Effects Of CYP3A5 Polymorphisms Research Articles

Effects of CYP3A5 Polymorphism on Rapid Progression of Chronic Kidney Disease: A Prospective, Multicentre Study

Effects of CYP3A5 Polymorphism on Rapid Progression of Chronic Kidney Disease: A Prospective, Multicentre Study

Relationship between CYP3A5 Polymorphism and Tacrolimus Blood Concentration Changes in Allogeneic Hematopoietic Stem Cell Transplant Recipients during Continuous Infusion

A polymorphism in the gene encoding the metabolic enzyme cytochrome P450 family 3 subfamily A member 5 (CYP3A5) is a particularly influential factor in the use of tacrolimus in Japanese patients. Those who are homozygotic for the *3 mutation lack CYP3A5 activity, which results in substantial individual differences in tacrolimus metabolism. The aim of this study was to analyze the relationship between individual differences in tacrolimus blood concentration changes and CYP3A5 polymorphisms in allogeneic hematopoietic stem cell transplantation recipients during the period of increasing blood concentration of the drug following treatment onset. This was a prospective observational cohort study, involving 20 patients administered tacrolimus by continuous infusion. The subjects were divided into the *1/*3 and *3/*3 groups based on CYP3A5 polymorphism analysis. The tacrolimus blood concentration/dose (C/D) ratio increased from day 1 and was largely stable on day 5, and a significant difference was observed between the *1/*3 and *3/*3 groups in the time course of the C/D ratio during this period (p < 0.05). This study reveals the effects of CYP3A5 polymorphism on continuous changes in tacrolimus blood concentration.

Effects of CYP3A5 Polymorphisms on Efficacy and Safety of Tacrolimus Therapy in Patients with Idiopathic Membranous Nephropathy.

BackgroundTacrolimus (TAC) is beneficial for patients with idiopathic membranous nephropathy (IMN). It has a narrow therapeutic concentration range and many factors influence TAC blood concentration. CYP3A5 is the most important enzyme in TAC metabolism. The aim of this study was to analyze the effects of CYP3A5 gene polymorphisms on the efficacy and safety of TAC in IMN patients.Patients and MethodsPatients with IMN who received oral TAC (0.05–0.075mg/kg/day) combined with prednisone (0.5mg/kg/day) from March 2016 to October 2018 were included. The data of clinical characteristics, therapeutic drugs and adverse reactions of patients were collected at baseline and during 24 weeks of treatment. Patients were divided into two groups according to different CYP3A5 genetic polymorphisms. The significant differences in the efficacy and side effects between the two groups were analyzed.ResultsA total of 76 patients who completed follow-up were divided into CYP3A5 nonexpresser (CYP3A5*3/*3) group and CYP3A5 expresser (CYP3A5 *1/*3) group. The significant association between the CYP3A5 phenotype and TAC metabolism was observed. A total of 43 case-times patients exhibited adverse effects. The infection rate in CYP3A5 nonexpresser group (21.95%) was remarkably higher than the rate in CYP3A5 expresser group (5.71%). Blood concentration and C0/D levels were risk factors for adverse events through logistic regression analysis. There was no statistical difference between the study groups with respect to the efficacy.ConclusionOur results demonstrated that CYP3A5 polymorphisms had important guiding roles in the treatment of IMN with tacrolimus. CYP3A5 expressers required higher daily doses of TAC to achieve the target drug concentration, but with fewer side effects. CYP3A5 genetic polymorphism might be used for TAC dosing adjustment to optimize the treatment for patients with IMN.

Effects of CYP3A5 polymorphism and the tacrolimus 12 h concentration on tacrolimus-induced acute renal dysfunction in patients with lupus nephritis

1. The purpose of the present study was to investigate the effect of tacrolimus concentration in blood 12 h after administration (C12h) on acute renal dysfunction in patients with lupus nephritis (LN) taking tacrolimus once daily.2. Five of the 35 LN patients experienced tacrolimus-induced acute renal dysfunction.3. The average annual C12h of tacrolimus was higher for patients with events of elevated serum creatinine level than for patients not experiencing these events [6.4 (5.6–8.8) versus 2.8 (2.2–4.6) ng/mL, respectively, p = 0.001].4. The average annual tacrolimus C12h was higher for patients with CYP3A5*3/*3 (PM) than for patients with the CYP3A5*1 allele (EM) [4.6 (3.2–6.6) versus 2.5 (2.0–3.1) ng/mL, respectively, p = 0.002].5. The area under the receiver operating characteristic was 0.887, which gave the best sensitivity (80.0%) and specificity (86.7%) at a tacrolimus C12h (average annual C12h or C12h at events) threshold of 5.2 ng/mL.6. C12h measurements, CYP3A5 genotyping and dose adjustments of tacrolimus should be performed to prevent acute renal dysfunction in LN patients taking tacrolimus once daily.

The effect of CYP3A5 polymorphism on cyclosporine plasma level in Egyptian renal transplant recipients

Cyclosporine (CsA) and tacrolimus are immunosuppressants used for the prevention of rejection of transplanted organs. The genes encoding cytochrome (CYP) P450 enzymes, CYP3A4, and CYP3A5 are the main ones involved in the pharmacokinetics of calcinurin inhibitors (CNI). Several single nucleotide polymorphisms were identified in these genes such as CYP3A5*3 (6986A>G). The association of the CYP3A5*3/*3 genotype with decreased clearance of its substrates was reported among different ethnic populations. This study aims to evaluate the effect of CYP3A5*3 polymorphism on CsA plasma levels in Egyptian renal transplant patients at the first week and first month of transplantation. A total of 44 renal transplant recipients receiving CsA were genotyped for CYP3A5*3 polymorphism. The C0 and C2 of CsA were measured and their relationships with CYP3A5*3 genotypes were investigated. CYP3A5*3 allele was present in six patients and the CsA level didn’t differ significantly between the CYP3A5*3 the CYP3A5*1 allele carriers at the first week and the first month post transplantation. Large-scale studies with the involvement of multiple genetic markers claimed to affect the CsA pharmacokinetics are highly recommended to elucidate their pharmacogenetic role in renal transplant patients.

Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients

Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on TAC metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and TAC disposition in a cohort of Brazilian transplant recipients. Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan® PCR technique. Diplotypes were analyzed for correlation with the TAC dose-normalized ratio (Co : dose). We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1 TTT/TTT diplotype showed a higher Co : dose ratio compared with wild type subjects [median (interquartile range) 130.2 (97.5-175.4) vs. 71.3 (45.6-109.0), P < 0.0001 and 151.8 (112.1-205.6) vs. 109.6 (58.1-132.9), P = 0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1 TTT/TTT individuals showed a higher Co : dose ratio compared with non-TTT/TTT individuals [167.8 (130.4-218.0) vs. 119.4 (100.2-166.3), P = 0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors. CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC PK, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect TAC disposition, showing independent and additive effects on the TAC dose-normalized concentration.

CYP3A5 Genotype Does Not Influence Everolimus In Vitro Metabolism and Clinical Pharmacokinetics in Renal Transplant Recipients

CYP3A5 genotyping might be useful to guide tacrolimus and sirolimus dosing. The aim of this study was to assess the influence of CYP3A5 polymorphism on everolimus metabolism and pharmacokinetics. We investigated the effect of CYP3A5 6986A>G polymorphism (CYP3A5*1/*3 alleles) on the pharmacokinetics of everolimus in 28 renal transplant patients and on its in vitro hepatic metabolism using a bank of genotyped human liver microsomes (n=49). We further evaluated in vitro the contribution of CYP3A4, CYP3A5, and CYP2C8 to everolimus hepatic metabolism using recombinant enzymes. We found no association between CYP3A5 polymorphism and everolimus pharmacokinetics in renal transplant patients. On the other hand, no effect of CYP3A5 polymorphism was observed on the intrinsic clearance of everolimus by human liver microsomes, whereas that of tacrolimus (positive control) was 1.5-fold higher in microsomes carrying the CYP3A5*1 allele than in noncarriers. In vitro data showed that CYP3A4 is a better catalyst of everolimus metabolism than CYP3A5, whereas the opposite was observed for tacrolimus. This study provides direct and indirect evidence that CYP3A5 genotyping cannot help improve everolimus therapy.

Effect of cytochrome P450 3A5 polymorphism on platelet reactivity after treatment with clopidogrel in patients scheduled for percutaneous coronary intervention

Abstract Purpose: The aim of the present work is to study the effect of CYP3A5 polymorphism on clopidogrel response and post-stent complications among Egyptian patients scheduled for PCI. In addition, to assess post-clopidogrel platelet reactivity (PPR) as a predictor of post-stent complications. Subjects and methods: This study included 45 patients scheduled for elective PCI at Ain Shams University Hospital. All the studied patients were subjected to detection of CYP3A5 A6986G polymorphism and assessment of clopidogrel response using adenosine diphosphate (ADP)-induced platelet aggregation. Results: Wild, heterozygous and homozygous genotypes were detected in 2.2%, 31.1% and 66.7% of the patients, respectively. A trend for lower PPR in expressor genotype group was found ( p = 0.08). No influence of the CYP3A5 genotypes on post-stent complications was found ( p = 1.0). Clinical presentation, smoking, previous acute coronary syndrome ( p p = 0.04 and 0.05, respectively). Conclusion: CYP3A5 genetic polymorphism does not contribute to the observed variability in the inhibitory effect of clopidogrel. Low response to clopidogrel is a novel risk factor for ischemic events after PCI. The evaluation of low response to clopidogrel may help to identify patients at increased risk that may benefit from intensified antiplatelet strategy.

The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients: a meta-analysis

Cyclosporine (CsA) is a substrate of cytochrome P450 (CYP) 3A5 and has a narrow therapeutic range with large inter-individual variability. CYP3A5*3 polymorphism is reported to be functional and may contribute to the inter-individual variability. The objective of this meta-analysis was to accurately estimate the effect of CYP3A5*3 allele on CsA dose-adjusted blood concentration. A computerized literature search was conducted in PubMed. A total of 12 and 6 studies meeting the inclusion criteria were, respectively, included in meta-analysis about dose-adjusted trough concentration (C(0)/D) and dose-adjusted peak concentration (C(2)/D). The combined weighted mean difference (WMD) between CYP3A5 expressers (*1/*3 + *1/*1) and non-expressers (*3/*3) was significant in C(2)/D (WMD = -12.73 (ng ml(-1))/(mg kg(-1)), 95% confidence interval (CI) -25.23 to -0.22, P = 0.046), whereas it was marginally significant in C(0)/D (WMD = -3.75 (ng ml(-1))/(mg kg(-1)), 95% CI -7.58 to 0.07, P = 0.054). Exclusion of an outlier study greatly increased the association of CYP3A5 polymorphism with C(0)/D to be significant (WMD = -4.92 (ng ml(-1))/(mg kg(-1)), 95% CI: -8.27 to -1.58, P = 0.011). This meta-analysis showed that CYP3A5*3 polymorphism is associated with CsA dose-adjusted concentration in renal transplant recipients. Patients carrying the CYP3A5*3/*3 genotype will require a lower dose of CsA to reach target levels compared with the CYP3A5*1/*1 or *1/*3 carriers.

Population Estimation Regarding the Effects of Cytochrome P450 2C19 and 3A5 Polymorphisms on Zonisamide Clearance

We aimed to evaluate the effects of cytochrome P450 (CYP) 2C19 and CYP3A5 polymorphisms on zonisamide (ZNS) clearance. The pharmacokinetics of the 282 ZNS concentrations at a steady state obtained from 99 Japanese epileptic patients was performed with a nonlinear mixed-effect modeling program, using a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight, gender, ZNS daily dose, CYP2C19 and CYP3A5 genotypes, and the coadministered antiepileptic drugs. The final model of ZNS apparent clearance was as follows: CL = 1.22 x (BW/44)0.77 x DOSE(-0.17 x 0.84CYP2C19 hetero EM x 0.70CYP2C19 PM x 1.24CBZ x 1.28PHT x 1.29PB x eetaCL where CL is the apparent oral clearance of ZNS, DOSE is ZNS daily dose, and CYP2C19 heterozygous extensive metabolizer (EM) or CYP2C19 poor metabolizer (PM) is equal to 1 if one or two CYP2C19-defective alleles are carried, respectively; otherwise, it is 0. Carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB) is equal to 1 if carbamazepine, phenytoin, or phenobarbital is coadministered, respectively; otherwise, it is 0. etaCL is the independent random error distributed normally with the mean zero and variance equal to omegaCL. The CL of ZNS was lower in the CYP2C19 heterozygous extensive metabolizers and poor metabolizers than in the homozygous extensive metabolizers by 16% and 30%, respectively (P < 0.001). An effect of CYP3A5 polymorphisms was not identified. The coadministration of carbamazepine, phenytoin, or phenobarbital increased the CL of ZNS by 24% to 29%. This report demonstrates that the CYP2C19 genotype affects the ZNS metabolism in Japanese epileptic subjects. The clinical relevance of these changes remains to be explored in future studies.

Influence of Cytochrome P450 (CYP)??3A5 Polymorphisms on the Pharmacokinetics of Lansoprazole Enantiomers in CYP2C19 Extensive Metaboliser Renal Transplant Recipients

Lansoprazole is extensively metabolised by cytochrome P450 (CYP) 2C19 and CYP3A4. The purpose of this study was to evaluate the effects of CYP3A5 polymorphism (A6986G) on the pharmacokinetics of lansoprazole enantiomers in renal transplant recipients who are CYP2C19 extensive metabolisers (EMs). Among 40 Japanese CYP2C19 EMs, 20 had the CYP3A5*1 allele (*1/*1 in two subjects and *1/*3 in 18 subjects) and 20 had the CYP3A5*3/*3 genotype. After repeated oral doses of racemic lansoprazole 30mg once daily for 28 days, plasma concentrations of lansoprazole enantiomers were determined using high performance liquid chromatography. The mean area under the plasma concentration-time curves from 0 to infinity (AUC(infinity)) of (R)- and (S)-lansoprazole in recipients with the CYP3A5*1 allele were 3145 and 384 ng * h/mL, respectively, compared with 4218 and 587 ng * h/mL in recipients with the CYP3A5*3/*3 genotype. The AUC(infinity) and the maximum plasma concentration of (R)- and (S)-lansoprazole in subjects with the CYP3A5*3/*3 genotype were greater than subjects with CYP3A5*1/*1 + *1/*3 alleles. The mean R/S ratio for AUC of lansoprazole in each CYP3A5 genotype group was the same (12.6). Our findings show that CYP3A5 genotype is not an important determinant of enantioselective disposition of lansoprazole. Based on our results and those of previous studies, the enantioselective disposition of lansoprazole appears to be primarily influenced by enantioselective metabolism by CYP2C19 rather than by CYP3A.