What are the most important Cytochrome P450 (CYP450) enzymes to know in anesthesiology?

Key CYP450 Enzymes in Anesthesiology

The most critical CYP450 enzymes for anesthesiologists to know are CYP2E1 (for volatile anesthetics), CYP2B6 (for propofol and ketamine), CYP3A4 (for multiple agents including ketamine and fentanyl), and CYP2D6 (for opioid metabolism, particularly codeine). 1, 2

Volatile Anesthetic Metabolism

CYP2E1 - Primary Enzyme for Halogenated Agents

• CYP2E1 is the dominant enzyme metabolizing halothane, isoflurane, sevoflurane, enflurane, and desflurane, making it the single most important CYP enzyme for volatile anesthetic metabolism 1
• CYP3A4 and CYP2A6 contribute to halothane metabolism as secondary pathways, but CYP2E1 remains the primary route 1
• Genetic polymorphisms in CYP2E1 exist and may theoretically alter volatile anesthetic metabolism, though clinical significance remains under investigation 1

Intravenous Anesthetic Metabolism

CYP2B6 - Critical for Propofol and Ketamine

• CYP2B6 plays a key role in propofol metabolism through hydroxylation, working alongside UGT enzymes that handle glucuronidation 1
• CYP2B6, CYP3A4, and CYP2C9 are all relevant for ketamine metabolism, with CYP2B6 being particularly important 1
• CYP2B6 is highly polymorphic with significant interindividual variability in enzyme activity 1, 3

CYP3A4 - Broad Substrate Profile

• CYP3A4 contributes to ketamine metabolism and is involved in the metabolism of many perioperative medications including fentanyl and midazolam 1, 2
• CYP3A4 is responsible for approximately 50% of overall drug elimination in clinical practice, making it the most abundant drug-metabolizing enzyme 2
• Bicalutamide (an anti-androgen) reduces CYP3A4 activity and causes marked increases in midazolam concentrations, requiring dose adjustments 4

Opioid Metabolism

CYP2D6 - Essential for Codeine and Tramadol

• CYP2D6 converts codeine (a prodrug) to its active metabolite morphine, with genetic polymorphisms creating poor metabolizers (5-10% of Caucasians) and ultrarapid metabolizers (up to 28% in Middle Eastern populations) 4, 5
• Codeine should not be used in breastfeeding women because ultrarapid metabolizers produce dangerously high morphine concentrations in breast milk, potentially causing severe neonatal depression and death 4
• Poor metabolizers receive minimal analgesia from codeine, while ultrarapid metabolizers experience excessive effects and toxicity 4, 5
• Approximately 1-7% of the population are ultrarapid metabolizers who break down CYP2D6 substrates too quickly, leading to treatment failure 5

CYP2C19 - Secondary Opioid Pathway

• CYP2C19 works alongside CYP2D6 in metabolizing certain analgesics, with 2-5% of Caucasians being poor metabolizers 5
• This enzyme is particularly relevant when CYP2D6 pathways are compromised or saturated 5

Drug-Drug Interactions in Anesthesia

CYP2D6 Inhibitors

• Strong CYP2D6 inhibitors include paroxetine, fluoxetine, and bupropion, which can dramatically alter opioid metabolism 4, 5
• When SSRIs are used with tamoxifen in breast cancer patients, mild CYP2D6 inhibitors (sertraline, citalopram, venlafaxine, escitalopram) are preferred over potent inhibitors to avoid reducing tamoxifen efficacy 4

P-Glycoprotein Interactions

• While not a CYP enzyme, P-glycoprotein (P-gp) significantly affects drug bioavailability and interacts with anesthetic agents 4
• Oestrogen is bound by sugammadex, potentially reducing serum concentrations with unclear clinical effects 4

Clinical Pitfalls and Considerations

Genetic Polymorphism Impact

• Multiple metabolizer phenotypes exist: poor, intermediate, normal/extensive, and ultrarapid, each requiring different dosing strategies 5, 1
• Ethnic variations are substantial—ultrarapid CYP2D6 metabolism occurs in up to 28% of Middle Eastern populations but only 1% of Asians 4

Multi-Enzyme Metabolism

• Most anesthetic drugs are metabolized by multiple CYP enzymes, providing backup pathways when one enzyme is impaired 5, 1
• Propofol metabolism involves CYP2B6, CYP2C enzymes, UGTs, SULT1A1, and NQO1, demonstrating the complexity of anesthetic drug elimination 1

Testing Limitations

• The EGAPP Working Group found insufficient evidence that routine CYP450 genetic testing improves clinical outcomes for most medications, though it may prevent toxicity in poor metabolizers 4, 5
• Pharmacogenetic testing should be considered for patients with prior adverse reactions or treatment failures, particularly with opioids 5

Thiopental and Etomidate

• The specific CYP enzymes responsible for thiopental and etomidate metabolism remain incompletely characterized, limiting pharmacogenetic predictions for these agents 1