Associations of ABCB1 3435C&gt;T and IL-10-1082G&gt;A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients

Sam, Wai Johnn; Chamberlain, Christine; Lee, Su-Jun; Goldstein, Joyce A.; Hale, Douglas A.; Mannon, Roslyn B.; Kirk, Allan D.; Hon, Yuen Yi

doi:10.1097/tp.0b013e3182384ae2

Cited by 28 publications

(17 citation statements)

References 35 publications

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“…Mean TC and LDL-C levels were 26.9 mg/dL and 24.9 mg/dL higher in ABCB1 3435T carriers than 3435CC homozygotes for an average SRL trough of 4 ng/mL with no concomitant medication. These results agree with the trends of higher basal TC and LDL-C levels in ABCB1 3435T carriers with hypercholesterolemia (17), and are consistent with our previous finding showing higher SRL log C/D in ABCB1 3435T carriers, further confirming the role of ABCB1 gene in SRL pharmacokinetics (9) and pharmacodynamics. Presumably, the presence of the ABCB1 3435T allele leads to lower p-glycoprotein (P-gp) activity causing higher SRL trough concentration (9) and enhanced SRL toxicity.…”

Section: Discussionsupporting

confidence: 92%

“…These results agree with the trends of higher basal TC and LDL-C levels in ABCB1 3435T carriers with hypercholesterolemia (17), and are consistent with our previous finding showing higher SRL log C/D in ABCB1 3435T carriers, further confirming the role of ABCB1 gene in SRL pharmacokinetics (9) and pharmacodynamics. Presumably, the presence of the ABCB1 3435T allele leads to lower p-glycoprotein (P-gp) activity causing higher SRL trough concentration (9) and enhanced SRL toxicity. Aggravated lipid elevations may be resulted from reduced P-pg mediated transport of steroids as well (18).…”

Section: Discussionsupporting

confidence: 92%

“…The variant allele frequencies for the ABCB1 1236C>T , 2677 G>T/A , and 3435C>T , CYP3A4 -392A>G , CYP3A5 6986A>G and 14690G>A , IL-10 -1082G>A , and TNF - 308 G>A polymorphisms were summarized in a previous report (9). The frequencies for ApoEε2, ε3, and ε4 alleles were 0.119, 0.75, and 0.131, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…While CYP3A5 6986A>G was significant in the univariate analyses, it was not included in the multivariate analyses because it was not in Hardy-Weinberg equilibrium (9). Multivariate analyses showed that ABCB1 3435C>T under the dominant model was the only significant genetic factor associated with TC and LDL-C values after SRL administration (p = 0.0001 and <0.0001, respectively, in the final model).…”

Section: Resultsmentioning

confidence: 99%

“…The adenosine triphosphate-binding cassette, subfamily B, member 1 ( ABCB1 ) 3435C>T under the dominant genetic model and interleukin ( IL ) -10 -1082G>A under the recessive genetic model were found to be significantly associated with log-transformed SRL dose-adjusted, weighted-normalized trough concentration (C/D) (9). Mean SRL C/D was 48% higher in patients with ABCB1 3435CT/TT genotype than that with 3435CC genotype.…”

Section: Introductionmentioning

confidence: 99%

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Associations of ABCB1 and IL-10 Genetic Polymorphisms With Sirolimus-Induced Dyslipidemia in Renal Transplant Recipients

