What is phase 1 metabolism?

From the Guidelines

Phase 1 Metabolism

Phase 1 metabolism is the initial stage of biotransformation where lipophilic substances are converted into more hydrophilic compounds through enzymatic reactions such as oxidation, reduction, and hydrolysis 1. This phase is primarily mediated by the cytochrome P450 enzyme family, with specific isoenzymes like CYP3A4 playing a crucial role in the metabolism of various medications 1.

• Key characteristics of phase 1 metabolism include:
  • Involvement of the cytochrome P450 enzyme family
  • Enzymatic reactions such as oxidation, reduction, and hydrolysis
  • Conversion of lipophilic substances into more hydrophilic compounds
  • Crucial role in the metabolism of various medications, including those used in cancer treatment and management of comorbidities For example, CYP3A4 is responsible for the metabolism of more than 50% of all drugs in the market, including tyrosine kinase inhibitors (TKIs) 1. Understanding phase 1 metabolism is essential for predicting and managing potential drug-drug interactions, especially in cancer patients who often receive multiple medications concurrently 1.

From the FDA Drug Label

Metabolism: Simvastatin is metabolized by CYP3A4. Metoprolol is primarily metabolized by CYP2D6.

Phase 1 metabolism refers to the initial stage of drug metabolism, which involves the conversion of a lipophilic drug into a more hydrophilic compound through chemical reactions such as oxidation, reduction, or hydrolysis.

• Key enzymes involved in phase 1 metabolism include the cytochrome P450 (CYP) enzymes, such as CYP3A4 and CYP2D6.
• Examples of phase 1 metabolism include the hydrolysis of simvastatin to its active β-hydroxyacid form and the metabolism of metoprolol by CYP2D6. Based on the provided drug labels, it can be concluded that phase 1 metabolism is the process by which drugs like simvastatin and metoprolol are metabolized by enzymes such as CYP3A4 and CYP2D6, respectively 2 3 3.

From the Research

Definition of Phase 1 Metabolism

• Phase 1 metabolism involves functionalization reactions, which introduce or expose a functional group on the parent compound 4, 5, 6.
• These reactions are mainly oxidative and result in the loss of pharmacological activity 4.
• Phase 1 reactions are enzymatic in nature and are localized primarily in the liver, although every tissue examined has some metabolic activity 4.
• The cytochrome P450 monooxigenase system is the cornerstone and major catalyst of drug biotransformation reactions, including phase 1 metabolism 4, 7, 8.

Characteristics of Phase 1 Metabolism

• Phase 1 metabolism is the first step in the biotransformation of drugs and other xenobiotics 5, 6.
• The reactions involved in phase 1 metabolism include oxidation, reduction, and hydrolysis 6.
• The products of phase 1 metabolism are often more polar than the parent compound, but may still be pharmacologically active 6.
• Phase 1 metabolism is followed by phase 2 metabolism, which involves conjugation reactions that further increase the polarity of the compound and enhance its elimination from the body 4, 5, 6.

Enzymes Involved in Phase 1 Metabolism

• The cytochrome P450 superfamily of enzymes plays a major role in phase 1 metabolism 4, 7, 8.
• Other enzymes involved in phase 1 metabolism include flavin-containing monooxygenases and monoamine oxidases 8.
• The activity of these enzymes can be influenced by various factors, including concomitant drug administration, diet, and smoking 4.