analyzed the haplotypes and a linkage disequilibrium (LD) of the SNPs determined. The frequency of 9 SNPs from theMDR1 gene was determined by PCR-RFLP analyses of 100 to 500 healthy individuals. The frequcies of the SNPs were C3435T (47.7%), G2677T (37.6%), G2677A (4.4%), T1236C (21.7%), T129C (8%), A2956G (2.5%), T307C (1.5%), A41aG (9.2%), C145G (0%), and G4030C (0%). Analyses of the haplotype structure and an estimation of the LD of the combined polymorphisms demonstrated that the frequency of the 1236T-2677G-3435T haplotype is much higher in Koreans (14.1%) than in Chinese and western black Africans and the C3435T SNP in Koreans appears to have LD with T129C in Koreans for the first time. These results provide insight into the genetic variation ofMDR1 in Koreans, and demonstrated the possibility of a new LD in this gene.     

MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients

AIM: This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients. METHODS: Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C(0)) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype. Additionally, CYP3A5 genotype (6956G > A) was determined. RESULTS: No significant differences were observed between groups. Differences in mean tacrolimus C(0) values between carriers and noncarriers of each haplotype ranged from -0.04 microg/litre (95% confidence interval: -0.53 to 0.60) to -23 microg/litre (-1.07 to 1.53). No association was found between CYP3A5*1/*3 genotype and tacrolimus Co concentractions. CONCLUSION: MDR1 haplotypes derived from the SNPs 2677G > T (exon 21) and 3435C > T (exon 26) do not influence the pharmacokinetics of tacrolimus in renal transplant patients.     

MDR1 genotypes do not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic males

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The absorption of valacyclovir presents a highly negative correlation with the level of P-glycoprotein expression.
• It has been confirmed that a polymorphism of the MDR1 gene in exon 26 is related to the level of P-glycoprotein expression in intestine.
• This study was conducted to find the relationship between polymorphism of MDR1 gene and absorption of valacyclovir.

WHAT THIS STUDY ADDS

• Linkage disequilibrium exists between G2677T/A in exon 21 and C3435T in exon 26, between C1236T in exon 12 and C3435T, but not between C1236T and G2677T/A of MDR1 gene in the Chinese Han ethnic population.
• Three single nucleotide polymorphisms of MDR1 gene do not influence the absorption of valacyclovir in the healthy Chinese Han ethnic population.

AIMS

To investigate the influence of three single nucleotide polymorphisms (SNPs) in exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) of MDR1 gene on the absorption of valacyclovir after a single oral administration in the Chinese Han ethnic population.

METHODS

Two hundred healthy Chinese subjects were genotyped for the SNPs of C1236T, G2677T/A and C3435T in the MDR1 gene using allele-specific polymerase chain reaction. Linkage disequilibrium (LD) was analysed. Twenty-four subjects derived from a large random sample (n = 200) received a single oral dose of 600 mg valacyclovir. Plasma concentrations of acyclovir were determined up to 14 h after administration to obtain a pharmacokinetic profile.

RESULTS

LD existed between G2677T/A in exon 21 and C3435T in exon 26 (P < 0.001), between C1236T in exon 12 and C3435T (P < 0.001), but not between C1236T and G2677T/A (P > 0.05). C_max, AUC_{0–1.5 h} and AUC_0–∞ were used as indices of valacyclovir absorption. AUC_0–∞ for the 2677TA genotype was 17.45 ± 2.40 µg × h/ml, which was much higher compared with the 2677GG, GA and TT genotypes of 10.44 ± 1.00, 11.84 ± 2.83, 11.34 ± 2.32 µg × h/ml, respectively (P < 0.05). Similarly, a statistically significant difference of AUC_0–∞ was also observed for different linked genotypes at position 2677 vs. 3435, and 1236 vs. 3435 (P < 0.05). However, there was no significant difference in valacyclovir absorptive pharmacokinetics between carriers and noncarriers of different haplotypes (P > 0.05).

CONCLUSIONS

Three SNPs of MDR1 gene did not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic subjects.     

Pharmacokinetics of paclitaxel in ovarian cancer patients and genetic polymorphisms of CYP2C8, CYP3A4, and MDR1

Interindividual differences in the pharmacokinetics of paclitaxel and its metabolites in Japanese ovarian cancer patients were investigated in relation to genetic polymorphisms of the CYP2C8, CYP3A4, and MDR1 genes. The area under the concentration-time curve (AUC) ratios of paclitaxel/6alpha-hydroxypaclitaxel and paclitaxel/3 -p-hydroxypaclitaxel calculated as the metabolic index of CYP2C8 and CYP3A4 showed 13- and 12-fold interindividual variations, respectively. No patient had any CYP2C8 variants, while 2 patients were heterozygotes of CYP3A4*16. For the MDR1 gene, the frequencies of -129C, 1236C, 2677T, 2677A, and 3435T alleles were 2.2%, 8.7%, 56.5%, 4.4%, and 52.2%, respectively. Subjects possessing the 3435T allele had a significantly (P < .05) higher AUC of 3'- p-hydroxypaclitaxel compared to those possessing the 3435C allele. Leukocytopenia was significantly (P < .05) related to the AUC of paclitaxel. Genotyping of the CYP2C8, CYP3A4, and MDR1 genes might not be essential to predict adverse effects of paclitaxel in Japanese patients, although an allelic variant of MDR1 may functionally affect the pharmacokinetics of its metabolite.     

