title: Influence of adult age on the total and free clearance and protein binding of (R)- and (S)-warfarin.
abstract: BACKGROUND
  Hepatic drug clearance is thought to be reduced with age. However for highly protein bound drugs, which are cleared by capacity-limited metabolism, studies on total clearance have been conflicting. The hypothesis that protein binding decreases with age has been used to explain this. Warfarin is a highly protein bound drug, which is cleared by capacity-limited metabolism. There are conflicting or little data on the relationship between adult age and total and free clearance and protein binding of (R)- and (S)-warfarin.
  
  
  CONCLUSIONS
  In a clinical study of 72 patients (18-89 years) on warfarin therapy, both total and free clearance of (R)-warfarin decreased with age. For (S)-warfarin there was a stronger signal of a decrease in free than total clearance. Protein binding was found not to correlate with age for (R)- and (S)-warfarin. In an ex vivo study, in which warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years), no correlation between protein binding and age was found. These data support the hypothesis that hepatic drug clearance decreases with age. This should be taken into consideration when individualizing dosing, particularly in the elderly.
  
  
  OBJECTIVE
  To test the hypothesis that the clearance (CL) of warfarin, a very highly protein bound drug with capacity-limited metabolism, decreases with age.
  
  
  METHODS
  In a clinical study, a steady-state blood sample was taken from 72 patients (18-89 years) on routine treatment with warfarin. Concentrations of (R)- and (S)-warfarin were determined in plasma (total) and ultrafiltrate (free) by LC-MS/MS. Total and free CL and protein binding were determined and regressed against age and other covariates. In an ex vivo study, warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years) and protein binding was regressed against age and other covariates.
  
  
  RESULTS
  For (R)-warfarin a significant decrease with age was found for both total and free CL (P < 0.001). For (S)-warfarin there was a stronger signal of a decrease with age in free CL (P= 0.005) vs. total CL (P= 0.045). The decrease in CL of (R)- and (S)-warfarin was 0.3-0.5% per year. Other covariates influencing CL were lean body weight for both (R)- and (S)-warfarin and CYP2C9 genotype and blood sampling time for (S)-warfarin. Protein binding of (R)- and (S)-warfarin was not found to change significantly with age in either the clinical or the spiked samples, despite a slight decrease in albumin concentration with age.
  
  
  CONCLUSIONS
  These data support the hypothesis that the CL of (R)- and (S)-warfarin decreases with age. More accurate information was gained when measuring free CL for (S)-warfarin. Warfarin protein binding did not change significantly with age.
authors.affiliation: Clinical Pharmacology, Department of Medicine, University of Otago-Christchurch, New Zealand. berit.jensen@cdhb.health.nz
authors.forename: Berit Packert
authors.initials: BP
authors.lastname: Jensen
authors.forename: Paul Ken Leong
authors.initials: PK
authors.lastname: Chin
authors.forename: Rebecca Lee
authors.initials: RL
authors.lastname: Roberts
authors.forename: Evan James
authors.initials: EJ
authors.lastname: Begg
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001798:Blood Proteins / Q000378:metabolism*; D001800:Blood Specimen Collection / Q000379:methods; D002853:Chromatography, Liquid; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014859:Warfarin / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D001798:Blood Proteins; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases