Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies

Abstract

The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

“…The CYP3A5 gene codes for the main metabolic enzyme for tacrolimus, and in the main functional variant, CYP3A5 6986A>G (rs776746), a guanine is substituted for adenine. Carriers of the A allele (AA or AG, CYP3A5 expressers) can produce very high levels of functional CYP3A5 compared with homozygous GG carriers (CYP3A5 non-expressers) [12] . Thus, GG genotype patients need less TAC (high C0/D ratio) to reach the target blood concentration than the A allele carriers.…”

“…TAC forms a complex with the immunophilin FK-binding protein 12 (FKBP12) and strongly inhibits calcineurin phosphatase activity, IL-2 expression, and subsequently, T-cell activation [7] . Genetic polymorphisms in TAC pharmacokinetic pathways have been widely investigated (www.pharmgkb.org), and it has been confirmed that a single-nucleotide polymorphism, 6986A>G, within intron 3 of the CYP3A5 gene can affect the pharmacokinetics of tacrolimus [5,12] . Recent studies have also shown that TAC pharmacokinetics can be affected by polymorphisms in CYP3A4 (*22, *B, *1G), ABCB1 (2677G>A/T, 1236C>T, 3435C>T), P450 (cytochrome) oxidoreductase (POR) *28, nuclear receptor subfamily 1, group I, member 2 (NR1I2), catechol-O-methyltransferase (COMT), Toll-like receptor 4 (TLR4), and IL-18 [13][14][15][16][17][18][19][20] .…”

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

“…Previous studies have found that gene polymorphisms, particularly in CYP3A5, affect tacrolimus concentration-dose relationships, so predicting initial dose requirements in lung transplant recipients (32)(33)(34). In kidney transplant recipients, a polymorphism of CYP3A5 was found to be a risk factor for acute rejection and nephrotoxicity (35). Single nucleotide polymorphism analysis of 240 Chinese kidney transplant recipients has revealed a number of other polymorphisms affecting tacrolimus metabolism (36).…”

Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

“…Clinically relevant examples of this pharmacogenetic variation have been observed with CYP2C9 (for warfarin) (Cooper et al, 2008;Takeuchi et al, 2009), CYP2C19 (for clopidogrel and omeprazole) (Hou et al, 2014), CYP2D6 (for tamoxifen and codeine) (Madadi et al, 2013;Gryn et al, 2014), and CYP3A5 (for tacrolimus) (Rojas et al, 2015). In some instances, the resulting protein is still functional but exhibits reduced activity (e.g., CYP2C9; Steward et al, 1997); in other cases, the resulting variant protein may be completely devoid of activity or is not expressed (e.g., , such as CYP2D6, CYP2C19, and CYP3A5; Dahl et al, 1992;de Morais et al, 1994;Kuehl et al, 2001, respectively).…”