CYP2B6∗6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: Impact on adverse effects

Li, Y; Jackson, KA; Slon, B; Hardy, JR; Franco, M; William, L; Poon, P; Coller, JK; Hutchinson, MR; Currow, DC; Somogyi, AA

CYP2B6∗6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: Impact on adverse effects

Li, Y Jackson, KA Slon, B Hardy, JR Franco, M William, L Poon, P Coller, JK Hutchinson, MR Currow, DC

Somogyi, AA

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Publication Type:: Journal Article
Citation:: British Journal of Clinical Pharmacology, 2015, 80 (2), pp. 276 - 284
Issue Date:: 2015-08-01

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Field	Value	Language
dc.contributor.author	Li, Y	en_US
dc.contributor.author	Jackson, KA	en_US
dc.contributor.author	Slon, B	en_US
dc.contributor.author	Hardy, JR	en_US
dc.contributor.author	Franco, M	en_US
dc.contributor.author	William, L	en_US
dc.contributor.author	Poon, P	en_US
dc.contributor.author	Coller, JK	en_US
dc.contributor.author	Hutchinson, MR	en_US
dc.contributor.author	Currow, DC https://orcid.org/0000-0003-1988-1250	en_US
dc.contributor.author	Somogyi, AA	en_US
dc.date.available	2015-02-16	en_US
dc.date.issued	2015-08-01	en_US
dc.identifier.citation	British Journal of Clinical Pharmacology, 2015, 80 (2), pp. 276 - 284	en_US
dc.identifier.issn	0306-5251	en_US
dc.identifier.uri	http://hdl.handle.net/10453/118532
dc.description.abstract	© 2015 The British Pharmacological Society. 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 24h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (C<inf>ss,k</inf>) and norketamine (C<inf>ss,nk</inf>) were determined using HPLC. Results The median plasma clearance of ketamine after 100mg 24h<sup>-1</sup> dose was significantly lower in patients with the CYP2B6∗6/∗6 (21.6l h<sup>-1</sup>) and CYP2B6∗1/∗6 (40.6l h<sup>-1</sup>) genotypes compared with patients with the CYP2B6∗1/∗1 genotype (68.1l h<sup>-1</sup>, 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 (45.6l h<sup>-1</sup>) than those who did not (52.6l h<sup>-1</sup>, P=0.04). The CYP2B6∗6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in C<inf>ss,k</inf>, 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.	en_US
dc.relation.ispartof	British Journal of Clinical Pharmacology	en_US
dc.relation.isbasedon	10.1111/bcp.12614	en_US
dc.subject.classification	Pharmacology & Pharmacy	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Ketamine	en_US
dc.subject.mesh	DNA	en_US
dc.subject.mesh	Analgesics	en_US
dc.subject.mesh	Metabolic Clearance Rate	en_US
dc.subject.mesh	Linear Models	en_US
dc.subject.mesh	Double-Blind Method	en_US
dc.subject.mesh	Gene Frequency	en_US
dc.subject.mesh	Genotype	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Chronic Pain	en_US
dc.subject.mesh	Cytochrome P-450 CYP2B6	en_US
dc.title	CYP2B6∗6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: Impact on adverse effects	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	80	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/IMPACCT
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	80	en_US

Abstract:

© 2015 The British Pharmacological Society. 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 24h 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 100mg 24h^-1 dose was significantly lower in patients with the CYP2B6∗6/∗6 (21.6l h^-1) and CYP2B6∗1/∗6 (40.6l h^-1) genotypes compared with patients with the CYP2B6∗1/∗1 genotype (68.1l 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 (45.6l h^-1) than those who did not (52.6l 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.

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http://hdl.handle.net/10453/118532