Learning Objectives
Master the biochemical transformations of Drug Metabolism. Distinguish between Phase I and Phase II reactions, identify the role of the CYP450 system, and recognize how patient factors like age and genetics (acetylation status) impact drug clearance for the USMLE Step 1.
1. Overview of Drug Metabolism
The primary goal of drug metabolism is to convert lipophilic (fat-soluble) substances into polar, hydrophilic (water-soluble) metabolites that can be easily excreted.
| Concept | Details |
|---|---|
| Purpose | To bioactivate or deactivate substances for excretion in serum (urine, sweat) or bile (stool). |
| Sequence | Does not have to be sequential (Phase II can occur before Phase I). |
| Geriatrics | Elderly patients typically lose Phase I metabolism first. |
2. Phase I: Modification
Phase I reactions primarily “unmask” or insert a functional group. While these reactions often deactivate drugs, they can also create reactive oxygen metabolites.
| Parameter | Details |
|---|---|
| Mechanism | Reduction, Oxidation, Hydrolysis. |
| Enzymes | Predominantly CYP450-dependent. |
| Result | Slightly polar metabolites (active or inactive). |
3. Phase II: Conjugation
Phase II reactions involve the attachment of a polar molecule to the drug to make it very polar and hydrophilic.
| Parameter | Details |
|---|---|
| Mechanism | Methylation, Glucuronidation, Acetylation, Sulfation. |
| Acetylation Note | Slow acetylators have a $\downarrow$ rate of metabolism, leading to $\uparrow$ adverse effects (e.g., Isoniazid). |
| Result | Very polar, hydrophilic metabolites (exception: some acetylated metabolites). |
4. Clinical Correlates
| Factor | Impact on Metabolism |
|---|---|
| Aging | Loss of Phase I reactions; Phase II is relatively preserved. |
| Genetic Polymorphism | Slow vs. Fast acetylators; affects drugs like Isoniazid, Procainamide, and Hydralazine. |
| Prodrugs | Phase I or II may be required to bioactivate the drug into its functional form. |
Activity:
High-Yield Clinical Pearls:
- Mnemonic (GAS): Phase II reactions involve Glucuronidation, Acetylation, and Sulfation.
- Elderly Safety: Benzodiazepines like Lorazepam, Oxazepam, and Temazepam (LOT) undergo only Phase II metabolism and are safer for the elderly.
- Slow Acetylators: These patients are at higher risk for Drug-Induced Lupus Erythematosus (DILE) when taking Hydralazine or Procainamide.