Tacrolimus Concentrations in Relation to CYP3A and ABCB1 Polymorphisms Among Solid Organ Transplant Recipients in Korea

Jun, Kyung Ran; Lee, Woochang; Jang, Mi Sook; Chun, Sail; Song, Gi‐Won; Park, Kwan Tae; Lee, Sung Gyu; Han, Duck Jong; Kang, Changwon; Cho, Daeyeon; Kim, Jin Q; Min, Won‐Ki

doi:10.1097/tp.0b013e31819f117e

Cited by 44 publications

(42 citation statements)

References 19 publications

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“…This could be due to the higher rates of metabolism in CYP3A5 expressors and thus, the dose required to achieve target concentration in patients with donor genotype CYP3A5 expressors was higher than non-expressors. Our finding was consistent with results from other studies [5,6,9]. However, similar impact on C0/D ratio was not demonstrated in patients with donor ABCB1 variant alleles.…”

Section: Discussionsupporting

confidence: 83%

“…It would be of clinical interest to understand changes in pharmacokinetic parameters in relation to gene polymorphisms in an Asian population. Although some studies have been conducted in China, Japan and Korean liver transplant populations [4][5][6]9], as well as Singapore and Korean renal transplant populations [8][9], the influence of both donor and recipient gene polymorphisms on the pharmacokinetics of tacrolimus remains to be clearly defined.…”

Section: Introductionmentioning

confidence: 99%

“…Advances in pharmacogenetics discovered several single nucleotidepolymorphisms in CYP3A subfamily and ABCB1. Studies have shown that the gene polymorphisms of CYP3A5 and ABCB1 contribute to the variability of tacrolimus dose-adjusted concentrations [4,5,8,9]. Most of the studies on the influences of gene polymorphisms were conducted in the immediate post transplant period, ranging from Week 1 to Week 5 [4][5][6][7][8], while some others have not specified time post liver transplant [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Influences of Donor and Recipient Gene Polymorphisms on Tacrolimus Dosing and Pharmacokinetics in Asian Liver Transplant Patients

Yee¹,

Tan²,

Sia³

et al. 2013

OJOTS

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Background: Tacrolimus pharmacokinetics has large inter-individual variability. Objectives: This study aimed to investigate the impact of donor and recipient gene polymorphisms on tacrolimus dosing and pharmacokinetics in Asian liver transplant patients. Methods: Steady-statetacrolimus concentrations at 0, 1, 2, 4 and 6 h were measured. Pharmacokinetic parameters were estimated with a one-compartment linear model using WinNonlin 6.1 program. DNA from donor liver and recipient blood samples were genotyped for CYP3A and ABCB1 polymorphisms. 3) (64.48 versus 129.21 (mcg/L)/(mg/kg/day), P = 0.040). Hence, the dose required to achieve target concentration in patients with donor genotype CYP3A5 expressors was higher than non-expressors (0.12 versus 0.08 mg/kg, P = 0.045). Recipient with ABCB1-C3435T genotype TT demonstrated higher apparent oral clearance of tacrolimus as compared to genotype CC (17.7 versus 7.9 L/h, P = 0.033). Conclusions: Donor liver CYP3A polymorphism could potentially affect tacrolimus C0/D ratio as early as the first week post liver transplant. Genotyping of liver donors may be useful to achieve the optimal drug concentration during this critical period.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Influences of Donor and Recipient Gene Polymorphisms on Tacrolimus Dosing and Pharmacokinetics in Asian Liver Transplant Patients

Yee¹,

Tan²,

Sia³

et al. 2013

OJOTS

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“…For MDR1 and tacrolimus pharmacokinetics, carriers of 2677T or 3435T alleles were found to have higher average levels of tacrolimus compared to 2677 G homozygotes (GG) and 3435 C homozygotes (CC) 98,99 . This association was not confirmed by other authors 100,101 and the significance of other variants of the ABCB1 (MDR1) gene for pharmacokinetics of tacrolimus is unclear 97 .…”

Section: Pharmacokinetics and Pharmacogenetics Of CImentioning

confidence: 45%

“…Despite of limitations associated with low population CYP3A4*1B allele frequency, lower C 0 concentrations of tacrolimus were demonstrated in its carriers in 3 rd and 12 th month after transplantation, compared to CYP3A4*1 homozygotes 94 . Patients with CYP3A5*3 polymorphism and missing enzyme activity exhibited higher blood levels and required lower maintenance doses of tacrolimus compared to the CYP3A5*1 variant 95,96,90,97 . For MDR1 and tacrolimus pharmacokinetics, carriers of 2677T or 3435T alleles were found to have higher average levels of tacrolimus compared to 2677 G homozygotes (GG) and 3435 C homozygotes (CC) 98,99 .…”

Section: Pharmacokinetics and Pharmacogenetics Of CImentioning

confidence: 99%

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

Krejčí¹,

Tichý²,

Bachleda³

et al. 2010

BIOMED PAP

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Background. The introduction of the calcineurin inhibitors (CI) cyclosporine and tacrolimus into immunosuppressive protocols initiated a new era in organ transplantation with excellent short-term graft survival. Nevertheless, the chronic nephrotoxicity of these drugs represents a significant adverse factor limiting their long-term use. Patients treated with a CI can be at risk for developing renal failure and this problem is especially pronounced in patients after renal transplantation.Methods and Results. In a review paper we summarize the clinical aspects, histological manifestations and pitfalls of diagnostics of acute and chronic CI nephrotoxicity in patients after kidney transplantation. We look in detail at the disputed relationship between blood concentrations of cyclosporine and tacrolimus and histological manifestation of toxicity and summarize data showing that for toxic effects, local renal exposure to CI and their metabolites can play a more significant role than systemic exposure. We also include recent views on the pathophysiologic and molecular mechanisms underlying these changes; factors influencing local susceptibility to CI nephrotoxicity are discussed, including variability of expression and activity of P-glycoprotein and cytochrome P450. Last but not least we summarize our own experience with clinically manifest and subclinical forms of nephrotoxicity and their impact on the progression of chronic graft changes.Conclusions. Owing to their unique effects, CI remain the cornerstone of most immunosuppressive protocols for renal transplantation. Together with optimization of local kidney exposure to CI and their metabolites, efforts to reduce systemic levels as much as possible are the most important preventive measure for reducing toxic renal graft damage.

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Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

Dolžan

2012

Pharmacogenetics and Individualized Therapy

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Tacrolimus Concentrations in Relation to CYP3A and ABCB1 Polymorphisms Among Solid Organ Transplant Recipients in Korea

Abstract: The CYP3A5 genotype of the liver is considered to show the most important association with tacrolimus concentrations. Ultimately, genotyping for CYP3A5 may help optimal individualization of immunosuppressive drug therapy for patients undergoing solid organ transplantation.

Cited by 44 publications

References 19 publications

Influences of Donor and Recipient Gene Polymorphisms on Tacrolimus Dosing and Pharmacokinetics in Asian Liver Transplant Patients

Influences of Donor and Recipient Gene Polymorphisms on Tacrolimus Dosing and Pharmacokinetics in Asian Liver Transplant Patients

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

Pharmacogenetics in Drug Metabolism: Role of Phase I Enzymes

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