Association of P450 Oxidoreductase Gene Polymorphism with Tacrolimus Pharmacokinetics in Renal Transplant Recipients: A Systematic Review and Meta-Analysis

Abstract

There are conflicting results regarding the effect of the P450 oxidoreductase (POR) *28 genotype on the tacrolimus (TAC) pharmacokinetics (PKs) during the early post-transplantation period in adult renal transplant recipients. Thus, we characterized the impact of POR*28 on TAC PKs. We conducted a systematic review on the association between POR*28 and PKs of TAC in adult renal transplant recipients. Structured searches were conducted using PubMed, Web of Science, and Embase. TAC standardized trough concentration (ng/mL per mg/kg) data were extracted. Mean differences (MD) and their corresponding 95% confidence intervals (CIs) were used to identify the differences between the POR*28 genotype and PKs of TAC. The subgroup analysis was conducted according to CYP3A5 expression status. Six studies (n = 1061) were included. TAC standardized trough concentrations were significantly lower in recipients with the POR*28 allele compared to recipients with POR*1/*1 (MD: 8.30 ng/mL per mg/kg; 95% CI: 1.93, 14.67; p = 0.01). In the subgroup analysis, TAC standardized trough concentrations were lower for subjects who were POR*28 carriers than those who were POR*1/*1 in CYP3A5 expressers (MD: 20.21 ng/mL per mg/kg; 95% CI: 16.85, 23.56; p < 0.00001). No significant difference between POR*28 carriers and POR*1/*1 was found in the CYP3A5 non-expressers. The results of our meta-analysis demonstrated a definite correlation between the POR*28 genotype and PKs of TAC. Patients carrying the POR*28 allele may require a higher dose of TAC to achieve target levels compared to those with POR*1/*1, especially in CYP3A5 expressers.

Impacts of pregnane X receptor and cytochrome P450 oxidoreductase gene polymorphisms on trough concentrations of apixaban in patients with non-valvular atrial fibrillation

“…Second, as the number of patients enrolled in the study was small, we were unable to detect the effects of the interaction of the POR*28 and CYP3A5*3 genotypes on the C 0h of apixaban (data not shown). It has been reported that the dose-and weight-adjusted C 0h of tacrolimus, a substrate of CYP3A5, was different between POR*28 genotypes in renal transplant recipients with the CYP3A5*1 allele but not in those with the CYP3A5*3/*3 genotype [39]. Therefore, the effect of this interaction on the PK of apixaban requires further investigation.…”

Evaluation of Pharmacogenetics of Drug-Metabolizing Enzymes and Drug Efflux Transporter in Renal Transplants Receiving Immunosuppressants

“…We observed a reduction of around 27% with cyclosporine, and an 18.5% reduction with tacrolimus dose-adjusted concentrations amongst the carriers of POR*28 . A recent meta-analysis also concluded that POR*28 carriers showed a mean difference of 8.3 ng/mL per mg/kg tacrolimus concentrations compared to the wild genotype [ 31 ]. The only other study that has evaluated the influence of POR*28 on sirolimus concentrations was that by Woillard et al, where the authors observed a significant, but minor, reduction in serum concentrations amongst carriers [ 32 ].…”

Effects of CYP3A4*22 and POR*28 variations on the pharmacokinetics of tacrolimus in renal transplant recipients: a meta-analysis of 18 observational studies

“…Up to now, researchers were attracted by some genetic polymorphisms such as CYP3A4*22 (poor metabolizer) or cytochrome P450 oxidoreductase (POR) *28 (extensive metabolizer) variants, but the impact on the pharmacokinetics of tacrolimus remained controversial. Actually, a meta-analysis demonstrated a definite correlation between the POR*28 genotype and the pharmacokinetics of tacrolimus, emphasizing the POR*28 carriers required a higher dose of tacrolimus to achieve target levels compared to those with POR*1/*1 [ 14 ]. However, as the author stated, the meta-analysis existed some limitations, firstly, it only focused on the impact of POR polymorphism in the early stage of transplantation, with six studies, lacking investigation on other processes of the transplantation; secondly, due to the small number of included studies, subgroup analysis stratified by the ethnicity cannot be conducted.…”