What role do Cytochrome P450 (CYP450) enzymes play in the body's absorption, distribution, and clearance of medications?

From the Guidelines

Cytochrome P450 (CYP450) enzymes play a vital role in the body's absorption, distribution, and clearance of medications, with the main CYP enzyme, CYP3A4, responsible for the metabolism of more than 50% of all drugs in the market. The CYP450 family of enzymes is central to the metabolism of drugs, nutrients, endogenous substances, and environmental toxins 1. These enzymes are responsible for the phase I metabolism of many drugs, and their activity can be induced or inhibited by other drugs, leading to potential drug-drug interactions (DDIs) 1. Some key points to consider about CYP450 enzymes include:

• They are primarily located in the liver and transform medications into more water-soluble compounds that can be eliminated through urine or bile
• They participate in first-pass metabolism, affecting the bioavailability of medications
• They influence how drugs bind to plasma proteins and distribute throughout tissues
• Specific isoforms like CYP3A4, CYP2D6, and CYP2C9 metabolize approximately 50% of commonly prescribed medications, leading to potential DDIs when multiple medications compete for the same P450 enzyme 1
• Genetic variations in P450 enzymes can explain why individuals respond differently to the same medication, with some people being poor metabolizers requiring lower doses, while others are rapid metabolizers needing higher doses for therapeutic effect. For example, a study highlighted that co-prescription of drugs that induce or inhibit metabolic pathways used by tyrosine kinase inhibitors (TKIs) was high, with overall co-prescribing rates for DDI drugs that may decrease TKIs effectiveness ranging from 23–57%, while co-prescribing rates with drugs that may increase TKI toxicity ranged from 24–74% 1. This emphasizes the importance of considering CYP450 enzymes in medication management to minimize the risk of adverse interactions and optimize therapeutic outcomes.

From the FDA Drug Label

Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A

The CYP450 enzymes play a crucial role in the body's absorption, distribution, and clearance of medications, such as clopidogrel, by metabolizing the drug into its active metabolite. The active metabolite is then responsible for inhibiting platelet aggregation. Specifically, CYP2C19 is the primary enzyme involved in the formation of the active metabolite, with contributions from other CYP enzymes, including CYP1A2, CYP2B6, and CYP3A 2.

From the Research

Role of Cytochrome P450 (CYP450) Enzymes in Medication Absorption, Distribution, and Clearance

• CYP450 enzymes play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of drugs 3
• These enzymes are responsible for the metabolism of approximately 75% of drugs, representing a major clearance route 4
• CYP450 enzymes, along with other drug-metabolizing enzymes such as UDP-glucuronosyltransferases, aldehyde oxidase, and sulfotransferases, contribute significantly to the elimination pathways of new chemical entities 4

Mechanism of CYP450 Enzymes in Drug Metabolism

• CYP450 enzymes are mainly expressed in the liver and intestine, where they mediate phase I metabolism and first-pass metabolism, influencing drug action, safety, and bioavailability 5, 6
• These enzymes can also affect treatment outcomes by mediating local drug metabolism in sites of action, such as the brain and tumors 5
• Genetic polymorphisms and epigenetic changes in CYP genes, as well as environmental factors, can contribute to interethnic and interindividual variations in drug response 6

Importance of CYP450 Enzymes in Drug Therapy

• CYP450 enzymes have multifarious influences on treatment outcomes, affecting drug response, safety, and bioavailability 5
• Understanding the role of CYP450 enzymes in drug metabolism is critical for predicting human clearance and optimizing drug therapy 4, 6
• CYP450 enzymes can also be targeted for their ability to activate prodrugs or enhance the efficacy of coadministered drugs, highlighting their potential as therapeutic targets 7