Ketamine

Ketamine is a phencyclidine‑derivative that produces dose‑dependent dissociative anaesthesia, profound analgesia and amnesia. It is approved for induction and maintenance of anaesthesia (brand: Ketalar) and is used off‑label for refractory pain, treatment‑resistant depression and status epilepticus.

Therapeutic indications include procedural sedation, battlefield or pre‑hospital analgesia, peri‑operative analgesia and, at sub‑anaesthetic doses, rapid‑acting antidepressant therapy.Zarate 2016 :contentReference[oaicite:0]{index=0}

Pharmacodynamically, ketamine is a non‑competitive antagonist at the N‑methyl‑D‑aspartate (NMDA) receptor that decreases excitatory glutamatergic transmission. Secondary actions include opioid‑receptor agonism, monoamine transporter inhibition and interaction with HCN and voltage‑gated Ca²⁺ channels.

CYP2B6 encodes a phase‑I hepatic mono‑oxygenase responsible for the major pathway of ketamine biotransformation, N‑demethylation to norketamine. At clinically relevant concentrations, recombinant enzyme data show CYP2B6 accounts for approximately 60 – 70 % of intrinsic clearance, with CYP3A4 and CYP2C9 providing minor contributions.Yuan 2024 :contentReference[oaicite:1]{index=1}

Allelic variation in CYP2B6 is extensive. More than 40 star‑alleles have been catalogued. The most prevalent loss‑of‑function haplotype is *6 (Q172H + K262R). Reduced expression and catalytic efficiency translate into lower hepatic intrinsic clearance in microsomal and hepatocyte experiments.Rao 2016 :contentReference[oaicite:2]{index=2}

Ketamine plasma exposure and recovery time correlate inversely with hepatic N‑demethylation. Subjects homozygous for CYP2B6*6 demonstrate up to 40 % lower systemic clearance and higher norketamine : ketamine ratios compared with *1/*1 individuals in steady‑state studies of chronic pain patients.Domino 2019 :contentReference[oaicite:3]{index=3} A 2024 Drug Metabolism & Disposition report confirmed that the same allele halves in‑vitro demethylation of each enantiomer at clinically relevant concentrations.Yuan 2024 :contentReference[oaicite:4]{index=4}

No convincing association has been observed between CYP2B6 ultrarapid star‑alleles (e.g. *4) and clinically meaningful sub‑therapeutic exposure, but population numbers are small and most trials used single low doses.Duan 2021 review :contentReference[oaicite:5]{index=5}

Functional consequence is categorised by predicted metabolic capacity:

Ultrarapid or Rapid Metabolisers (e.g. *4/*4, *1/*4)

• Effect: Increased N‑demethylation rate
• Implication: Lower ketamine exposure may shorten anaesthetic duration or reduce antidepressant efficacy
• Side effects: None unique; theoretical risk of inadequate sedation

Normal Metabolisers (*1/*1)

• Effect: Reference clearance and duration
• Implication: Predictable recovery times
• Side effects: Standard profile

Intermediate Metabolisers (*1/*6, *1/*18)

• Effect: Moderately reduced clearance (≈25‑40 %)
• Implication: Prolonged psychomimetic and haemodynamic effects
• Side effects: Higher incidence of dysphoria and delayed emergence in observational data

Poor Metabolisers (*6/*6, rare nulls)

• Effect: Marked reduction in clearance
• Implication: Two‑ to three‑fold higher AUC, extended recovery and increased risk of hypertension or excessive sedation
• Side effects: Documented increase in psychotomimetic reactions and haemodynamic stress

Indeterminate/Not Available

• Effect: Unknown
• Implication: No specific guidance; follow standard dosing with clinical monitoring

CYP2B6 Dosing Guideline

CYP2B6*6 allele frequency varies widely: 15‑25 % in most European cohorts, ~45 % in West‑African groups and up to 60 % in specific Iranian Kurdish populations.KNMP 2025 factsheet :contentReference[oaicite:6]{index=6} Shahbazi 2022 :contentReference[oaicite:7]{index=7} Accordingly, the proportion of patients predicted to be intermediate or poor metabolisers is highest in populations with African ancestry, emphasising the importance of genotype‑guided dosing in these groups.

• Yuan M et al. The CYP2B6*6 Allele Significantly Alters the N‑Demethylation of Ketamine. Drug Metab Dispos. 2024.
• Rao LK et al. Role of CYP2B6 Polymorphisms in Ketamine Metabolism and Clearance. Anesthesiology. 2016.
• Domino KB et al. CYP2B6*6 Allele and Age Reduce Steady‑State Ketamine Clearance. Br J Clin Pharmacol. 2019.
• Duan F et al. CYP2B6 Functional Variability in Drug Metabolism. Front Genet. 2021 (review).
• Zarate CA et al. Ketamine for Depression – Pharmacokinetic and Pharmacodynamic Interactions. J Clin Psychiatry. 2016.
• Royal Dutch Pharmacists Association (KNMP). Pharmacogenetics – CYP2B6. Factsheet 2025.
• Shahbazi S et al. Frequency of CYP2B6 Alleles in Iranian Ethnicities. Genet Res. 2022.