et al. 2012

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Backgrounds Hyperlipidemia is a common adverse effect of sirolimus (SRL). We previously showed significant associations of ABCB1 3435C>T and IL-10 -1082G>A with log-transformed SRL dose-adjusted, weighted-normalized trough. We further examined to see whether these polymorphisms were also associated with SRL-induced dyslipidemia. Methods Genotyping was performed for ABCB1 1236C>T, 2677 G>T/A, and 3435C>T, CYP3A4 -392A>G, CYP3A5 6986A>G and 14690G>A, IL-10 -1082G>A, TNF - 308G>A, and ApoEε2,ε3, and ε4 alleles. The longitudinal changes of total cholesterol (TC), low-density lipoprotein (LDL)-C, and triglyceride (TG) levels after SRL treatment prior to statin therapy were analyzed by a linear mixed-effects model, with adjustments for selected covariates for each lipid. Results Under the dominant genetic model, ABCB1 3435C>T was associated with TC (p=0.0001) and LDL-C (p<0.0001) values after SRL administration. Mean TC and LDL-C levels were 26.9 and 24.9 mg/dL higher, respectively, in ABCB1 3435T carriers than 3435CC homozygotes at an average SRL trough concentration of 4 ng/mL without concomitant medication. ABCB1 1236C>T under the recessive model and IL-10 -1082G>A under the dominant model were associated with log-transformed TG values (p=0.0051 and 0.0436, respectively). Mean TG value was 25.1% higher in ABCB1 1236TT homozygotes compared to ABCB1 1236C carriers and was 12.4% higher in IL-10-1082AA homozygotes than -1082G carriers. Conclusions ABCB1 polymorphisms were found to be associated with lipid responses to SRL treatment, confirming the role of ABCB1 gene in SRL pharmacokinetics and pharmacodynamics. Further studies are necessary to define the role of ABCB1 and IL-10 polymorphisms on SRL-induced dyslipidemia in renal transplantation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Associations of ABCB1 and IL-10 Genetic Polymorphisms With Sirolimus-Induced Dyslipidemia in Renal Transplant Recipients

et al. 2012

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ABCB1 haplotype influences the sirolimus dose requirements in Chinese renal transplant recipients

Lee

Huang

Chen

et al. 2013

Biopharm & Drug Disp

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Sirolimus, an immunosuppressive drug used to prevent organ rejection after renal transplantation, has a narrow therapeutic index and a large inter-individual variability of pharmacokinetics. The aim of this study was to analyse the dose-normalized trough blood concentrations (C0 /D ratio) of sirolimus in patients with different genotypes and attempt to investigate the possible associations between ABCB1/CYP3A5 genotypes and sirolimus dose requirements in Chinese renal transplant recipients. Blood samples were collected from 85 Chinese renal transplant recipients who were treated with sirolimus for at least 3 months and polymorphisms of the ABCB1 and CYP3A5 were determined by the SNaPShot multiplex assay. The blood concentrations of sirolimus were determined with HPLC. A significant allele-dependent effect was observed between the CYP3A5*3 polymorphism and the C0 /D ratio of sirolimus. The patients bearing at least one CYP3A5*1 allele had a lower sirolimus C0/D ratio compared with those with a homozygous CYP3A5*3 genotype (p < 0.05). No significant differences of sirolimus C0/D ratios were observed among various ABCB1 1236C>T, 2677G>T/A and 3435C>T genotype groups. However, haplotype analysis including ABCB1 1236C>T, 2677G>T/A and 3435C>T SNPs showed that the mean sirolimus C0/D of subjects carrying the CGC/CGC diplotype was about 30% lower compared with those carrying the CGC/TTT or TTT/TTT diplotype, whether or not they expressed the CYP3A5 (p < 0.05). These results demonstrated that the haplotype of ABCB1 might be a better index for the prediction of sirolimus blood concentration than single SNPs. Genotyping of ABCB1 and CYP3A5 might help to optimize individualized sirolimus treatments for Chinese renal transplant recipients.

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Renal Drug Transporters and Drug Interactions

et al. 2017

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Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.

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Associations of ABCB1 3435C>T and IL-10-1082G>A Polymorphisms With Long-Term Sirolimus Dose Requirements in Renal Transplant Patients

Cited by 28 publications

References 35 publications

Associations of ABCB1 and IL-10 Genetic Polymorphisms With Sirolimus-Induced Dyslipidemia in Renal Transplant Recipients

Associations of ABCB1 and IL-10 Genetic Polymorphisms With Sirolimus-Induced Dyslipidemia in Renal Transplant Recipients

ABCB1 haplotype influences the sirolimus dose requirements in Chinese renal transplant recipients

Renal Drug Transporters and Drug Interactions

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