Contribution of CYP3A4, CYP2B6, and CYP2C9 Isoforms toN-Demethylation of Ketamine in Human Liver Microsomes

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Ketamine is a widely used drug for its anesthetic and analgesic properties; it is also considered as a drug of abuse, as many cases of ketamine illegal consumption were reported. Ketamine is Ndemethylated by liver microsomal cytochrome P450 into norketamine. The identification of the enzymes responsible for ketamine metabolism is of great importance in clinical practice. In the present study, we investigated the metabolism of ketamine in human liver microsomes at clinically relevant concentrations. Liver to plasma concentration ratio of ketamine was taken into consideration. Pooled human liver microsomes and human lymphoblastexpressed P450 isoforms were used. N-demethylation of ketamine was correlated with nifedipine oxidase activity (CYP3A4-specific marker reaction), and it was also correlated with S-mephenytoin N-demethylase activity (CYP2B6-specific marker reaction). Orphenadrine, a specific inhibitor to CYP2B6, and ketoconazole, a specific inhibitor to CYP3A4, inhibited the N-demethylation of ketamine in human liver microsomes. In human lymphoblast-expressed P450, the activities of CYP2B6 were higher than those of CYP3A4 and CYP2C9 at three concentrations of ketamine, 0.005, 0.05, and 0.5 mM. When these results were extrapolated using the average relative content of these P450 isoforms in human liver, CYP3A4 was the major enzyme involved in ketamine N-demethylation. The present study demonstrates that CYP3A4 is the principal enzyme responsible for ketamine N-demethylation in human liver microsomes and that CYP2B6 and CYP2C9 have a minor contribution to ketamine N-demethylation at therapeutic concentrations of the drug.Ketamine is a N-methyl-D-aspartate receptor antagonist used in clinical practice since 1970 for its anesthetic, sedative, and analgesic properties. It is frequently used for induction of anesthesia in short term surgical operations, in maintaining anesthesia with other anesthetic agents, and as a postoperative pain relief agent in intensive care units (Nimmo and Clements, 1981;White et al., 1982). In recent years, there is increasing evidence of ketamine abuse, many cases of illegal ketamine consumption, and dependence was reported (Jansen and Darracot-Cankovic, 2001;Moore et al., 2001).Ketamine is N-demethylated by cytochrome P450 (P450 1 ) enzymes in the liver into norketamine (Fig. 1). In humans and animals, norketamine (NK) is considered as the major metabolite (Kaka and Hayton, 1980;Woolf and Adams, 1987), and it may contribute to the analgesic effect following ketamine administration (Shimoyama et al., 1999). In a recent study (Yanagihara et al., 2001), the human liver microsomal enzyme CYP2B6 was identified as the main P450 isoform responsible for the N-demethylation of ketamine in pooled human liver microsomes obtained from 10 donors, at a ketamine concentration of 0.005 mM. The expression of CYP2B6 is very low in comparison with other P450 isoforms (Ͻ1% of total P450). In addition, CYP2B6 shows a large interindiv...

Gauging circadian variation in ketamine metabolism by real-time breath analysis

“…This is in line with previous observations on the time-of day variation of the hypnotic effects ("sleep time") of ketamine in rodents; 10 ; early morning injection of ketamine led to longer sleep time compared to evening injection. In line with these results, we found higher Ketamine is metabolized by liver microsomal cytochrome (CYP) P450, 11 , which are under circadian control. 12 .…”

Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S‐ketamine and Ticlopidine in Healthy Human Volunteers

“…Dense sampling after S ‐ketamine dosing allowed us to model the gut wall clearance with a low uncertainty level. CYP3A4 has been proposed in the literature as the major enzyme responsible for S ‐ketamine demethylation to norketamine,37 but our results demonstrate that the gut wall clearance is not an important player in S ‐ketamine biotransformation, suggesting that CYP3A contribution to S ‐ketamine metabolism is lesser than previously anticipated. Gut wall expression of CYP2B6 is negligible,33 therefore, the contribution of gut wall to total clearance can be attributed to the intestinal CYP3A4 reservoir only.…”

“…The pharmacokinetic models for both of these substances demonstrated adequate precision and provided a good model fit. Our results indicate that the both gut wall and liver contribute significantly to norketamine metabolism to 6‐hydroxy‐norketamine ( Table 2), which has been previously reported to take place rapidly 37. Norketamine elimination was described with a well‐stirred clearance model at both elimination sites.…”

Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

“…[43][44][45][46] Oral ketamine undergoes extensive first-pass hepatic metabolism mainly to norketamine (via CYP3A4). 47,48 Norketamine is about one-third as potent as parenteral ketamine for anesthesia; however, it is equipotent as an analgesic. The maximum blood concentration of norketamine is actually greater after oral administration than after parenteral administration.…”