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CYP2B6 * 6 allele and age substantially reduce steady‐state ketamine clearance in chronic pain patients: impact on adverse effects
Author(s) -
Li Yibai,
Jackson Kate A.,
Slon Barry,
Hardy Janet R.,
Franco Michael,
William Leeroy,
Poon Peter,
Coller Janet K.,
Hutchinson Mark R.,
Currow David C.,
Somogyi Andrew A.
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12614
Subject(s) - ketamine , cyp2b6 , medicine , genotype , adverse effect , pharmacokinetics , pharmacogenetics , anesthesia , pharmacology , gastroenterology , metabolism , biology , cytochrome p450 , cyp3a4 , genetics , gene
Aims 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 ( C ss,k ) and norketamine ( C ss,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 C ss,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.