CYP3A5 and ABCB1 genotype influence tacrolimus and sirolimus pharmacokinetics in renal transplant recipients.

Yi Li,Yangjuan Bai,Yunying Shi,Lanlan Wang,Jiangtao Tang,Lin Yan

doi:10.1186/s40064-015-1425-5

Yi Li, Yangjuan Bai + Show 4 more

Open Access

https://doi.org/10.1186/s40064-015-1425-5

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Abstract

CYP3A5 and ABCB1 polymorphisms have been shown to influence tacrolimus blood concentrations and dose requirements, but the conclusion in the current reports were inconformity. Sirolimus are also metabolized by CYP3A subfamily and are substrates of the P-gp. The aim was to determine whether these polymorphisms affect tacrolimus (TAC) and sirolimus (SRL) trough concentrations and dose requirements after renal transplantation. 153 renal transplant recipients were enrolled into this study, 112 were treated with TAC-based regimen, Another 43 recipients received SRL-based regimen. The recipients’ mean follow-up time was 20 mo (range 15–27 mo). All renal transplant recipients were all in a stable stage. The trough concentration and daily dose of TAC and SRL were gained from each recipient. All recipients were genotyped for CYP3A5 (6986A>G), CYP3A4 intron 6 (CYP3A4*22), CYP3A4*18, ABCB1 exon 26 (3435C>T), exon 12 (1236C>T) and 2677G>T/A SNPs by HRM analysis (high-resolution melting curve analysis). The TAC and SRL concentration/dose ratio (C/D) in recipients with CYP3A5 (*)3/(*)3 were significantly higher than that of those with (*)1 allele (P < 0.05). However, there was no significant correlation between adjusted TAC and SRL trough concentrations or dose requirements with CYP3A4 and ABCB1 SNPs genetic polymorphisms. In recipients with TAC-based or SRL-based therapy, the CYP3A5 genes (6986A>G) can influence the TAC and SRL pharmacokinetics in renal transplant recipients.

Highlights

The calcineurin inhibitors (CNI), tacrolimus (TAC) are the most widely used immunosuppression drugs to prevent allograft rejection after solid organ transplantation
There was no significant correlation between adjusted TAC and SRL trough concentrations or dose requirements with CYP3A4 and ABCB1 single-nucleotide polymorphisms (SNPs) genetic polymorphisms
Both CNI and SRL are the substrates of P-gp, an efflux transporter encoded by the MDR1/ABCB1 [adenosine triphosphate (ATP) binding cassette subfamily B, member 1] gene, which actively transports common drugs from the intracellular to the extracellular domain and thereby influencing their pharmacokinetics (Sakaeda et al 2003)

Summary

Introduction

The calcineurin inhibitors (CNI), tacrolimus (TAC) are the most widely used immunosuppression drugs to prevent allograft rejection after solid organ transplantation. Both these drugs display a narrow therapeutic index and high inter-individual pharmacokinetic variability, so monitoring their blood levels is required to avoid rejection and reduce toxicity (López-Montenegro Soria et al 2010). The calcineurin-inhibitor TAC and SRL undergo extensive first-pass metabolism in the human liver. This process is catalyzed by cytochrome P450 (CYP) 3A enzymes. Both CNI and SRL are the substrates of P-gp, an efflux transporter encoded by the MDR1/ABCB1 [adenosine triphosphate (ATP) binding cassette subfamily B, member 1] gene, which actively transports common drugs from the intracellular to the extracellular domain and thereby influencing their pharmacokinetics (Sakaeda et al 2003)

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