Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance

KETAMINE was originally developed in 1964 as a “dissociative” anesthetic and was Food and Drug Administration approved in 1970. Since that time, it has been widely used in anesthesia, in part, because unlike most other intravenous anesthetics, it does not significantly depress the respiratory and circulatory systems. In addition, ketamine causes significant antinociceptive and antihyperalgesic (i.e., analgesic) effects at low doses—lower than those that cause sedation and loss of consciousness. It can be administered by intravenous, intramuscular, oral, sublingual, intranasal, and rectal routes.

It has long been thought that ketamine primarily acts by antagonizing N-methyl-D-aspartate receptors; however, more recently, some evidence suggests that inhibition of hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 channels may also contribute to drug effects.¹  Oral ketamine has been evaluated extensively for use in chronic pain management.²  The use of ketamine in pediatric sedation, analgesia, and emergency room analgesia is also of interest.^3–6  More recently, it has been discovered that ketamine may be effective in the therapy of treatment-resistant depression, and with very fast response rates.^7–10  Thus, there is marked interest in better understanding the pharmacokinetics and pharmacodynamics, as well as other applications of this drug.

Ketamine is administered clinically as a racemic mixture of R- and S-ketamine although the S-ketamine isomer alone is used in some countries outside the United States. First-pass metabolism of oral ketamine is considerable; thus, it is only about 15% bioavailable.¹¹  Ketamine undergoes extensive metabolism, primarily via N-demethylation to norketamine and to several other metabolites^12–15  (fig. 1 ^14–18 ). The primary metabolites, norketamine and hydroxyketamine, are rapidly further metabolized to hydroxynorketamine and dehydronorketamine. There are minor stereoselective differences in ketamine enantiomer metabolism and disposition. It has recently been established that cytochrome P4502B6 (CYP2B6) is the major isoform catalyzing both ketamine N-demethylation and ketamine metabolism overall in vitro at therapeutic concentrations^{14,16,17,19,20}  and clinically.²¹  A recent clinical investigation showed the predominant role of CYP2B6 and lack of significant CYP3A involvement in ketamine pharmacokinetics and metabolism.²¹ 

CYP2B6 is a highly polymorphic enzyme.²²  The most common variant allele, CYP2B6*6, found mostly in Africans, African-Americans, and some Asian populations, is associated with both diminished hepatic CYP2B6 enzyme expression and diminished CYP2B6 catalytic activity toward several substrates, compared with wild-type CYP2B6*1/*1 carriers. A recent in vitro investigation demonstrated that CYP2B6.6 (the protein encoded by the CYP2B6*6 allele) has diminished catalytic activity toward ketamine N-demethylation compared with wild-type CYP2B6.1, and liver microsomes from humans heterozygous or homozygous for the CYP2B6*6 allele also had diminished catalytic activity toward ketamine N-demethylation, compared with CYP2B6*1/*1 genotypes.²⁰  It has been suggested that CYP2B6*6 carriers have diminished clinical ketamine N-demethylation.²⁰ 

Nonetheless, there is no formal evaluation of ketamine pharmacokinetics, metabolism, or clearance in CYP2B6*6 carriers. This investigation tested the hypothesis that CYP2B6 variants (CYP2B6*6 hetero- or homozygotes) in vivo will have decreased ketamine metabolism and clearance and potentially greater clinical effects. Better understanding of interpatient variability in drug metabolism and clearance would potentially allow for more accurate dosing to achieve clinical effectiveness and avoid side effects.

This was a single-center, single-session, open-label study of oral ketamine pharmacokinetics. The Institutional Review Board of Washington University in St. Louis (Missouri) approved the protocol, and the investigation was registered (ClinicalTrials.gov identifier: NCT01988922). All subjects provided written informed consent. Subjects were recruited from the greater St. Louis community and had been previously genotyped for CYP2B6. Eligible subjects were 18- to 50-year-old volunteers with CYP2B6*1/*1, CYP2B6*1/*6, or CYP2B6*6/*6 genotypes who were in good health without any remarkable medical conditions and with a body mass index less than 33 kg/m² (table 1). Genotyping was done as described previously.²³  Exclusion criteria included known history of liver or kidney disease; use of prescription or nonprescription medications, herbals, foods, or chemicals known to be metabolized by or affecting CYP2B6; females who were pregnant or nursing; known history of alcohol or drug addiction; or having direct physical access to and routine handling of addicting drugs in the regular course of duty. Each subject filled out a health self-assessment, including a structured interview to screen for history of substance abuse or addiction. The investigation was a pilot study, and 30 subjects, 10 with each with of the genotypes CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6, were studied.

