Effect Of ABCB1 Polymorphisms Research Articles

The effect of ABCB1 polymorphism on sirolimus in renal transplant recipients: a meta-analysis.

BackgroundSirolimus (SRL) is an immunosuppressive drug and substrate of the P-glycoprotein (P-GP) encoded by ABCB1. The relationship between ABCB1 polymorphism and the pharmacokinetics of SRL in different studies were conflicting in renal transplant recipients. Thus, this meta-analysis aims to investigate the influence of ABCB1 C3435T, C1236T, and G2677T/A polymorphisms on the dose-adjusted trough level (C/D) of SRL in renal transplant recipients.MethodsPubMed, Embase, and the Cochrane Library were searched for relevant studies. The quality of each eligible study was assessed according to Newcastle-Ottawa Scale. The STATA 15.0 was adopted to perform the meta-analysis. The fixed-effects model was used for pooled results with low heterogeneity (I2 ≤50%); otherwise, the random-effects model was used.ResultsA total of 6 studies were included in the meta-analysis. Results of pooled analysis showed no significant association of SRL C/D ratio with ABCB1 C3435T polymorphism. The subgroup analysis based on different ethnic groups and different time-points after SRL initiation in renal transplant recipients were also conducted. No significant association was observed in these subgroups. Significant associations were showed between ABCB1 C1236T polymorphism and the C/D ratio of SRL in the homozygous model (TT vs. CC; WMD: −45.54; 95% CI: −75.15, −15.94; P=0.003), and also in subgroup of Caucasian (TT vs. CC; WMD: −46.57; 95% CI: −91.90, −1.25; P=0.044 and TT vs. CC + CT; WMD: −52.10; 95% CI: −95.38, −8.82; P=0.018). Significant differences were found in association between the ABCB1 G2677T/A polymorphism and the C/D ratio of SRL, including the homozygous model (TT vs. GG; WMD: −76.47; 95% CI: −126.37, −26.58; P= 0.003), the heterozygous model (GT vs. GG,WMD: 178.62; 95% CI: 125.03, 232.22; P= 0.000), the dominant model (GT + TT vs. GG; WMD: 82.23; 95% CI: 36.28, 128.17; P=0.000), the recessive model (TT vs. GG + GT; WMD: −179.38; 95% CI: −283.33, −75.42; P=0.001), and the over-dominant model (GT vs. GG + TT; WMD: 199.44; 95% CI: 84.84, 314.05; P=0.001).ConclusionsNo significant association exists between ABCB1 C3435T polymorphism and the C/D ratio of SRL in renal transplant recipients. To achieve target therapeutic concentrations, ABCB1 C1236T homozygous mutant TT genotype will require a higher dose of sirolimus than wild type GG, especially in Caucasian renal transplant recipients. ABCB1 G2677T/A TT genotype will also need a higher dose of sirolimus genotype. Genotyping of ABCB1 might help to improve the individualization of SRL for renal transplant recipients. Further studies are expected to provide high-quality evidence.

Influence of ABCB1 polymorphisms on the pharmacokinetics and toxicity of lenalidomide in patients with multiple myeloma.

Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration-time curve (AUC0-24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0-24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0-24 in 1236C>T and 2677G>A/T polymorphisms. AUC0-24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21)(median 6324.6ngh/mL vs. 2857.4ngh/mL, p = 0.028). The AUC0-24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0-24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.

The Effect of ABCB1 Polymorphisms on Serial Tacrolimus Concentrations in Stable Austrian Long-Term Kidney Transplant Recipients.

The multidrug resistance 1 gene (ABCB1) encodes P-glycoprotein (PGP), mainly expressed in the liver and engaged in metabolism of drugs including the immunosuppressant tacrolimus (TAC). ABCB1 single nucleotide polymorphisms (SNP) may significantly alter pharmacokinetics and influence TAC concentrations of kidney transplant recipients (KTR). The genotype distribution of ABCB1 1236C>T, 2677G>T/A and 3435C>T was investigated among 96 Austrian KTR who were converted from cyclosporin to TAC. Dose adjusted TAC trough levels and L/D ratios were assessed at week 1, 2, 4, and 8, and month 3, 12, and 24, and the influence of ABCB1 genotypes on dose adjusted TAC trough levels and level to dose (L/D) ratios were analyzed. The genotype distributions for ABCB1 1236C>T were CC 36.4%, CT 5.2%, TT 58.3%, for ABCB1 2677G>T/A GA 2%, GG 63.5%, GT 20.8%, TA 1%, TT 12.5%, and for ABCB1 3435C>T CC 20.8%, CT 7.2%, TT 71.8%. Dose adjusted TAC trough levels and L/D ratios were independent of ABCB1 genotypes except for ABCB1 1236C>T at a single time point (week 2: 0.02599 [CC] vs. 0.05704 [CT] vs. 0.03218 [TT]; p = 0.024). Serial analyses of TAC trough levels revealed no significant association with important ABCB1 genotypes among stable long-term Austrian KTR.

The Effect of ABCB1 Polymorphisms On Tacrolimus Metabolism in Stable Long-Term Kidney Transplant Recipients.

