CYP2B6*6 allele and age substantially reduce steady‐state ketamine clearance in chronic pain patients: impact on adverse effects. (1st June 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: British journal of clinical pharmacology. Volume 80:Number 2(2015:Aug.)
• Page Start: 276
• Page End: 284
• Publication Date: 2015-06-01
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12614
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12614-sec-0001" sec-type="section"> <title>Aims</title> <p>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 <italic>CYP2B6</italic>*<italic>6</italic> allele is associated with substantially reduced ketamine metabolism <italic>in vitro</italic> and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the <italic>CYP2B6</italic>*<italic>6</italic> allele on ketamine plasma clearance and on adverse effects in chronic pain patients.</p> </sec> <sec id="bcp12614-sec-0002" sec-type="section"> <title>Methods</title> <p> <italic>CYP2B6</italic> genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady‐state plasma concentrations of ketamine (<italic>C</italic><sub>ss, k</sub>) and norketamine (<italic>C</italic><sub>ss, nk</sub>) were determined using HPLC.</p> </sec> <sec id="bcp12614-sec-0003" sec-type="section"> <title>Results</title> <p>The median plasma clearance of ketamine after 100 mg 24 h<sup>–1</sup> dose was significantly lower in patients with the <italic>CYP2B6</italic>*<italic>6</italic>/*<italic>6</italic> (21.6 l h<sup>–1</sup>) and <italic>CYP2B6</italic>*<italic>1</italic>/*<italic>6</italic> (40.6 l h<sup>–1</sup>) genotypes compared with patients with the <italic>CYP2B6</italic>*<italic>1</italic>/*<italic>1</italic> genotype (68.1 l h<sup>–1</sup>, <italic>P</italic> < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the <italic>CYP2B6</italic>*<italic>6</italic>/*<italic>6</italic> genotype than in those with the <italic>CYP2B6</italic>*<italic>1</italic>/*<italic>6</italic> and the <italic>CYP2B6</italic>*<italic>1</italic>/*<italic>1</italic> genotypes (<italic>P</italic> < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h<sup>‐1</sup>) than those who did not (52.6 l h<sup>‐1</sup>, <italic>P</italic> = 0.04). The <italic>CYP2B6</italic>*<italic>6</italic> genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in <italic>C</italic><sub>ss, k</sub>, respectively. Similar results were observed after higher doses.</p> </sec> <sec id="bcp12614-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The <italic>CYP2B6</italic>*<italic>6</italic> 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.</p> </sec> </abstract>