Subjects were required to abstain from (1) alcohol for 48 h before and during study days; (2) caffeine-containing beverages the day of study drug administration; (3) grapefruit, oranges, apples, or their juices for 5 days before the study day; (4) food or liquids after midnight the day before drug administration (to eliminate food influence on oral drug absorption); and (5) nonstudy medications (including over the counter and/or herbal medications) for 3 days before the study visit, without previous principal investigator approval.

Subjects had a peripheral intravenous catheter inserted for blood sampling. They were orally administered 0.4 mg/kg of a parenteral formulation of racemic ketamine with 200 ml water (average dose, 31 ± 6 mg). This dose was intended to have a small detectable pharmacologic effect, but be subsedating, and was based on other studies in healthy volunteers.^21,24  Venous blood samples were drawn before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h after ketamine administration. Coincident with blood sampling, subjective self-assessment of drug effect was performed using a visual analog scale for levels of alertness/sedation (almost asleep to wide awake), energy level (no energy to full of energy), confusion (confused to clear headed), clumsiness (extremely clumsy to well coordinated), anxiety (calm/relaxed to extremely nervous), and nausea (no nausea to worst nausea). Subjects used an unruled 100-mm slider to indicate their response. After the response was given, a numerical score was assigned according to the location of the cursor on the ruler. Clinically detectable ketamine effects were not expected given the ketamine dose, and were recorded so that any effects detected in certain genetic variants could be followed up on with subsequent studies. Two hours after dosing, subjects were free to move around and were given a standard meal. They had free access to food and water during the study session. Urine was continuously collected for 24 h after ketamine administration.

Ketamine, norketamine, and dehydronorketamine concentrations in plasma and urine were determined by enantioselective high-performance liquid chromatography (HPLC)–tandem mass spectrometry, using solid-phase extraction, based on a modification of a published method.²⁵  Ketamine (undeuterated, d0 and deuterated, d4), norketamine (undeuterated, d0 and deuterated, d4), and dehydronorketamine were from Cerilliant (Round Rock, USA). Strata-X 33u (30 mg) solid-phase extraction plates were from Phenomenex (USA). Other reagents were from Sigma-Aldrich (USA).

To thawed subject plasma, calibration, or quality control samples (250 μl), an internal standard (1.25 ng RS-ketamine-d4 and 1.25 ng RS-norketamine-d4) and 0.75 ml 10 mM ammonium acetate in water were added (pH 9.5). Solid-phase extraction plates were conditioned with 1 ml methanol, water, and then 10 mM ammonium acetate in water (pH 9.5). Plasma samples were loaded under soft (5 mmHg) vacuum at 0.5 ml/min and the plate was washed with water and then completely dried under high vacuum (10 to 15 mmHg for 2 to 5 min). Samples were eluted with 0.5 ml methanol by gravity for 15 min and then under vacuum (10 to 15 mmHg) and then evaporated to dryness under nitrogen at 35°C. For analysis, samples were resuspended in 200-μl mobile phase (10 mM ammonium acetate, pH 7.6). Calibration samples contained 0, 0.1, 0.25, 0.5, 1, 2.5, 5, 10, 25, 50, 100, and 250 ng/ml racemic ketamine, norketamine, and dehydronorketamine (base). Quality control samples contained 0.5, 5, and 25 ng/ml racemic ketamine, norketamine, and dehydronorketamine (base).

To thawed subject urine, calibration, or quality control samples (25 μl), an internal standard (1.25 ng RS-ketamine-d4 and 1.25 ng RS-norketamine-d4) and 1,000 units β-glucuronidase in 100 μl 100 mM ammonium acetate (pH 5.0) were added; samples were incubated at 37°C overnight and then diluted with 1 ml 10 mM ammonium acetate in water (pH 9.5). Solid-phase extraction was performed as described above. Calibration samples contained 0, 20, 50, 100, 200, 500, 1,000, 1,500, and 2,000 ng/ml racemic ketamine, norketamine, and dehydronorketamine (base). Quality control samples contained 200 and 1,000 ng/ml racemic ketamine, norketamine, and dehydronorketamine (base).

