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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.Copyright © 2015 The British Pharmacological Society.

Ketamine [2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride] is being increasingly used as an adjuvant analgesic in chronic pain management. Ketamine is primarily metabolized to norketamine (weakly active) by hepatic CYP2B6 and CYP3A41. The CYP2B6*6 allele is the most prevalent and clinically important variant of CYP2B6, which affects plasma concentrations and in vitro metabolism of many CYP2B6 substrates2. However, little is known regarding its effect on ketamine metabolism. The hypothesis of this study is that the CYP2B6*6 allele alters ketamine metabolism to norketamine. We examined the impact of the CYP2B6*6 allele on ketamine pharmacokinetics using steady-state blood samples obtained from 23 chronic cancer pain patients who had received 100 mug racemic ketamine by continous 24 hour subcutaneous infusion, and on metabolism of ketamine enantiomers in cDNA-expressed CYP2B6.1 and CYP2B6.6 variant and human liver microsomes (HLMs) from 11 donors that were selected based on CYP2B6 genotype. Plasma concentrations of ketamine and norketamine and the kinetics of norketamine formation from separate ketamine enantiomers were determined and compared between CYP2B6 genotypes. The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data. The intrinsic clearance rate for both ketamine enantiomers by the high affinity enzyme (CYP2B6) in HLMs with CYP2B6*1/*1 genotype (n=4) were at least 2- and 6-fold higher, respectively, than those with CYP2B6*1/*6 (n=4) and CYP2B6*6/*6 genotypes (n=3) (Jonckheere-Terpstra p=0.008 and 0.001 for S- and R-ketamine, respectively). The intrinsic ketamine clearance rates for CYP2B6.1 were approximately 2-fold higher than those for CYP2B6.6. At 100 mug dose, the plasma ketamine clearance rate was significantly higher in patients with CYP2B6*1/*1 genotype (861+/-290 [mean+/-SD] ml/min, n=10) compared with those with CYP2B6*1/ *6 (637+/-135 ml/min, n=10) and CYP2B6*6/*7 genotypes (350 ml/min, n=1) [Jonckheere-Terpstra p=0.016].

This paper examines the independent variables of perceived environmental uncertainty (PEU) and the cultural beliefs of collectivism/individualism between two countries, Australia and South Africa. These countries were chosen because Australia is a stable democracy and South Africa is an emerging democracy which is undergoing significant political, social and economic transformation. The purpose of this paper is to determine whether accountants' commitment to an organisation is associated with perceived environmental uncertainty, collectivism and nationality. The results of this study suggest that individuals' organizational commitment is associated with nationality (South African and Australian) and that relationship is associated with their cultural beliefs (collectivism/individualism) and an environmental variable, perceived environmental uncertainty. This research is regarded as important in that multi-national organisations operating in different political and social environments may choose to use different means to ensure the maximum organisational commitment from their employees, in particular, those who are professional accountants.