The role of the CYP2B6 enzyme in drug metabolism is crucial, especially for individuals undergoing HIV treatment. CYP2B6 intermediate metabolizers, who possess a moderate level of enzyme activity due to genetic polymorphisms, face unique challenges when prescribed HIV medications metabolized by this enzyme, such as efavirenz. Efavirenz, a cornerstone antiretroviral drug, relies on CYP2B6 for its metabolism. Intermediate metabolizers often exhibit slower drug clearance compared to normal metabolizers, which can lead to elevated drug levels in the bloodstream. This increases the risk of adverse effects, including central nervous system (CNS) toxicity, characterized by dizziness, vivid dreams, insomnia, and, in severe cases, psychiatric disturbances. Furthermore, sustained high plasma concentrations may exacerbate drug toxicity while potentially reducing adherence to treatment. Pharmacogenetic testing can help identify intermediate metabolizers, enabling clinicians to tailor efavirenz dosing or opt for alternative therapies to optimize efficacy and minimize side effects.

CYP2B6: An Overview

CYP2B6 is an important enzyme within the cytochrome P450 superfamily, primarily expressed in the liver and to a lesser extent in the brain, kidneys, and lungs. CYP2B6 activity is influenced by genetic polymorphisms, leading to variations in how individuals metabolize drugs. Variants in the CYP2B6 gene, such as CYP2B6 516G>T and CYP2B6 983T>C, are known to alter enzyme function. These polymorphisms may result in decreased or increased enzyme activity, making patients intermediate, poor, or ultrarapid metabolizers of drugs processed by CYP2B6. Importantly, CYP2B6-mediated drug metabolism significantly impacts therapeutic outcomes and the risk of side effects, emphasizing its crucial role in personalized medicine.

The CYP2B6 enzyme metabolizes many drugs, including antidepressants, anticonvulsants, chemotherapeutic agents, and anesthetics.

Antidepressants

Bupropion: Metabolized by CYP2B6, Bupropion is an antidepressant and smoking cessation aid marketed under different brand names such as Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, and bupropion hydrochloride.

Anticonvulsants

Methylphenobarbital: Primarily metabolized by CYP2B6, Methylphenobarbital is used to treat partial epilepsy. This is sold under different brand names such as Mebaral, Mephyltaletten, Phemiton, and Prominal.

Chemotherapeutic agents

• Cyclophosphamide: Primarily metabolized by the cytochrome P450 enzyme CYP2B6, Cyclophosphamide (Cytoxan) is a proven beneficial antineoplastic agent for treating nonmalignant diseases such as rheumatoid arthritis and multiple sclerosis (a chronic disease that damages the central nervous system).
• Ifosfamide: An antineoplastic agent primarily metabolized by CYP3A4, however, CYP2B6 plays a secondary role in its breakdown in the body.

Anesthetics

• Propofol: During the anesthesia, an anesthetic (prevents pain and discomfort during medical procedures) that is administered intravenously and is primarily metabolized by CYP2B6. CYP2B6 Genotype Guided Dosing of Propofol Anesthetic may be beneficial for the elderly.
• Ketamine: An anesthetic that is also administered as an anti-depressant (however is not suitable for everyone suffering from depression) is also primarily metabolized by CYP2B6.

Other drugs

• Efavirenz: An antiretroviral that CYP2B6 metabolizes
• Nevirapine: An antiretroviral that CYP2B6 metabolizes
• Pethidine: A synthetic opioid that CYP2B6 metabolizes
• Methadone: A synthetic opioid that CYP2B6 metabolizes
• Selegiline: An anti-Parkinsonian drug that CYP2B6 metabolizes

What Are Enzymes and the CYP2B6 Family?

Enzymes are biological catalysts that accelerate chemical reactions in the body, playing important roles in processes such as digestion and metabolism. The cytochrome P450 (CYP) family comprises enzymes responsible for metabolizing various substances, including drugs. CYP2B6 is a significant member of this family, involved in the metabolism of several clinically important medications.

Genotyping and Its Importance

Genotyping involves analyzing an individual’s DNA to identify genetic variations that affect enzyme activity. Variations in the CYP2B6 gene can classify individuals into different metabolizer statuses:

• Poor Metabolizers: Significantly reduced enzyme activity.
• Intermediate Metabolizers: Moderate enzyme activity.
• Normal (Extensive) Metabolizers: Standard enzyme activity.
• Rapid Metabolizers: Increased enzyme activity.
• Ultrarapid Metabolizers: Substantially increased enzyme activity.

Identifying an individual’s metabolizer status through genotyping can guide personalized medication strategies, ensuring optimal efficacy and minimizing adverse effects.

Efavirenz Effects on Intermediate Metabolizers: HIV Management

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is commonly used in antiretroviral therapy for HIV. The metabolism of efavirenz is significantly influenced by CYP2B6 activity. Intermediate metabolizers may experience higher plasma concentrations of the drug, leading to an increased risk of side effects such as dizziness, insomnia, and vivid dreams. Conversely, poor metabolizers might face even higher risks due to slower drug clearance.

According to Mayo Clinic, “Efavirenz lowers the amount of HIV in the blood and may help delay some medical conditions that result from HIV. alone will not cure HIV (human immunodeficiency virus), instead, it is used in combination with other medicines to treat HIV.

Can Pharmacogenetic Testing Help?

Pharmacogenetic tests analyze your genetic variations to predict how you will respond to certain medications, such as a CYP2B6 Intermediate Metabolizer may be at higher risk of adverse drug effects as compared to a normal metabolizer. A test report from RPh labs clearly shows how you may react to 250+ medications, helping doctors tailor your medication per your unique DNA. Thus, minimizing the adverse drug reactions and improving treatment outcomes.

Conclusion

The CYP2B6 enzyme plays a key role in the metabolism of numerous drugs, including antidepressants and HIV medications, such as bupropion and Efavirenz. CYP2B6 Intermediate Metabolizers may show slower drug clearance, resulting in adverse drug reactions. Genetic differences influencing CYP2B6 enzyme activity in our body can significantly impact drug effectiveness and safety. Pharmacogenetic testing, by giving insights into your DNA (genetic makeup) offers a way to personalized medicine, allowing treatment plans that align with an individual’s genetic profile. Tailored medications may not only save you from trial and error, but they tend to be more effective and time savvy.

References:

https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/bupropion-hydrochloride-marketed-wellbutrin-zyban-and-generics-information#:~:text=Bupropion%20hydrochloride%20(marketed%20as%20Wellbutrin%2C%20Zyban%2C%20and%20generics)%20Information,-Share&text=Bupropion%20hydrochloride%20is%20marketed%20under,Wellbutrin%20SR

https://www.sciencedirect.com/topics/medicine-and-dentistry/cyp2b6#:~:text=CYP2B6%20is%20highly%20expressed%20in,%25%20decrease%20in%20CL/F.

https://pmc.ncbi.nlm.nih.gov/articles/PMC8863776/