Understanding Drug Absorption
How drugs cross biological membranes to enter the bloodstream, and the factors that determine absorption rate and extent.
## What Is Drug Absorption?
Drug absorption is the process by which a drug moves from its site of administration into the systemic circulation. For any non-intravenous route, absorption is the first pharmacokinetic step and often the most variable.
## Mechanisms of Absorption
Drugs cross biological membranes through several mechanisms:
- **Passive diffusion** accounts for the majority of drug absorption. Lipophilic, un-ionized molecules cross cell membranes down their concentration gradient without energy expenditure. Fick's law governs the rate: it increases with greater surface area, higher lipophilicity, and larger concentration difference.
- **Active transport** uses carrier proteins and ATP to move drugs against concentration gradients. Peptide transporters (PEPT1) in the small intestine absorb drugs like cephalosporins and ACE inhibitors.
- **Facilitated diffusion** relies on carrier proteins but follows the concentration gradient, requiring no energy. Nucleoside transporters move certain antiviral drugs this way.
- **Paracellular transport** allows small, hydrophilic molecules to pass between intestinal epithelial cells through tight junctions.
## Factors Affecting Oral Absorption
The oral route introduces the most variability. Key determinants include:
- **Gastric pH** influences ionization. Weak acids (aspirin, NSAIDs) are un-ionized in acidic environments and absorb from the stomach, while weak bases (metformin) absorb better in the alkaline small intestine.
- **Gastric emptying rate** controls how quickly drug reaches the absorptive surface of the duodenum. Opioids slow emptying; metoclopramide speeds it.
- **Surface area** of the small intestine (~200 m²) makes it the primary absorption site regardless of ionization state.
- **Blood flow** to the gut maintains the concentration gradient. Splanchnic blood flow is reduced by heart failure and shock.
- **Drug formulation** (tablet coating, particle size, salt form) directly affects dissolution rate and therefore absorption speed.
- **Food effects** can increase absorption (griseofulvin with fatty meals), decrease it (tetracycline with dairy), or have no effect.
## The pH-Partition Hypothesis
The Henderson-Hasselbalch equation predicts that un-ionized drug fractions cross membranes more readily. For a weak acid with pKa 3.5, approximately 99% is un-ionized at gastric pH 1.5, favoring gastric absorption. However, the vast surface area of the small intestine means most absorption occurs there regardless.
## Key Takeaways
- Absorption determines how much drug reaches the blood from non-IV routes
- Passive diffusion is the dominant mechanism for most oral drugs
- Gastric emptying, pH, surface area, and formulation are the main variables
- The small intestine is the primary absorption site for virtually all oral drugs