Impact of Cytochrome P450 3A and ATP-Binding Cassette Subfamily B Member 1 Polymorphisms on Tacrolimus Dose-Adjusted Trough Concentrations Among Korean Renal Transplant Recipients

Cho, J.-H.; Yoon, Y.-D.; Park, J.-Y.; Song, Eun Joo; Choi, Ji-Young; Yoon, Se-Hee; Park, S.-H.; Kim, Y.-L.; Kim, C.-D.

doi:10.1016/j.transproceed.2011.11.004

Cited by 33 publications

(26 citation statements)

References 19 publications

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“…The result of our study is in concordance with the reports of Crettol et al [2] who found that CYP3A4 rs4646437C[T polymorphism significantly influenced cyclosporine dose requirement and dose-adjusted trough concentrations (p \ 0.01). Cho et al [19] studied the relation between tacrolimus pharmacokinetics and cytochrome P450 3A polymorphisms. They found that CYP3A5 expressers group required higher tacrolimus dose and showed a greater tendency toward CNI toxicity after transplantation than non expressers.…”

Section: Discussionmentioning

confidence: 99%

“…According to Hardy-Weinberg equilibrium none of the observed frequencies was significant different from the expected frequencies. Recently Cho et al [19] studied 70 Korean renal transplant recipients who have been genotyped for MDR1 exon 21 G2677T/A polymorphism using TaqMan SNP genotyping assays. However, G2677T/A analysis was performed by pyrosequencing.…”

Section: Discussionmentioning

confidence: 99%

“…It is in linkage disequilibrium with another silent C1236T polymorphism in exon 12 and a non-synonymous substitution G2677T/A in exon 21 [13]. Variant alleles in ABCB1 C1236T, G2677T/A, and C3435T, whether present individually or in linkage, were reported to significantly decrease p-glycoprotein activity when compared with ABCB1 wild-type alleles [14]. The two SNPs in MDR1 2677 result in distinct amino acid changes, Ala 893 ser (G2677T) and Ala 893 Thr (G2677A).…”

Section: Introductionmentioning

confidence: 99%

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Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients

et al. 2014

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Advances in immunosuppressive therapy allowed renal transplantation to become the treatment of choice for suitable candidates with (end stage renal disease) ESRD. The post-transplant therapeutic strategy is difficult due to narrow therapeutic indices for the currently used immunosuppressive drugs. Inter-individual differences in drug bioavailability are related to genetic and non genetic factors. The idea of targeted and personalized therapy is to achieve therapeutic success. The empirical dose has lost its value in the post-transplant therapy and an individualized dosage regimen must be established. Interindividual heterogeneity in expression of ABCB1 and CYP3A4 has been suspected to be one of the factors resulting in cyclosporine (CsA) pharmacokinetic variation. This study aimed to investigate the impact of inter-individual CYP3A4 rs4646437C>T and MDR1 G2677T/A polymorphisms on cyclosporine dose requirements among a sample of renal transplant Egyptian recipients. Fifty adult Egyptian patients on CsA were genotyped for CYP3A4 rs4646437C>T and MDR1 G2677T/A and correlated with CsA dose requirement and dose-adjusted CsA (C0) blood levels at 3, 6, and 9 months post transplantation. CYP3A4 rs4646437C>T influenced significantly cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. Daily dose requirements were also significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9 months post transplantation. Genotyping of both CYP3A4 and MDR1 SNPs may be helpful in providing pre-transplant pharmacogenetic information to individualize CsA dosing. Heterozygous CT genotype is the most frequent CYP3A4 rs4646437C>T genotype in the studied group of Egyptian population (48 %) followed by CC genotype and TT genotype. Daily dose requirements were significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9 months post transplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients

et al. 2014

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“…A polymorphism in intron 3 of CYP3A5, the CYP3A5*3 allele, results in a premature stop codon, whereas individuals carrying the CYP3A5*1 allele express this enzyme normally . Several studies have associated the presence of CYP3A5*1 allele with lower doseadjusted tacrolimus blood concentrations and higher tacrolimus dose requirements (Glowacki et al, 2011;Cho et al, 2012). On the other hand, the influence of ABCB1 polymorphisms (gene coding for P glycoprotein) on tacrolimus pharmacokinetics and clinical outcomes is still controversial Glowacki et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

et al. 2012

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Pharmacogenetics correlates certain genetic variants, such as single nucleotide polymorphisms (SNPs), with blood drug levels, efficacy, and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible for omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. Seventyfive renal transplant recipients treated with tacrolimus and concomitant omeprazole were genotyped in a panel of 37 SNPs with use of Sequenom MassArray. The patients with CYP2C19*2/*2 genotype (n = 4) showed a median posttransplantation hospital stay of 27.5 days (95% confidence interval [CI], 23-39 days), compared with 12 days (95% CI, 10-15 days) in patients with CYP2C19*1/*1 or CYP2C19*1/*2 (n = 71; P = 0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels (C min /[dose/weight]) during the first week after trasplantation (in 59 patients with data on levels; P = 0.021, Kruskal-Wallis), excluding the patients with atypical metabolisms due to

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“…The *1/*1 genotype frequencies were not in Hardy-Weinberg equilibrium, wherein a greater than expected number of the wild-type homozygotes was observed (p=0.0007). There were contradicting reports on whether CYP3A5*3 polymorphism follows Hardy-Weinberg equilibrium in various ethnic groups (25)(26)(27)(28). The likely explanation for the deviation from HardyWeinberg equilibrium is that differential selection process in some geographical region could be operating against the *3 allele, given that the CYP3A5 activity is associated with xenobiotic detoxification and the lack of activity could pose a significant risk (27).…”

Section: Frequencies Of Abcb1 C3435t and Cyp3a5 A6986g Polymorphism Imentioning

confidence: 99%

A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

Heuberger

Shilbayeh³

et al. 2013

AAPS J

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Abstract. The SNP A6986G of the CYP3A5 gene (*3) results in a non-functional protein due to a splicing defect whereas the C3435T was associated with variable expression of the ABCB1 gene, due to protein instability. Part of the large interindividual variability in tacrolimus efficacy and toxicity can be accounted for by these genetic factors. Seventy-two individuals were examined for A6986G and C3435T polymorphism using a PCR-RFLP-based technique to estimate genotype and allele frequencies in the Jordanian population. The association of age, hematocrit, platelet count, CYP3A5, and ABCB1 polymorphisms with tacrolimus dose-and body-weight-normalized levels in the subset of 38 pediatric renal transplant patients was evaluated. A Markov model was used to evaluate the time-dependent probability of an adverse event occurrence by CYP3A5 phenotypes and ABCB1 genotypes. The timedependent probability of adverse event was about double in CYP3A5 non-expressors compared to the expressors for the first 12 months of therapy. The CYP3A5 non-expressors had higher corresponding normalized tacrolimus levels compared to the expressors in the first 3 months. The correlation trend between probability of adverse events and normalized tacrolimus concentrations for the two CYP3A5 phenotypes persisted for the first 9 months of therapy. The differences among ABCB1 genotypes in terms of adverse events and normalized tacrolimus levels were only observed in the first 3 months of therapy. The information on CYP3A5 genotypes and tacrolimus dose requirement is important in designing effective programs toward management of tacrolimus side effects particularly for the initial dose when tacrolimus blood levels are not available for therapeutic drug monitoring.

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Impact of Cytochrome P450 3A and ATP-Binding Cassette Subfamily B Member 1 Polymorphisms on Tacrolimus Dose-Adjusted Trough Concentrations Among Korean Renal Transplant Recipients

Cited by 33 publications

References 19 publications

Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients

Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

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