A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients

Elens, Laure; Bouamar, Rachida; Hesselink, Dennis A.; Haufroid, Vincent; Heiden, Ilse P. van der; Gelder, Teun van; Schaik, Ron H.N. van

doi:10.1373/clinchem.2011.165613

Cited by 214 publications

(198 citation statements)

References 31 publications

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“…4,5) However, a newly identified SNP in the CYP3A4 gene, CYP3A4*1G affects the pharmacokinetics of some drugs. 7,9,21,22) Although some SNPs in the CYP3A4 gene such as CYP3A4*1B and CYP3A4*22 have been reported to affect the pharmacokinetics of tacrolimus, 17,23) the frequencies of CYP3A4*1B and CYP3A4*22 have not been observed in Chinese and Japanese patients. 19,[24][25][26] In the present study, CYP3A4*1G genotype showed a significant association with the C/D ratio of tacrolimus in living-donor liver transplant patients comparable with data reported in kidney transplantation.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Based on these observations, it has been proposed to prescribe different Tac doses for ultrarapid (CYP3A5 expressers and CYP3A4*1/*1), intermediate (CYP3A5 non-expressers and CYP3A4*1/*1) and poor (CYP3A5 non-expressers and CYP3A4*22 carriers) CYP3A metabolizers, respectively. [36][37][38] In pediatric heart transplantation, an association between CYP3A4*22 and Tac dose requirement has also been observed. [39] CYP3A4*22 carriers needed 30% less Tac to reach similar target concentrations compared with CYP3A4*1/*1 carriers.…”

Section: Cyp3a4mentioning

confidence: 99%

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Tang

Andrews

Gelder

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

117

114

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Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

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“…All patients had been previously genotyped for CYP3A4*22 and CYP3A5*3 alleles [1]. The required patient characteristics were inserted in the equation [3] to obtain the predicted tacrolimus CL/F for each individual.…”

Section: Boxmentioning

confidence: 99%

“…As the CYP3A4*22 allele has been previously associated with a reduced tacrolimus clearance [1,2], it is not surprising that an algorithm that does not take into account the CYP3A4*22 genotype will overrate the individual's ability to metabolize the drug. Indeed, predose concentrations are thus underestimated and, as a result, a negative bias is observed.…”

Section: Boxmentioning

confidence: 99%

The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

Elens

Hesselink

Schaik

et al. 2013

Brit J Clinical Pharma

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A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients

Cited by 214 publications

References 31 publications

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

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

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

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A New Functional CYP3A4 Intron 6 Polymorphism Significantly Affects Tacrolimus Pharmacokinetics in Kidney Transplant Recipients

Cited by 214 publications

References 31 publications

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

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

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

The CYP3A4*22 allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations

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The CYP3A422* allele affects the predictive value of a pharmacogenetic algorithm predicting tacrolimus predose concentrations