Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation

Abstract

Summary We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.

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

“…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.…”

“…3,6) The CYP3A5*3 genotype is well-known to be associated with the pharmacokinetics of tacrolimus in patients with liver, kidney and heart transplant. [17][18][19][20] Hepatic and intestinal CYP3A5 plays a significant role in the clearance of tacrolimus after oral administration in liver transplant patients. 4,5) However, a newly identified SNP in the CYP3A4 gene, CYP3A4*1G affects the pharmacokinetics of some drugs.…”

CYP1A2 polymorphism in Chinese patients with acute liver injury induced by Polygonum multiflorum

“…For example, CYP450 1A2 gene polymorphisms are thought to be involved in the metabolism of theophylline; a study by Uslu et al (2010) suggested that genetic alterations in CYP1A2 play a role both in the pharmacogenetics of theophylline and in the development of chronic obstructive pulmonary disorder. Gervasini et al (2012) found that the CYP3A4*1B-CYP3A5*1 haplotype may have a profound impact on tacrolimus pharmacokinetics, which may be related to the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.…”

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

“…The most frequent variants are TPMT*2, TPMT*3A and TPMT*3C [Cheok et al, 2009;Gervasini et al, 2012].…”