MDR1 genetic polymorphisms and comparison of MDR1 haplotype profiles in Korean and Vietnamese populations

Two representative genetic variants of the MDR1 gene, 3435C>T and 2677G>T/A, show wide interethnic differences in its genetic polymorphism. In this study, the authors evaluated the genetic polymorphisms of MDR1 and directly compared MDR1 haplotype profiles of the Korean and Vietnamese populations. The 3435C>T and 2677G>T/A variations were analyzed in 632 Koreans and 142 Vietnamese using pyrosequencing. The allelic frequencies of 3435C>T did not significantly differ between the Korean (39.3%) and Vietnamese (36.6%) groups. However, the frequencies of mutant alleles at 2677 locus (T or A allele) showed a significant difference between Koreans (56.2%) and Vietnamese (41.9%), as the frequency of 2677A allele in the Korean subjects (17.1%) was much higher than that of the Vietnamese subjects (6.3%). Linkage analysis revealed that 2677A allele is closely linked to 3435C allele. The frequency of 2677A-3435C haplotype in Koreans was 15.4%, which was significantly higher than that found in Vietnamese subjects (6.3%). In conclusion, the frequencies of MDR1 variants and haplotype profiles showed significant differences between the Korean and Vietnamese populations, especially with respect to the 2677G>T/A variants. Because the 2677A allele was recently found to be functional in vivo and was detected at a high frequency in Koreans, the genotyping of this variant is necessary for pharmacogenetic studies of MDR1 in this population. In addition, by virtue of strong linkage disequilibrium, 2677A-3435C haplotype may help improve the predictability of MDR1 genetic polymorphism for MDR1 functional changes.     

C1236T、 G2677T/A 和C3435T 基因多态性与乳腺癌分子分型的关系及意义

摘要： 目的 观察多药耐药基因 1 （MDR1） 第 12、 21 及 26 外显子 C1236T、 G2677T/A 和 C3435T 基因多态性在乳腺癌患者外周血中的分布, 分析其与分子分型的关系。方法 应用高分辨熔解曲线 （HRM） 技术检测 400 例乳腺癌患者 C1236T、 G2677T/A 及 C3435T 基因多态性。采用 Hardy-Weinberg 遗传平衡检验进行基因型分布遗传平衡吻合度检验。参照 2013 年 St.Gallen 国际专家乳腺癌分子分型共识。分析乳腺癌患者中 C1236T、 G2677T/A 和 C3435T 基因型分布特点, 并探讨其与分子分型的关系。结果 （1）400 例乳腺癌患者中 C1236T、 G2677T/A 和 C3435T 中分别有 2 例、 3 例和 2 例标本未得出基因分型结果, C1236T 位点 CC、 CT 和 TT 基因型分别占 16.08% （64/398）、 44.22% （176/398） 和 39.70% （158/398）; G2677T/A 位点 GG、 GT、 GA、 TT 和 AT 基因型分别占 16.62% （66/397）、 44.33% （176/ 397）、 7.05% （28/397）、 27.46% （109/397） 和 4.54% （18/397）; C3435T 位点 CC、 CT 和 TT 基因型分别占 21.11% （84/ 398）、 56.03% （223/398） 和 22.86% （91/398）。经 Hardy-Weinberg 遗传平衡检验, 认为 C1236T、 G2677T/A 和 C3435T 基因多态性具有群体代表性 （P > 0.05）。（2） 分子分型显示, 11例人类表皮生长因子受体2 （HER-2, 2+） 患者未行荧光原位杂交 （FISH） 检测予以剔除, 其中Luminal A型占41.90% （163/389）, Luminal B型占32.65% （127/389）, HER-2过表达型占13.62% （53/389）, 三阴型占11.83% （46/389）。（3） C3435T位点CT/TT基因型在Luminal A型患者中的频率高于其在HER-2过表达型和三阴型患者中的频率 （χ2 =12.011, P=0.001; χ2 =13.976, P < 0.001）, C1236T和G2677T/A基因多态性在不同分子分型中的分布差异无统计学意义 （P > 0.05）。结论 MDR1基因C3435T位点多态性可以为乳腺癌异质性提供更合理的补充, 不同乳腺癌分子分型患者中CT/TT基因表型可能对药物治疗更敏感。