Absorption, first pass, and bioavailability

Vivian Imbriotis | Dec. 22, 2025

Absorption is the process of a drug moving from its site of administration to the plasma. Absorption occurs prior to first pass metabolism.

Oral absorption has two steps:

The dissolution of the tablet in chyme
The movement of the drug across the GIT membrane.

Most drugs are absorbed by simple or facilitated diffusion, and are therefore governed by Fick's law:

$$\frac{dX}{dt} = \text{D} \cdot \Delta C \propto \frac{\text{SA}\cdot\text{solubility}}{\text{Thickness}\sqrt{MW}}$$

First pass metabolism has two components:

Enterocyte metabolism of drug (e.g. of midazolam)
Hepatic metabolism of drug

Neglecting the first component, for a drug that only undergoes hepatic metabolism, the bioavailability is expressed as $1 - HER$

$$\underbrace{\text{Drug in tablet} \to \text{drug in chyme} \to}_{\text{Absorption}} \underbrace{\text{drug in portal plasma} \to \text{drug in systemic plasma}}_{\text{First pass metabolism}}$$

Drug factors influencing oral absorption

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Step 1: Tablet dissolution

Tablet disintegration: Stability of tablet determines rate of drug dispersion

Particle size: Smaller particles increase rate of drug elution into chyme

Step 2: Movement across membrane

Mode of transport: Passive diffusion, vs facilitated diffusion (gabapentin), vs active absorption (levodopa), vs active excretion by pumps (digoxin).

Concentration gradient: higher doses result in higher flux.

Molecular mass: lower molecular mass = faster absorption

Lipophilicity and pKa: More lipophilic substances are absorbed more readily. Weak acids are ionized when pH is above their pKa i.e. they are UNionized and absorbed in an ACIDIC environment (the stomach). Weak bases are unionized and absorbed in the basic environment of the small bowel.

Patient factors influencing oral absorption

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Gastric motility: decreased motility decreases absorption of all drugs (even those well-absorbed in the stomach) because the small intestine has such a large surface area, and the

Intestinal motility: If very high transit diarrhoea, the transit time in the small bowel will be insufficient

Splanchnic perfusion: to maintain concentration gradient

Available surface area: lost in crohn's, coeliac disease, necrosis of villi in shock

Intestinal content: food and other drugs that interact with the drug of interest

Enterohepatic recirculation: Increases AUC of the drug through reabsorption.

Gut microbiota: Metabolism will inactivate the drug

Metabolism in intestinal wall: Contributes to first-pass (e.g. of midazolam by CYP)

Factors influencing non-oral absorption

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IM and subcut: depends on regional blood flow

Sublingual: Small surface area. Bypasses portal circulation = no first pass.

Rectal: Small surface area. Distal rectal circulation bypasses portal circulation = partial first pass.

Inhaled: Depends on particle size. Particles < 5 micron diameter will reach bronchioles for local effect (e.g. salbutamol). Particles < 1 micron diameter will reach alveoli $\to$ rapid systemic absorption due to large surface area, high blood flow, no first pass.

Transdermal: Surface area, skin thickness, drug lipophilicity (and therefore pKa and skin pH), molecular weight.

Absorption in critical illness

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Delayed gastric emptying = decreased drug absorption (paracetamol)

Gastric pH is higher = decreased drug absorption (clopidogrel)

Increased GIT permeability = increased drug absorption (electrolyte replacement)

Decreased mesenteric perfusion = decreased drug absorption (paracetamol)

Increased preabsorptive interactions = decreased drug absorption (NG feeds and phenytoin)

Decreased active efflux = increased drug absorption (digoxin)

Decreased skin/muscle perfusion tissue = decreased absorption from subcutaneous or intramuscular injections (heparin)

Antibiotic use = less bacterial metabolism = increased absorption (digoxin)

Absorption in shock

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Anaphylactic shock: increased IM / subcut / transdermal absorption due to systemic vasodilation.

Decreased inhalational absorption due to bronchospasm.

Decreased GI absorption due to decreased GIT blood flow, delayed gastric emptying, intestinal wall oedema.

All other forms of shock: Decreased IM / subcut / transdermal absorbtion due to decreased perfusion.

Decreased inhalational absorption due to consolidation ($\downarrow$ SA), low CO ($\downarrow$ perfusion $\to$ $\downarrow \ \Delta C$), and alveolar oedema ($\uparrow$ membrane thickness).

Decreased GI absorption due to decreased GIT blood flow, delayed gastric emptying, intestinal wall oedema.