Drug-Drug PK Interactions
How co-administered drugs alter each other's absorption, distribution, metabolism, and excretion through pharmacokinetic mechanisms.
## PK Interactions Overview
Pharmacokinetic drug-drug interactions alter the concentration-time profile of one or both drugs without changing their intrinsic pharmacological activity. These interactions occur at every ADME stage and are among the most common causes of adverse drug events.
## Absorption Interactions
- **pH changes**: Proton pump inhibitors raise gastric pH, reducing absorption of drugs requiring acid for dissolution (ketoconazole, iron salts, dasatinib).
- **Chelation**: Divalent cations (calcium, magnesium, aluminum in antacids) chelate tetracyclines and fluoroquinolones, forming unabsorbable complexes. Separate administration by 2 hours.
- **Motility effects**: Metoclopramide accelerates gastric emptying, increasing absorption rate of co-administered drugs. Opioids slow emptying, delaying absorption.
- **P-glycoprotein (P-gp) effects**: Verapamil inhibits intestinal P-gp, increasing oral bioavailability of digoxin by reducing gut efflux.
## Metabolism Interactions (Most Clinically Significant)
### CYP Inhibition
Inhibitors block enzyme activity, increasing substrate levels rapidly (within hours to days):
| Inhibitor | CYP Target | Clinical Consequence |
|-----------|-----------|---------------------|
| Ketoconazole | CYP3A4 | Increases cyclosporine, simvastatin levels |
| Fluoxetine | CYP2D6 | Reduces codeine efficacy (blocks morphine conversion) |
| Ciprofloxacin | CYP1A2 | Increases theophylline toxicity risk |
| Fluconazole | CYP2C9 | Increases warfarin effect, bleeding risk |
Mechanism-based (irreversible) inhibitors like erythromycin destroy the enzyme, and recovery requires new enzyme synthesis (3-5 days).
### CYP Induction
Inducers upregulate enzyme expression over 1-2 weeks, reducing substrate levels:
| Inducer | CYP Target | Clinical Consequence |
|---------|-----------|---------------------|
| Rifampin | CYP3A4, 2C9, 2C19 | Reduces oral contraceptive efficacy |
| Carbamazepine | CYP3A4, 2C9 | Reduces warfarin effect |
| St. John's Wort | CYP3A4 | Reduces cyclosporine, HIV protease inhibitor levels |
## Distribution Interactions
Protein binding displacement is frequently overemphasized. While one drug can displace another from albumin (e.g., valproate displacing phenytoin), the resulting increase in free drug is transient — enhanced elimination quickly restores equilibrium. Clinically significant displacement interactions are rare in isolation.
## Excretion Interactions
- **Renal tubular secretion**: Probenecid blocks OAT-mediated secretion of penicillins, historically used to prolong antibiotic effect. Cimetidine inhibits OCT2, reducing metformin renal clearance.
- **Urine pH**: Sodium bicarbonate alkalinizes urine, increasing excretion of salicylates.
- **Biliary excretion**: Cyclosporine inhibits biliary transporters, increasing rosuvastatin exposure.
## Key Takeaways
- CYP inhibition and induction are the most clinically important PK interactions
- Absorption interactions are prevented by separating doses in time
- Protein binding displacement alone rarely causes sustained clinical effects
- Renal transporter interactions can significantly alter drug levels
- Always check interaction databases when adding new medications