HPLC–mass spectrometry analysis was performed on an ultrafast liquid chromatography system (Shimadzu Scientific Instruments, USA) with a CMB-20A system controller, two LC-20ADXR pumps, DGU-20A3 degasser, SIL-20AC autosampler, FCV-11AL solvent selection module, and CTO-20A column oven (30°C) containing a ChiralPak AGP analytical column (100 × 2.0 mm; 5 μm) and AGP guard column (10 × 2.0 mm; Chiral Technologies, USA), coupled to an API 4000 QTrap LC-MS/MS linear ion trap triple-quadrupole tandem mass spectrometer (Applied Biosystems/MDS Sciex, USA). For both plasma and urine, the mobile phase (0.22 ml/min) was 10 mM ammonium acetate in water (pH 7.60; A) and isopropanol (B). The column was equilibrated with 4% B, maintained after injection for 0.1 min, then a linear gradient to 16.8% B was applied for 12 min, then reverted back to 4% B for 0.5 min and reequilibrated for 3 min. Total run time was 16 min. Under these conditions, approximate retention time for each compound was 7.0 and 8.1 min for S- and R-ketamine, 4.9 and 6.9 min for S- and R-norketamine, 4.1 and 7.3 min for S- and R-dehydronorketamine, and 2.4 min for both hydroxynorketamine isomers (fig. 2). The mass spectrometer electrospray ion source was operated in positive-ion multiple reaction monitoring mode. The [M + H]⁺ transitions were optimized for each analyte as follows: m/z, 238.0 → 125.1 and 242.1 → 129.2 for d0- and d4-ketamine, 224.0 → 125.0 and 228.2 → 129.1 for d0- and d4-norketamine, and 222.1 → 142.1 for dehydronorketamine. Because a standard for hydroxynorketamine was not available, the transition m/z 240.0 → 125.0 was based on previous reports,²⁵  and the retention time was confirmed by incubating ketamine with human liver microsomes. No stereochemistry was assigned to the hydroxynorketamine peak. Mass spectrometer settings for the declustering potential (36 to 70 V), collision energy (30 to 39 V), entrance potential (10 V), and collision cell exit potential (12 to 22 V) were optimized for each transition. Optimized global parameters were: source temperature, 350°C; ionspray voltage, 5,500 V; nitrogen (psig) curtain gas 20, gas 1 70, gas 2 10, collision gas medium. Calibration curves of peak area ratio versus analyte concentration were fit using linear least-squares analysis and 1/x² weighting. Analyte concentrations in patient samples were quantified using calibration curves for ketamine and norketamine (for norketamine, hydroxynorketamine, and dehydronorketamine).

Sample sizes for this pilot study were determined after a priori power calculations. Pharmacokinetic data were analyzed using noncompartmental methods (Phoenix; Pharsight Corp, USA), assuming complete absorption, as described previously.²⁶  Apparent oral clearance (CL/F) was dose divided by concentration–time area under the curve (AUC)_0–∞. Metabolite formation clearance was the percentage of the ketamine dose excreted in urine as metabolite multiplied by ketamine CL/F. Results are reported as the arithmetic mean ± SD. The primary outcome measure was ketamine N-demethylation, measured as the plasma norketamine/ketamine concentration–time AUC_0–∞ ratio (and also as the sum of N-demethylated ketamine metabolites/ketamine). Secondary outcomes were plasma ketamine enantiomer and metabolite AUC, maximum concentrations, apparent ketamine oral clearance, and metabolite formation clearances. Differences between CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6 genotypes for pharmacokinetic parameters were analyzed using one-way ANOVA followed by the Student–Newman–Keuls test for multiple comparisons (Sigmaplot 12.5; Systat Software, Inc, USA). Nonnormal data were log transformed for analysis but reported as the nontransformed results. Statistical significance was assigned at P < 0.05.

Plasma ketamine and metabolite concentrations are shown in figure 3 for the three genotype groups (CYP2B6*1/*1, CYP2B6*1/*6, and CYP2B6*6/*6). Enantiomeric data are shown for ketamine, norketamine, and dehydronorketamine, which were chromatographically resolvable, while hydroxynorketamine diastereomers were nonresolvable and are quantified together (fig. 2). Pharmacokinetic parameters are provided in table 2. There was no significant difference in ketamine N-demethylation, for either R- or S-ketamine measured by plasma norketamine/ketamine AUC ratios (or norketamine/ketamine C_max ratios, not shown), in CYP2B6*6 carriers (CYP2B6*6 hetero- or homozygotes) compared to the wild-type CYP2B6*1/*1 genotype (fig. 3). There was also no significant difference between CYP2B6 genotypes in ketamine N-demethylation, measured by norketamine formation clearance (fig. 4) or by other measures of CYP2B6-dependent metabolism that incorporate secondary metabolism (dehydronorketamine/ketamine, norketamine plus dehydronorketamine/ketamine, hydroxynorketamine/ketamine, or norketamine plus dehydronorketamine plus hydroxynorketamine/ketamine AUC ratios; table 2). These ratios are less reliable, however, because S-dehydronorketamine and hydroxynorketamine are elimination-rate limited rather than formation-rate limited (half-life is longer than that of the parent drug). There was no significant influence of CYP2B6*6 hetero- or homozygote genotypes on maximum ketamine enantiomer plasma concentration, time to maximum plasma concentration, ketamine AUC, CL/F, apparent volume of distribution, elimination half-life, or renal clearance. Excepting the AUC for hydroxynorketamine, there was also no significant difference in the maximum plasma concentration, AUC, elimination half-life, or formation clearance of the primary metabolite norketamine or the secondary metabolites, dehydronorketamine and hydroxynorketamine.

Ketamine clinical effects were measured by subjects’ subjective self-assessment (fig. 5). The dose was deliberately chosen for safety reasons to have a small (and nonsedating) pharmacologic effect but sufficient to reveal clinical effects if there were genotype-dependent increases in plasma concentration. There were essentially no significant effects, compared with predrug baseline, in alertness, energy, confusion, clumsiness, anxiety, or nausea, in any genotype group, and no significant differences between groups in any assessment scale.

Previous investigations established that CYP2B6 is the major enzyme catalyzing hepatic ketamine N-demethylation and ketamine metabolism at clinically relevant concentrations. Human liver microsomal ketamine N-demethylation is catalyzed by a high-affinity (low Michaelis-Menten constant, Km) CYP and a low-affinity (high Km) CYP.^17,20,27  Although both expressed CYP2B6 and CYP3A4 can N-demethylate ketamine at high substrate concentrations, CYP2B6 predominates at low, clinically relevant concentrations.^17–20  Several investigations using expressed enzymes and human liver microsomes showed that CYP2B6 and CYP3A4 were the low-Km (clinically relevant) and high-Km enzymes, respectively, that the activity (intrinsic clearance) of CYP2B6 is 6 to 8 times greater than that of CYP3A4, and that inhibitors (chemical and antibody) of CYP2B6 but not CYP3A4 diminished ketamine N-demethylation at clinically relevant concentrations.^14,17–20  Available clinical studies corroborate these findings, as the CYP2B6 inhibitor ticlopidine, but not the CYP3A4 inhibitor itraconazole, diminished oral ketamine N-demethylation and increased plasma ketamine concentrations,²¹  although some results are inconsistent.²⁸  CYP3A4 in the intestine may participate in intestinal presystemic metabolism of oral ketamine, at high local concentrations,²⁹  as intestinal CYP2B6 expression is low or nonexistent.³⁰ 

The CYP2B6 gene is highly polymorphic, with some alleles causing altered activity.²²  The most common variant allele, CYP2B6*6, found mostly in Africans, African-Americans, and some Asian populations, is associated with both diminished hepatic CYP2B6 enzyme expression and diminished CYP2B6 catalytic activity toward several substrates, compared with wild-type CYP2B6*1/*1 carriers. Additionally, the rate of ketamine N-demethylation by recombinant-expressed CYP2B6.6 (the enzyme coded for by CYP2B6*6) is considerably less than by wild-type CYP2B6.1, and ketamine N-demethylation in liver microsomes from individuals hetero- or homozygous for the CYP2B6*6 allele was significantly decreased compared with wild-type CYP2B6*1/*1.^19,20  Interindividual variability in ketamine metabolism and plasma concentrations has been thought likely to CYP2B6 genetic polymorphisms.³¹  A preliminary finding of a reduced plasma norketamine to ketamine concentration ratio in CYP2B6*6 carriers was reported.²⁰  The purpose of this investigation was to determine if the CYP2B6*6 polymorphism influenced clinical ketamine plasma concentrations and metabolism.

The major finding of this investigation was that there was no significant difference between CYP2B6*1/*1 (wild-type), CYP2B6*1/*6, and CYP2B6*6/*6 subjects in the plasma concentrations of ketamine, the primary metabolite norketamine, or the secondary metabolite dehydronorketamine, for either ketamine enantiomer. There was also no genetic difference in the N-demethylation of ketamine, assessed either as the plasma norketamine/ketamine AUC ratio or norketamine formation clearance. Because norketamine also undergoes further biotransformation, CYP2B6-dedependent ketamine metabolism was also assessed using both primary and secondary metabolites. Although potentially influenced by the slower elimination of the secondary metabolites, the metabolite/parent plasma AUC area ratios reflecting all CYP2B6-dependent metabolites, including dehydronorketamine/ketamine, norketamine+dehydronorketamine/ketamine, hydroxynorketamine/ketamine, and norketamine+dehydronorketamine+hydroxynorketamine/ketamine, were also not different from wild-type in CYP2B6*6 carriers. The major conclusion is that the CYP2B6*6 polymorphism did not affect oral ketamine metabolism, clearance, and pharmacokinetics in healthy human volunteers in vivo.

Oral ketamine undergoes extensive first-pass metabolism and has a high CL/F. The CL/F of R- and S-ketamine observed was 131 ± 57 and 182 ± 79 ml · kg⁻¹ · min⁻¹, respectively. Assuming hepatic blood flow of approximately 20 ml · kg⁻¹ · min⁻¹ in healthy subjects, representing maximum clearance, the bioavailability of R- and S-ketamine was only approximately 15% and 10%, respectively, which is in accordance with previously reported racemic bioavailability of approximately 16 to 20%^11,20  and an extraction ratio of 0.85. For drugs with high extraction and extensive hepatic metabolism, changes in metabolism, clearance, and plasma concentrations will be greater for oral than intravenous administration.³²  Specifically, for ketamine, this has been proposed²⁰  and confirmed.³¹  The expectation is that given the lack of effect of the CYP2B6*6 polymorphism on oral ketamine disposition, this polymorphism would not affect metabolism, clearance, and pharmacokinetics of intravenous ketamine in vivo.

Because CYP2B6 is the major isoform involved in clinical ketamine metabolism and only CYP2B6-catalyzed metabolic pathways were of interest, only CYP2B6-dependent metabolites (norketamine, deydronorketamine, and hydroxynorketamine) were studied. There is also some CYP3A-mediated metabolism of ketamine to hydroxyketamine. However, CYP3A involvement is not thought to be significantly involved in ketamine pharmacokinetics and metabolism.^12–15  Moreover, knowledge of hydroxyketamine concentrations would not inform or alter the conclusion of this investigation.

Assay of ketamine and metabolite enantiomers and diasteromers is challenging, and until recently, most pharmacokinetic studies evaluated only ketamine and norketamine, without chiral discrimination. The analytical method developed and implemented by Wainer and colleagues^14,15  enabling quantification of several ketamine and metabolite enantiomers and diastereomers, was a major advance. That assay used achiral analysis for total metabolite quantification, followed by chiral analysis using an α₁-acid glycoprotein HPLC column to determine the relative enantiomeric concentrations of R- and S-ketamine, R- and S-norketamine, and R- and S-dehydronorketamine. Because the current investigation did not aim to quantify the minor and non-CYP2B6–dependent metabolite hydroxyketamine, nor did it aim to individually quantify the various hydroxynorketamine regioisomers (4, 5, and 6-hydroxylation) and diastereomers, all analyses and quantification were performed using an α₁-acid glycoprotein HPLC column. It has been reported previously that the major circulating hydroxynorketamine diastereomers are 2S,6S;2R,6R>2S,5R;2R,5S.¹⁵  Knowledge of individual hydroxynorketamine diastereomer concentrations would not inform or alter the conclusion of this investigation.

Although the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro,²⁰  this allelic variant did not affect ketamine metabolism, clearance, and pharmacokinetics in vivo in the current investigation. A potential explanation why in vitro genetic differences did not translate to in vivo differences is that ketamine is a high-extraction drug (extraction ratio, 0.85), rendering it less sensitive to variations in hepatic enzyme activity than intermediate- or low-extraction drugs.³²  Nevertheless, inhibition of hepatic CYP2B6 activity (by ticlopidine) did diminish clinical S-ketamine N-demethylation and increase plasma ketamine concentrations after oral administration.²¹  Possibly, this ticlopidine effect was mediated partially through transporters,³³  as well as by CYP2B6 inhibition. Nevertheless, as a “positive control,” it strengthens the current conclusion that reduced hepatic CYP2B6 activity due to the CYP2B6*6 polymorphism did not affect low-dose oral ketamine metabolism, clearance, and pharmacokinetics in humans in vivo.

