CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation

Goto, Maki; Masuda, Satohiro; Kiuchi, Tetsuya; Ogura, Yasuhiro; Oike, Fumitaka; Okuda, Masahiro; Tanaka, Kōichi; Inui, Ken Ichi

doi:10.1097/01.fpc.0000114747.08559.49

Cited by 179 publications

(155 citation statements)

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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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“…Previously, we showed that the cytochrome P450 (CYP) CYP3A5*1 allele not only in the liver (donor genotype) but also in the small intestine (recipient genotype) achieved lower concentration/dose (C/D) ratio of tacrolimus than that with CYP3A5*3 (rs776746)/*3 homozygotes in living-donor liver transplant patients. [3][4][5][6] Recently, a new SNP in the CYP3A4 gene, CYP3A4*1G in intron 10, has been found in human lymphoblastoid cell lines from different ethnic groups and is the most common SNP in Japanese patients. 7,8) Miura et al 9) reported that dose-adjusted area under the concentration-time curve and trough level of tacrolimus in renal transplant patients with CYP3A4*1G/*1G was lower than those in patients with CYP3A4*1/*1.…”

Section: Influence Of Cytochrome P450 (Cyp)mentioning

confidence: 99%

Influence of Cytochrome P450 (CYP) <i>3A4*1G</i> Polymorphism on the Pharmacokinetics of Tacrolimus, Probability of Acute Cellular Rejection, and mRNA Expression Level of CYP3A5 Rather than CYP3A4 in Living-Donor Liver Transplant Patients

Uesugi

Hosokawa

Shinke

et al. 2013

Biological & Pharmaceutical Bulletin

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Association between cytochrome P450 (CYP) 3A4*1G genotype of donors (n 412) and/or recipients (n 410), and the pharmacokinetics of tacrolimus and the risk of acute cellular rejection was examined in Japanese living-donor liver transplant patients between 2004 and 2011. The concentration/dose (C/D) ratio of tacrolimus in patients carrying graft liver with CYP3A4*1/*1 was significantly higher during 7 d after surgery than in that with CYP3A4*1/*1G (214 vs. 157 [ng/mL]/[mg/kg/day], p<0.01). After postoperative day 8, no significant difference was observed among CYP3A4*1G genotypes in the graft liver. However, the C/D ratio in CYP3A4*1/*1 of the intestine was significantly higher than that in CYP3A4*1G/*1G for 5 weeks after surgery (postoperative days 1-14; p<0.001, postoperative days 15-35; p<0.01). During postoperative days 14 and 26, acute cellular rejection incidences tended to be lower in the patients with graft liver carrying the CYP3A4*1/*1 allele than in the patients carrying CYP3A4*1G allele (8.7% vs. 14.6%, p 0.0973). However, CYP3A4*1G in the intestine had almost no effect on the incidence of rejection (9.9% in CYP3A4*1/*1 vs. 12.5% in CYP3A4*1G allele, p 0.4824). CYP3A4*1G was significantly related to mRNA expression of CYP3A5 rather than of CYP3A4 in the graft liver and intestine and was strongly linked with the CYP3A5*1. Thus, we elucidated that CYP3A4*1G genotype in the intestine was an important indicator of the pharmacokinetics of tacrolimus, whereas this genotype in the graft liver tended to influence the frequency of acute cellular rejection after transplantation.

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“…Goto et al (2004) indicated that the pharmacokinetics of tacrolimus are influenced by the graft CYP3A5 genotype. Yet another study revealed that patients with a liver graft with the CYP3A5*1 allele had a lower C/D ratio of tacrolimus than patients with a liver graft with the CYP3A5*3/*3 genotype (Rahsaz et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Benefits of minimizing immunosuppressive dosage according to cytochrome P450 3A5 genotype in liver transplant patients: findings from a single-center study

Wang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We evaluated the clinical efficacy of tailoring tacrolimus dosage to cytochrome P450 (CYP) 3A5 genotype in liver transplant patients. One hundred patients who received tacrolimus-based therapy were included in the retrospective study in which the relationship between the tacrolimus blood trough concentration/dosage ratio and the CYP3A5 genotype of both donors and recipients was determined. Subsequently, 106 patients were continuously enrolled in a prospective study and followedup for 6 months; the relationship between tacrolimus dosage and CYP3A5 genotype was also determined. Rates of acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, and hyperglycemia were compared between the groups. During the 6 months following liver transplantation, the mean tacrolimus concentration/dosage ratio among patients who did not have the CYP3A5*1 genotype and who received a transplant from a L. Wang et al. 3192©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 3191-3199 (2015) donor with the same genotype (24/100, 24% of patients) was higher than that among patients who did have the CYP3A5*1 genotype and/or had a donor with the same genotype (76/100, 76% of patients). In the second part of the study, the tacrolimus dosage was tailored to CYP3A5 genotype and 24 patients (22.64%) received a lower dose. There was an obvious decrease in acute rejection, hepatotoxicity, renal toxicity, neurotoxicity, hypertension, hyperglycemia, and Pneumocystis carinii infection among the latter group. A lower tacrolimus dose was suitable for about 25% of the liver transplant patients, as these patients did not have the CYP3A5*1 genotype and received a transplant from a donor with the same genotype. Tailoring the tacrolimus dosage according to the CYP3A5 genotype could reduce rejection and adverse effects.

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CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation

Cited by 179 publications

References 31 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

Influence of Cytochrome P450 (CYP) <i>3A4*1G</i> Polymorphism on the Pharmacokinetics of Tacrolimus, Probability of Acute Cellular Rejection, and mRNA Expression Level of CYP3A5 Rather than CYP3A4 in Living-Donor Liver Transplant Patients

Benefits of minimizing immunosuppressive dosage according to cytochrome P450 3A5 genotype in liver transplant patients: findings from a single-center study

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