The influence of recipient SLCO1B1 rs2291075 polymorphism on tacrolimus dose–corrected trough concentration in the early period after liver transplantation

Abstract

Purpose To explore the relationship between rs2291075 polymorphism in SLCO1B1 gene, which encodes an influx transmembrane protein transporter, and tacrolimus dose–corrected trough concentration (C/D, ng ml−1 mg−1 kg−1) in the early period after liver transplantation. Methods CYP3A5 rs776746 and SLCO1B1 rs2291075 polymorphisms of 210 liver transplantation patients and their corresponding donor livers were assessed by PCR amplification and DNA sequencing. The influence of gene polymorphisms on C/D values of tacrolimus was analyzed. The early postoperative period after liver transplantation was divided into the convalescence phase (1–14 days) and stationary phase (15–28 days) according to the change of liver function and tacrolimus C/D values. Results The combined analysis of donor and recipient CYP3A5 rs776746 could distinguish the metabolic phenotype of tacrolimus into three groups: fast elimination (FE), intermediate elimination (IE), and slow elimination (SE), which was entitled the FIS classification system. Tacrolimus C/D ratios of recipient SLCO1B1 rs2291075 CT and TT carriers were very close and were significantly lower than those of recipient SLCO1B1 rs2291075 CC genotype carriers in convalescence phase (p = 0.0195) and in stationary phase (p = 0.0152). There were no statistically significant differences between tacrolimus C/D ratios of patients carried with SLCO1B1 rs2291075 CT, TT genotype donors, and those carried with SLCO1B1 rs2291075 CC genotype donors. A model consisting of tacrolimus daily dose, total bilirubin, FIS classification, and recipient SLCO1B1 rs2291075 could predict tacrolimus C/D ratios in the convalescence phase by multivariate analysis. However, recipient SLCO1B1 rs2291075 genotype failed to enter forecast model for C/D ratios in stationary phase. Recipient SLCO1B1 rs2291075 genotype had significant effect on tacrolimus C/D ratios in convalescence phase (p = 0.0300) and stationary phase (p = 0.0400) in subgroup, which excluded the interference come from donor and recipient CYP3A5 rs776746. Conclusion SLCO1B1 rs2291075 could be a novel genetic locus associated with tacrolimus metabolism. The combined analysis of donor and recipient CYP3A5 rs776746, recipient SLCO1B1 rs2291075 genotypes, could be helpful to guide the personalized administration of tacrolimus in early period after liver transplantation.

Genotype-guided model significantly improves accuracy of tacrolimus initial dosing after liver transplantation

“…SLCO1B1 encodes the protein of organic anion transporting polypeptide 1B1, is highly expressed in the liver and is involved in the biliary excretion of tacrolimus. 26 , 27 CHST10 (Carbohydrate Sulfotransferase) encodes an enzyme adds sulfate to glucuronic acid to form a carbohydrate antigen, HNK -1 that is capable of transferring sulfate to glucuronidated steroid hormones and other lipophilic drugs to facilitate their excretion via urine. 28 The three recipient SNPs in the model suggested that drug distribution/elimination in extrahepatic organs such as intestine may be especially important in the early phase since the liver-related drug elimination may be weak before the restoration of liver function.…”

Are Genetic Modifiers the Answer to Different Responses to Hydroxyurea Treatment?—A Pharmacogenetic Study in Sickle Cell Anemia Angolan Children

“…The synonymous variant rs2291075 in Gene SLCO1B1, which has been previously associated with the pharmacokinetics of tacrolimus and some chemotherapeutic drugs [31,32], and which was present in 91 heterozygous and 66 homozygous children, was associated with response to HU treatment through the recessive model, its presence being an advantage. Gene SLCO1B1 encodes for an organic anion transporting polypeptide, the OATP1B1, HU being one substrate of this transporter.…”

Rapid clearance of tacrolimus blood concentration triggered by variant pharmacogenes

“…Shu et al reported SLCO1B1 rs2306283 polymorphism association with TAC blood concentrations 16 . A recently published study concluded that SLCO1B1 rs2291075 is probably a new variant associated with TAC metabolism 17 …”

“…study concluded that SLCO1B1 rs2291075 is probably a new variant associated with TAC metabolism. 17 According to available data, influx and efflux transporters have an important role in TAC pharmacokinetics/pharmacodynamics. 13 However, due to often controversial results and a small number of appropriate designed pharmacogenomics studies, there is an urgent need to raise the attention of clinicians and researchers to the pharmacogenomics of TAC.…”