The Effect of ABCB1 Polymorphisms On Tacrolimus Metabolism in Stable Long-Term Kidney Transplant Recipients.

Effect of ABCB1 polymorphism on the clinical outcome of osteosarcoma patients after receiving chemotherapy.

To investigate the role of three genetic polymorphisms of ABC proteins in response to chemotherapy and overall survival of osteosarcoma patients. A prospective study was conducted. Genotyping analyses of ABCB1 C3435T, ABCG2 C421A, and ABCC3 C-211T were conducted using the TaqMan methodology. Multivariate Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% CI of effect of each genotype of ABCB1 C3435T, ABCG2 c421A, and ABCC3 C-211T on PFS and OS. During the follow-up period, 135 patients (74.18%) were alive and 47 died (25.82). The median follow-up periods were 36.7 months. Individuals carrying with ABCB1 3435TT genotype and T allele showed less likely to have a poor response to chemotherapy. Cox regression analysis showed that individuals with ABCB1 TT genotype and T allele were associated with high risk of death from osteosarcoma when compared with wide-type genotype. However, we did not find significant association between ABCG2 C421A and ABCC3 C-211T polymorphisms and overall survival of osteosarcoma. ABCB1 C3435T polymorphism may be used as a genetic predictor of clinical outcome in osteosarcoma patients treated with chemotherapy. However, no association was found between polymorphisms in ABCG2 C421A and ABCC3 C-211T and clinical outcome of osteosarcoma.

Effect of ABCB1 polymorphisms and atorvastatin on sitagliptin pharmacokinetics in healthy volunteers

The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers. In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype (n = 9, CGC/CGC; n = 10, CGC/TTT; n = 10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin; in the other phase, participants received 40 mg of atorvastatin for 5 days, with a single 100 mg dose of sitagliptin administered on day 5. A 24-h pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period. Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with geometric mean ratios (90 % confidence intervals) for sitagliptin maximum plasma concentration, plasma concentration-time curve from zero to infinity, renal clearance, and fraction of sitagliptin excreted unchanged in the urine of 0.93 (0.86-1.01), 0.96 (0.91-1.01), 1.02 (0.93-1.12), and 0.98 (0.90-1.06), respectively. ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes.

A Drug Transporter for All Ages? ABCB1 and The Developmental Pharmacogenetics of Cyclosporine

Evaluation of: Fanta S, Niemi M, Jönsson S et al.: Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1polymorphisms. Pharmacogenet. Genomics 18(2), 77-90 (2008). The clinical use of the immunosuppressive agent cyclosporine is complicated by its toxicity, narrow therapeutic window and highly variable pharmacokinetics between individuals. In adults, genetic polymorphisms in the genes encoding the cyclosporine-metabolizing enzymes CYP3A4 and CYP3A5, as well as the ABCB1 gene, which encodes the efflux-pump P-glycoprotein, seem to have a limited effect, if any, on cyclosporine pharmacokinetics. However, the authors have now reported for the first time an association between cyclosporine oral bioavailability and the ABCB1 c.1236C>T and c.2677G>T polymorphisms, as well as the related haplotype c.1199G-c.1236C-c.2677G-c.3435C, in children with end-stage renal disease older than 8 years of age. Carriers of the variant alleles had a cyclosporine oral bioavailability that was around 1.5-times higher compared with noncarriers. This association was not observed in children younger than 8 years of age. In addition, no relation between cyclosporine disposition and genetic variation in the CYP3A4, CYP3A5, ABCC2, SLCO1B1 and NR1I2 genes was observed. These data suggest that the effect of ABCB1 polymorphisms on cyclosporine pharmacokinetics is related to age, and thus developmental stage. Although further study is necessary to establish the predictive value of ABCB1 genotyping for individualization of cyclosporine therapy in children older than 8 years, an important step towards further personalized immunosuppressive drug therapy has been made.

The Effect of ABCB1 Polymorphism on the Pharmacokinetics of Saquinavir Alone and in Combination with Ritonavir

This genotype panel study investigated the effect of ABCB1 polymorphism in exon 26 (C3435T), exon 21 (G2677T/A), and exon 12 (C1236T) on saquinavir pharmacokinetics and on the expression and activity of P-glycoprotein (P-gp) in peripheral blood monocytic cells (PBMCs). One hundred and fifty healthy volunteers were genotyped to identify 15 TT3435 and 15 CC3435 individuals. In these individuals, saquinavir pharmacokinetics were assessed after administration of a single oral dose of saquinavir 1,000 mg and saquinavir/ritonavir 1,000/100 mg. PBMC P-gp expression and activity were assessed in 15 and 19 subjects. The co-administration of ritonavir on study day 2 caused a significant increase in saquinavir exposure, in both TT3435 and CC3435 individuals. No correlation was observed between the ABCB1 C3435T, G2677T/A, and C1236T polymorphisms, separately and in haplotypes, with saquinavir pharmacokinetics, administered with or without ritonavir and with PBMC P-gp expression and activity. In conclusion, ABCB1 polymorphism has no pronounced effect on saquinavir exposure.