title: Effects of CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism on pharmacokinetics of Tacrolimus in Chinese adult liver transplant patients.
abstract: 1. The purpose of this study was to establish a population pharmacokinetic (PK) model of tacrolimus and evaluate the influence of clinical covariates, including the genetic polymorphisms of the cytochrome P450 3A5 gene (CYP3A5) and gene-encoding P-glycoprotein (ABCB1), on the PK parameters in Chinese adult liver transplant recipients. 2. Details of drug dose, sampling times and concentrations were collected retrospectively from routine therapeutic drug monitoring data early after liver transplant. Tacrolimus PKs was studied by a non-linear mixed-effect modeling (NONMEM) method. CYP3A5 genotypes, ABCB1 C3435T and G2677T/A polymorphism and a number of clinical covariates were tested for their influence on TAC PKs. 3. A one-compartment model with first-order absorption and elimination adequately described the data. Apparent clearance (CL/F) and apparent volumes of distribution (V/F) in final population model were 17.6 L/h and 225 L, respectively. The absorption rate constant (Ka) was fixed at 4.48 h(-1). The inter-individual variability in CL/F and V/F was 53.9 and 68%, respectively. In the final model, CYP3A5 genotype, post-operative day, alanine aminotransferase, total bilirubin, hematocrit and blood urea nitrogen were found to significantly influence the CL/F, whereas POD and HB influence V/F. 4. Population PK analysis of tacrolimus in Chinese adult liver transplant patients resulted in identification of the CYP3A5 genotype, POD, BUN, ALP, HCT, TBIL and HB as significant covariates on the PK parameters of tacrolimus.
authors: a Department of Pharmacy , Tianjin First Central Hospital , Tianjin , China and.
authors: LiQin
authors: L
authors: Zhu
authors: JianWei
authors: J
authors: Yang
authors: Yuan
authors: Y
authors: Zhang
authors: YaQing
authors: Y
authors: Jing
authors: YanWen
authors: Y
authors: Zhang
authors: Guang
authors: G
authors: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D003710:Demography; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: ABCB1 C3435T; CYP3A5; G2677T/A; liver transplant; tacrolimus