This investigation was a pilot study, and a small number of subjects were studied. However, based on conventional, a priori, sample size calculations, a clinically significant difference could be expected with this number of subjects, if such a difference in metabolism did exist. It is unlikely that evaluation of more subjects would change the results or conclusions.

The results of this investigation in healthy volunteers differ from a recent report on ketamine disposition and CYP2B6 polymorphisms in chronic pain patients³⁴  who received a 24-h subcutaneous ketamine infusion. A single steady-state plasma ketamine and norketamine achiral concentration was determined and used to calculate clearance. In CYP2B6*6 carriers, compared with CYP2B6*1/*1 patients, ketamine clearance was lower, with a gene dose effect, and the plasma norketamine/ketamine ratio was lower in CYP2B6*6/*6 patients compared with CYP2B6*1/*6 and CYP2B6*1/*1 genotypes. An explanation for the very different results of the current investigation is not clearly apparent. The difference cannot be attributed to the use of enantioselective versus achiral analysis since CYP2B6*6 affected neither R- nor S-ketamine in the current investigation. The route of ketamine administration did differ between studies. Conceptually, pharmacogenetic influences on hepatic metabolism should be even greater with oral than parenteral dosing, given extensive ketamine first-pass metabolism as was observed with methadone, another CYP2B6 substrate.²³  Possibly, CYP2B6 genetic influences on ketamine hepatic first-pass metabolism could be masked by non-CYP2B6 (i.e., CYP3A4)–dependent intestinal metabolism affecting bioavailability, although systemic (hepatic) ketamine elimination rates were not different between CYP2B6 genotypes. Perhaps the apparent influence of CYP2B6*6 polymorphisms differs between pharmacokinetic methods (metabolite and parent drug parameter determinations using single-point concentrations vs. multipoint AUCs). It is conceivable that the apparent influence of CYP2B6*6 polymorphisms differs between (1) single-dose and steady-state dosing; (2) study populations of healthy volunteers versus chronic and cancer pain patients, as inflammation and cancer are associated with down-regulation of hepatic and extrahepatic P450s³⁵ ; (3) route of administration (thus determining intravenous clearance vs. CL/F); (4) ketamine doses and resulting plasma concentrations, which were substantially greater in the study by Li et al.,³⁴  and (5) norketamine/ketamine concentration ratios, which were much higher in the current investigation (7 at C_max) compared with the study by Li et al.³⁴  (approximately 1 at steady state). It is also potentially pertinent that Li et al.³⁴  found an age-dependent decline in ketamine clearance, and the very small number of CYP2B6*6 subjects in their study were also the oldest; hence, there may be confounding between an age-dependent effect and an apparent genetic effect on ketamine metabolism and clearance.

The oral ketamine dose used in this investigation was intended to have a small pharmacologic effect, based on other studies in healthy volunteers.^21,24  It was conservatively chosen, anticipating potentially higher plasma concentrations and clinical effects in CYP2B6*6 carriers. Clinically measureable effects of ketamine were not observed, however, in any genotype group. This may be due to the deliberately small dose chosen or the different effect measures used herein and previously.²¹ 

In summary, in carriers of the CYP2B6*6 polymorphism, which results in diminished ketamine metabolism in vitro, compared with CYP2B6*1/*1 wild-type subjects, there was no significant difference in plasma ketamine or metabolite concentrations or in ketamine N-demethylation, measured as the plasma norketamine/ketamine AUC ratio or norketamine formation clearance, after single, low-dose oral ketamine administration. These results do not support the hypothesis that CYP2B6*6 pharmacogenetics affect single, low-dose oral ketamine metabolism, clearance, and pharmacokinetics in vivo. Similarly, CYP2B6*6 allele status would appear not to be a factor in single, low-dose oral ketamine dose or patient selection.

Supported in part by the Department of Anesthesiology, Washington University in St. Louis School of Medicine (St. Louis, Missouri) and grant R01-DA14211 from the National Institutes of Health (Bethesda, Maryland).

The authors declare no competing interests.

Full protocol available from Dr. Rao: raol@anest.wustl.edu. Raw data available from Dr. Rao: raol@anest.wustl.edu.