title: Population pharmacokinetics of mizoribine in adult recipients of renal transplantation.
abstract: BACKGROUND
  The aim of the present study was to estimate the population pharmacokinetic parameters of mizoribine in adult recipients of renal transplantation using a nonlinear mixed effects model (NONMEM) program.
  
  
  METHODS
  Pharmacokinetic data for population analysis were retrospectively collected from 114 recipients (66 males and 48 females) routinely treated with oral administration of mizoribine (25-450 mg/day). The range of creatinine clearance (CL(cr)) was 7.6-136.1 mL/min (mean 49.2 mL/min).
  
  
  RESULTS
  The pharmacokinetics of mizoribine in adult recipients of renal transplantation was well described by a 1-compartment model with first-order absorption. The mean value of the absorption lag time (ALAG) and absorption rate constant (KA) was estimated to be 0.581 and 0.983 h(-1), respectively. Apparent volume of distribution (V/F) was modeled as a function of body weight (WT), and the mean value was estimated to be 0.858 × WT L. Oral clearance (CL/F) was modeled as a function of creatinine clearance (CL(cr)), and the mean value was estimated to be 1.80 × CL(cr) × 60/1000 L/h. In addition, there was a strong correlation between CL(cr)-corrected CL/F and WT-corrected V/F in the adult recipients, indicating large interindividual variability in bioavailability (F) of mizoribine.
  
  
  CONCLUSIONS
  The present findings suggested that not only the rate of renal excretion but also the extent of intestinal absorption of mizoribine is responsible for the large interindividual pharmacokinetic variability of the drug.
authors.affiliation: Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishida
authors.forename: Masahiko
authors.initials: M
authors.lastname: Okamoto
authors.forename: Michio
authors.initials: M
authors.lastname: Ishibashi
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D001682:Biological Availability; D003404:Creatinine / Q000097:blood; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007564:Japan; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D012263:Ribonucleosides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D003404:Creatinine