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Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance

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Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance Lesley K. Rao, M.D., Alicia M. Flaker, A.S., Christina C. Friedel, B.S., Evan D. Kharasch, M.D., Ph.D. ABSTRACT Background: At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in vitro. This investigation tested whether humans with the CYP2B6*6 allele would have Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/125/6/1103/487909/20161200_0-00014.pdf by guest on 27 September 2021 decreased clinical ketamine metabolism and clearance. Methods: Thirty volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 genotypes (n = 10 each) received a subsedating dose of oral ketamine. Plasma and urine concentrations of ketamine and the major CYP2B6-dependent metabolites were determined by mass spectrometry. Subjects’ self-assessment of ketamine effects were also recorded. The primary outcome was ketamine N-demethylation, measured as the plasma norketamine/ketamine area under the curve ratio. Secondary outcomes included plasma ketamine enantiomer and metabolite area under the plasma concentration–time curve, maximum concentrations, apparent oral clearance, and metabolite formation clearances. Results: There was no significant difference between CYP2B6 genotypes in ketamine metabolism or any of the secondary outcome measures. Subjective self-assessment did reveal some differences in energy and level of awareness among subjects. Conclusions: These results show that while the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro, this allelic variant did not affect single, low-dose ketamine metabolism, clearance, and pharmacokinetics in vivo. While in vitro drug metabolism studies may be informative, clinical investigations in general are needed to validate in vitro observations. (ANESTHESIOLOGY 2016; 125:1103-12) ETAMINE was originally developed in 1964 as a What We Already Know about This Topic K “dissociative” anesthetic and was Food and Drug Admin- istration approved in 1970. Since that time, it has been widely • Ketamine is used in anesthesiology, chronic pain manage- used in anesthesia, in part, because unlike most other intra- ment, psychiatry, and emergency medicine • Cytochrome P4502B6 (CYP2B6) is the major P450 isoform venous anesthetics, it does not significantly depress the respi- catalyzing ketamine metabolism to norketamine and metabo- ratory and circulatory systems. In addition, ketamine causes lism overall significant antinociceptive and antihyperalgesic (i.e., analgesic) • In vitro, CYP2B6.6 (the protein encoded by the variant effects at low doses—lower than those that cause sedation and CYP2B6*6 allele) has diminished activity toward ketamine metabolism compared with wild-type CYP2B6.1 loss of consciousness. It can be administered by intravenous, intramuscular, oral, sublingual, intranasal, and rectal routes. What This Article Tells Us That Is New It has long been thought that ketamine primarily acts • Healthy volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 geno- by antagonizing N-methyl-D-aspartate receptors; how- types received a single oral ketamine dose ever, more recently, some evidence suggests that inhibi- • There was no significant difference between CYP2B6 geno- tion of hyperpolarization-activated cyclic nucleotide-gated types in ketamine or norketamine plasma concentrations or potassium channel 1 channels may also contribute to drug ketamine metabolism effects.1 Oral ketamine has been evaluated extensively for use in chronic pain management.2 The use of ketamine in Thus, there is marked interest in better understanding the pediatric sedation, analgesia, and emergency room analgesia pharmacokinetics and pharmacodynamics, as well as other is also of interest.3–6 More recently, it has been discovered applications of this drug. that ketamine may be effective in the therapy of treatment- Ketamine is administered clinically as a racemic mixture resistant depression, and with very fast response rates.7–10 of R- and S-ketamine although the S-ketamine isomer alone This article is featured in “This Month in Anesthesiology,” page 1A. Corresponding article on page 1085. Timothy J. Brennan, Ph.D., M.D., served as Handling Editor for this article. Submitted for publication February 10, 2016. Accepted for publication August 3, 2016. From the Division of Clinical and Transla- tional Research, Department of Anesthesiology (L.K.R., A.M.F., C.C.F., E.D.K.), and Department of Biochemistry and Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri; and the Center for Clinical Pharmacology, St. Louis College of Pharmacy and Wash- ington University in St. Louis School of Medicine, St. Louis, Missouri (E.D.K.). Copyright © 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2016; 125:1103-12 Anesthesiology, V 125 • No 6 1103 December 2016 Copyright © 2016, the American Society of Anesthesiologists,<zdoi;10.1097/ALN.0000000000001392> Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Role of CYP2B6 Polymorphisms in Ketamine Metabolism is used in some countries outside the United States. First- several substrates, compared with wild-type CYP2B6*1/*1 pass metabolism of oral ketamine is considerable; thus, it is carriers. A recent in vitro investigation demonstrated only about 15% bioavailable.11 Ketamine undergoes exten- that CYP2B6.6 (the protein encoded by the CYP2B6*6 sive metabolism, primarily via N-demethylation to norket- allele) has diminished catalytic activity toward ketamine 12–15 14–18 amine and to several other metabolites (fig. 1 ). The N-demethylation compared with wild-type CYP2B6.1, primary metabolites, norketamine and hydroxyketamine, and liver microsomes from humans heterozygous or homo- are rapidly further metabolized to hydroxynorketamine and zygous for the CYP2B6*6 allele also had diminished cata- dehydronorketamine. There are minor stereoselective differ- lytic activity toward ketamine N-demethylation, compared ences in ketamine enantiomer metabolism and disposition. with CYP2B6*1/*1 genotypes.20 It has been suggested It has recently been established that cytochrome P4502B6 that CYP2B6*6 carriers have diminished clinical ketamine (CYP2B6) is the major isoform catalyzing both ketamine Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/125/6/1103/487909/20161200_0-00014.pdf by guest on 27 September 2021 N-demethylation.20 N-demethylation and ketamine metabolism overall in vitro Nonetheless, there is no formal evaluation of ketamine at therapeutic concentrations14,16,17,19,20 and clinically.21 A recent clinical investigation showed the predominant role pharmacokinetics, metabolism, or clearance in CYP2B6*6 of CYP2B6 and lack of significant CYP3A involvement in carriers. This investigation tested the hypothesis that ketamine pharmacokinetics and metabolism.21 CYP2B6 variants (CYP2B6*6 hetero- or homozygotes) in CYP2B6 is a highly polymorphic enzyme.22 The most vivo will have decreased ketamine metabolism and clearance common variant allele, CYP2B6*6, found mostly in Afri- and potentially greater clinical effects. Better understanding cans, African-Americans, and some Asian populations, is of interpatient variability in drug metabolism and clearance associated with both diminished hepatic CYP2B6 enzyme would potentially allow for more accurate dosing to achieve expression and diminished CYP2B6 catalytic activity toward clinical effectiveness and avoid side effects. Fig. 1. Hepatic biotransformation of ketamine and responsible enzymes in humans at therapeutic concentrations. R- and S- ketamine enantiomers are N-demethylated to the major primary metabolite enantiomers R- and S-norketamine. A minor initial route of metabolism is 6-hydroxylation, yielding two pairs of diasteromers (2S,6S-, 2S,6R-, 2R,6R-, and 2R,6S-hydroxyketamine). The primary metabolite(s) R- and S-norketamine undergo further metabolism to the secondary metabolite enantiomers R- and S-dehydronorketamine. The primary metabolites may also undergo further N-demethylation or (4, 5, or 6)-hydroxylation to six pairs of diasteromeric hydroxynorketamine metabolites. In human liver microsomes, the major hydroxynorketamine formed from ketamine is 4-hydroxynorketamine, the major hydroxynorketamine from norketamine is 5-hydroxynorketamine, and the major hydroxynorketamine from hydroxyketamine is 6-hydroxynorketamine. After intravenous infusion of 0.5 mg/kg ketamine in humans, the major circulating metabolites were R- and S-norketamine, 2S,6S;2R,6R-hydroxynorketamine, 2S,5R;2R,5S- hydroxynorketamine, and R- and S-dehydronorketamine, with negligible concentrations of hydroxyketamine. Overall, cyto- chrome P450 (CYP)2B6 is the major isoform responsible for the metabolism of both R- and S-ketamine at therapeutic concen- trations. Rates of S-ketamine metabolism are moderately greater than R-ketamine, but relative amounts of metabolites formed and responsible CYPs are not substantially different between enantiomers except where shown. Based on previous reports.14–18 Anesthesiology 2016; 125:1103-12 1104 Rao et al.
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