Drug metabolism refers to the process by which the body breaks down and eliminates drugs. It occurs primarily in the liver and can be divided into two phases: phase 1 reactions and phase 2 reactions. Understanding these phases is important for predicting how a drug will be metabolized and eliminated from the body.
Phase 1 Drug Metabolism
Phase 1 metabolism, also known as functionalization reactions, introduces or unmasks functional groups on the drug molecule. This makes the drug more hydrophilic and prepares it for phase 2 metabolism. The most common phase 1 reactions include:
- Oxidation
- Reduction
- Hydrolysis
These reactions are carried out by enzymes known as the cytochrome P450 system. There are many different CYP enzymes and they show selectivity in the reactions they catalyze and the drugs they metabolize. The most important CYPs involved in drug metabolism are:
| CYP Enzyme | Drugs Metabolized |
|---|---|
| CYP3A4 | Macrolide antibiotics, benzodiazepines, statins, calcium channel blockers |
| CYP2D6 | Beta blockers, antidepressants, opioids |
| CYP2C9 | Non-steroidal anti-inflammatory drugs, sulfonylureas |
| CYP2C19 | Proton pump inhibitors, anticonvulsants |
| CYP1A2 | Caffeine, theophylline, clozapine |
Genetic polymorphisms can affect CYP activity, leading to poor, intermediate, extensive or ultra-rapid metabolizer phenotypes. This can influence drug efficacy and toxicity.
Phase 2 Drug Metabolism
Phase 2 metabolism, also called conjugation reactions, adds an endogenous substrate to increase the drug’s hydrophilicity and promote its excretion. Common phase 2 reactions include:
- Glucuronidation
- Sulfation
- Glutathionylation
- Acetylation
- Methylation
- Amino acid conjugation
The most prevalent enzyme system is the uridine 5′-diphospho-glucuronosyltransferase (UGT) family, which catalyzes glucuronidation reactions. Other key phase 2 enzymes are sulfotransferases (SULT), glutathione S-transferases (GST), N-acetyltransferases (NAT) and methyltransferases.
Phase 2 metabolism increases water solubility and ionization of the drug, aiding its elimination through urine or bile. Conjugation can also inactivate pharmacologically active compounds.
Phase 1 vs Phase 2 Metabolism
The key differences between phase 1 and phase 2 metabolism are:
| Phase 1 | Phase 2 |
|---|---|
| Also called functionalization reactions | Also called conjugation reactions |
| Introduces or unmasks functional groups (-OH, -NH2, -COOH) | Conjugates drug with endogenous compound (glucuronic acid, sulfate, glutathione) |
| Mediated by cytochrome P450 enzymes | Mediated by transferase enzymes like UGT and SULT |
| Increases drug hydrophilicity | Further increases drug hydrophilicity |
| Can produce pharmacologically active metabolites | Inactivates drug and yields inactive metabolites |
| Prepares drug for phase 2 | Prepares drug for excretion |
While both phases increase drug hydrophilicity, phase 1 exposes functional groups while phase 2 conjugates larger endogenous molecules. Phase 1 metabolites may still be pharmacologically active.
Order and Interplay of Metabolism Phases
Though named phase 1 and 2, the order and interplay between these metabolic steps is complex:
- A drug may undergo just phase 1, just phase 2, or a combination
- Reactions can occur simultaneously or sequentially
- A phase 1 metabolite may undergo phase 2 metabolism
- Some phase 2 reactions (like glutathione conjugation) may precede phase 1
The predominant pathway depends on the drug’s structure and physicochemical properties. However, both phases promote faster elimination of drugs and their metabolites.
Factors Affecting Drug Metabolism
Many factors can affect the activity of metabolizing enzymes and influence drug metabolism pathways including:
- Genetic polymorphisms – variants in metabolism genes like CYP2D6
- Age – decreased metabolism in newborns and elderly
- Sex hormones – increased CYP3A4 in women
- Pregnancy – increased drug metabolism
- Disease – liver/kidney dysfunction
- Drug interactions – enzyme induction or inhibition
- Smoking and alcohol – increased CYP1A2 activity
- Circadian rhythms – daily variation in enzyme levels
These can alter enzyme levels/activity and change the rate and pathway of drug metabolism in an individual. Genetic polymorphisms have a major influence on phase 1 metabolism.
Role of Drug Metabolism
Drug metabolism through phase 1 and phase 2 reactions serves several important purposes:
- Increases hydrophilicity for faster renal and biliary excretion
- Converts drugs into inactive metabolites that are easily eliminated
- Generates pharmacologically active metabolites in some cases
- Detoxifies and inactivates toxic compounds
- Modulates the pharmacological effect of drugs
- Aids in stopping drug action and limiting toxicity
Overall, drug metabolism facilitates termination of drug action and enhances elimination of medications and toxins from the body. Understanding phase 1 and phase 2 metabolism pathways allows prediction of drug-drug interactions and genetic variability in drug response.
Examples of Phase 1 and Phase 2 Metabolites
Here are some examples of drugs metabolized by phase 1 and phase 2 reactions:
Paracetamol
- Undergoes phase 1 oxidation by CYP2E1 to a reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI)
- NAPQI is detoxified by phase 2 glutathione conjugation
- The glucuronide and sulfate conjugates are renally excreted
Morphine
- Hydroxylated by CYP2D6 to active metabolite morphine-6-glucuronide
- Also forms morphine-3-glucuronide via phase 2 glucuronidation
- Morphine-6-glucuronide has analgesic effects
Ethanol
- Metabolized by alcohol dehydrogenase to acetaldehyde
- Acetaldehyde is oxidized by aldehyde dehydrogenase to acetate
- Acetate undergoes phase 2 metabolism to acetyl CoA
These examples illustrate how phase 1 functionalization and phase 2 conjugation act sequentially or in parallel to eliminate drugs and toxins from the body.
Conclusion
In summary, phase 1 metabolism introduces functional groups while phase 2 metabolism conjugates hydrophilic endogenous moieties to drugs. Though named sequentially, these pathways may occur in parallel or in reverse order depending on the compound. Both phases increase water solubility of drugs and toxins to expedite their excretion through urine or bile. Factors like genetics, age, and drug interactions can significantly impact the activity of metabolizing enzymes. Understanding phase 1 and phase 2 metabolism is vital for predicting elimination pathways and pharmacological effects of medications in the body.