title: Population pharmacokinetics and pharmacogenetics of tacrolimus in healthy Chinese volunteers.
abstract: OBJECTIVE
  The aim of this study was to establish population pharmacokinetic models of tacrolimus in healthy Chinese volunteers.
  
  
  METHODS
  A total of 956 tacrolimus whole blood concentrations from 73 healthy volunteers were determined using ultraperformance liquid chromatography mass spectrometry/mass spectrometry. Population pharmacokinetic analyses were performed using NONMEM. The final population pharmacokinetic models were validated with bootstrap and visual predictive check. A number of covariates were analyzed, including CYP3A5 and ABCB1 polymorphism, demographic characteristics and hematological and biological indices.
  
  
  RESULTS
  The structural model was a two-compartment model with first-order absorption, and a lag time was fitted to the data. The typical population values of tacrolimus for the pharmacokinetic parameters of apparent clearance (CL/F), apparent distribution volume of the central compartment (V(2)/F), intercompartmental clearance (Q/F), apparent distribution volume of the peripheral compartment (V(3)/F), absorption rate (ka) and lag time (ALAG) were 27.7 l/h, 37.5 liters, 34.4 l/h, 357 liters, 0.795 h(-1) and 0.226 h, respectively. The interindividual variabilities of these parameters were 63.3, 62.0, 50.8, 52.3, 32.9 and 4.45%, respectively, and the intraindividual variability of observed concentrations was 14.9%. The covariates that were retained in the final models were CYP3A5 genotype on CL/F, and body surface area and red blood count on V(3)/F.
  
  
  CONCLUSIONS
  Population pharmacokinetic models of tacrolimus were developed in healthy volunteers. These results could provide a reference for individualized tacrolimus therapy in the clinical setting.
authors.affiliation: Department of Clinical Pharmacology, First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xue
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Ma
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Rui
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Miao
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D001830:Body Surface Area; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004906:Erythrocyte Count; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus