title: CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects.
abstract: OBJECTIVE
  Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients.
  
  
  METHODS
  CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k ) and norketamine (Css,nk ) were determined using HPLC.
  
  
  RESULTS
  The median plasma clearance of ketamine after 100 mg 24 h(-1) dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h(-1) ) and CYP2B6*1/*6 (40.6 l h(-1) ) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h(-1) , P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h(-1) ) than those who did not (52.6 l h(-1) , P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k , respectively. Similar results were observed after higher doses.
  
  
  CONCLUSIONS
  The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Yibai
authors.initials: Y
authors.lastname: Li
authors.affiliation: Supportive and Palliative Care Unit, Monash Health and Monash University, Monash Medical Centre, Victoria, Australia.
authors.forename: Kate A
authors.initials: KA
authors.lastname: Jackson
authors.affiliation: Department of Anaesthesia, Monash Medical Centre, Victoria, Australia.
authors.forename: Barry
authors.initials: B
authors.lastname: Slon
authors.affiliation: Department of Palliative Care, Mater Adult Hospital, Brisbane, Australia.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Hardy
authors.affiliation: Supportive and Palliative Care Unit, Monash Health and Monash University, Monash Medical Centre, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Franco
authors.affiliation: Supportive and Palliative Care Unit, Monash Health and Monash University, Monash Medical Centre, Victoria, Australia.
authors.forename: Leeroy
authors.initials: L
authors.lastname: William
authors.affiliation: Supportive and Palliative Care Unit, Monash Health and Monash University, Monash Medical Centre, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Poon
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.affiliation: Discipline of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.affiliation: Department of Palliative and Supportive Service, Flinders University, Adelaide, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Currow
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.|Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia.|Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D059350:Chronic Pain / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged
chemical_list: D000700:Analgesics; D007649:Ketamine; D004247:DNA; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6
keywords: adverse effects; age factors; cytochrome P-450 CYP2B6; ketamine; metabolic clearance rate; polymorphism