Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients

Abstract

Advances in immunosuppressive therapy allowed renal transplantation to become the treatment of choice for suitable candidates with (end stage renal disease) ESRD. The post-transplant therapeutic strategy is difficult due to narrow therapeutic indices for the currently used immunosuppressive drugs. Inter-individual differences in drug bioavailability are related to genetic and non genetic factors. The idea of targeted and personalized therapy is to achieve therapeutic success. The empirical dose has lost its value in the post-transplant therapy and an individualized dosage regimen must be established. Interindividual heterogeneity in expression of ABCB1 and CYP3A4 has been suspected to be one of the factors resulting in cyclosporine (CsA) pharmacokinetic variation. This study aimed to investigate the impact of inter-individual CYP3A4 rs4646437C>T and MDR1 G2677T/A polymorphisms on cyclosporine dose requirements among a sample of renal transplant Egyptian recipients. Fifty adult Egyptian patients on CsA were genotyped for CYP3A4 rs4646437C>T and MDR1 G2677T/A and correlated with CsA dose requirement and dose-adjusted CsA (C0) blood levels at 3, 6, and 9 months post transplantation. CYP3A4 rs4646437C>T influenced significantly cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. Daily dose requirements were also significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9 months post transplantation. Genotyping of both CYP3A4 and MDR1 SNPs may be helpful in providing pre-transplant pharmacogenetic information to individualize CsA dosing. Heterozygous CT genotype is the most frequent CYP3A4 rs4646437C>T genotype in the studied group of Egyptian population (48 %) followed by CC genotype and TT genotype. Daily dose requirements were significantly higher in T allele MDR1 2677G>T GG genotype as compared to GT/TT genotypes at 3, 6, and 9 months post transplantation.

Prevalence of CYP2C19, CYP3A4 and FMO3 genetic polymorphisms in healthy northeastern Thai volunteers

“…The allele frequencies of "G" and "A" of CYP3A4 rs4646437 were 76.3% (n = 380) and 23.7% (n = 118), respectively. The frequencies were significantly different from both Asians and Caucasians (Table 4) [11,18,19]. The CYP3A4*22 mutant allele was not found in this study.…”

Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation

“…Similarly, a meta-analysis of studies showed no significant effect of the 3435C>T polymorphism on the pharmacokinetics of digoxin [88]. The literature data are summarized in Tables 2-4 [89][90][91][92][93].…”

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

“…As described above, ASV is eliminated primarily via CYP3A4-mediated oxidative metabolism [10,11]. rs4646437 is representative of CYP3A4 SNPs, and numerous studies have reported its relationship with drug metabolism and adverse events in the treatment for various diseases: adverse events caused by efavirenz in human immunodeficiency virus [23] and sunitinib in metastatic renal cell carcinoma [24]; finasteride exposure in prostate cancer risk [25]; immune responses to antiretroviral therapy in human immunodeficiency virus [26]; voriconazole exposure in invasive fungal infections [27]; tacrolimus metabolism among Chinese transplant recipients [28,29]; and cyclosporine kinetics in Egyptian and White transplant recipients [30,31]. Reportedly, rs4646437 influences the protein expression and enzymatic activity of hepatic CYP3A4 in a sex-dependent manner; females have higher expression/activity compared to males.…”