title: The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in Chinese adult liver-transplant patients.
abstract: OBJECTIVE
  The aims of this study were to determine the population pharmacokinetics of tacrolimus in Chinese adult liver-transplant recipients and to identify factors that may account for this variability.
  
  
  METHODS
  Tacrolimus dose and blood concentrations, along with clinical data, were collected retrospectively from 262 liver-transplant recipients. Data were analyzed using a nonlinear mixed-effects modeling method. A 1-compartment model with first-order absorption and elimination was selected as the base model. The influence of the following parameters were explored: (1) demographic characteristics, (2) biochemical and hematological laboratory test results, (3) surgery parameters, and (4) commonly used comedications.
  
  
  RESULTS
  The typical values (interindividual variability percent coefficient of variation) for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 20.9 L h (23.8%) and 808 l (70.4%), respectively. The residual variability was 33.6%. Finally, the 4 covariates that showed a strong correlation with CL/F in this study were daily dose, hematocrit, total plasma protein, and the coadministration of sulfonylureas. CL/F was reduced significantly with sulfonylureas cotherapy, higher hematocrit levels, and elevated total protein. Moreover, CL/F increased nonlinearly with larger daily doses of tacrolimus.
  
  
  CONCLUSIONS
  Concurrent therapy with sulfonylureas influenced tacrolimus CL/F in liver transplantation patients. These results and model will help clinicians to optimize tacrolimus regimens in Chinese liver transplantation patients.
authors.affiliation: Department of Pharmacy, Shanghai pulmonary Hospital, Tongji University School of Medicine, China.
authors.forename: Xiao-qing
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Zhao-wen
authors.initials: ZW
authors.lastname: Wang
authors.forename: Jun-wei
authors.initials: JW
authors.lastname: Fan
authors.forename: Yu-ping
authors.initials: YP
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Jiao
authors.forename: Jun-wei
authors.initials: JW
authors.lastname: Gao
authors.forename: Zhi-hai
authors.initials: ZH
authors.lastname: Peng
authors.forename: Gao-lin
authors.initials: GL
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002681:China; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006400:Hematocrit; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D013453:Sulfonylurea Compounds; D016559:Tacrolimus