From the Guidelines
Phase 1 reactions in drug metabolism involve a series of biochemical transformations that modify the chemical structure of a substance, typically a medication or xenobiotic. These reactions include functionalization reactions such as hydroxylation, reduction, and hydrolysis, but do not typically involve conjugation reactions like sulfation, glucosidation, or acetylation, which are characteristic of Phase 2 reactions 1.
Examples of Phase 1 Reactions
- Epoxidation: the formation of epoxides, as seen in the metabolism of polycyclic aromatic hydrocarbons (PAHs) 1
- One-electron oxidation: the formation of radical cation intermediates, also seen in the metabolism of PAHs 1
- Hydroxylation: the introduction of a hydroxyl group, as seen in the metabolism of propranolol 1
- Reduction: the reduction of a functional group, as seen in the metabolism of diazepam 1
- Isomerization: the rearrangement of a molecule's structure, as seen in the conversion of cis-cis to trans-trans retinoic acid These reactions are typically catalyzed by enzymes such as cytochrome P450 (CYP), which is responsible for the metabolism of many drugs and xenobiotics 1.
Key Enzymes Involved in Phase 1 Reactions
- CYP1A1: involved in the metabolism of PAHs 1
- CYP1A2: involved in the metabolism of various drugs, including propranolol 1
- CYP3A4: involved in the metabolism of many drugs, including sunitinib 1 Overall, Phase 1 reactions play a crucial role in the metabolism of drugs and xenobiotics, and understanding these reactions is essential for predicting and preventing adverse drug interactions.
From the FDA Drug Label
Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation
- Phase 1 reactions in drug metabolism include:
- Aromatic hydroxylation (mainly 4-hydroxylation)
- N-dealkylation followed by further side-chain oxidation These reactions are examples of Phase 1 reactions involved in the metabolism of propranolol 2
From the Research
Phase 1 Reactions in Drug Metabolism
Phase 1 reactions in drug metabolism involve the introduction of functional groups into the xenobiotic molecule or the exposure of preexisting functional groups, resulting in the formation of more polar, more water-soluble, chemically more reactive and sometimes biologically more active derivatives 3. These reactions are catalyzed by various enzymes, including:
- Cytochrome P450 enzymes, which play a major role in the biotransformation of most xenobiotics as well as in the metabolism of important endogenous substrates such as steroids and fatty acids 4, 5
- Alcohol dehydrogenase
- Aldehyde dehydrogenase
- Ester and amide hydrolases
- Epoxide hydrolase
- Flavine monooxygenases
Examples of Phase 1 Reactions
Examples of phase 1 reactions include:
- Hydrolysis
- Reduction
- Oxidative processes catalyzed by cytochrome P450 containing monooxygenases, which are the most important phase 1 type reactions in the biotransformation of hydrophobic, chemically stable organic pollutants 3
- Introduction of functional groups, such as hydroxyl or amino groups, into the xenobiotic molecule
Enzymes Involved in Phase 1 Reactions
The enzymes involved in phase 1 reactions are primarily located in the endoplasmic reticulum (ER) and include: