14.1 Absorption & Bioavailability

What ADME Means and Why Absorption Comes First

Pharmacokinetics describes what the body does to a drug, classically summarised as ADME: absorption, distribution, metabolism and excretion. Absorption is the movement of drug from the site of administration into the systemic circulation, and it determines how much drug is available to act.

Bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation in an unchanged, active form. By definition, an intravenous (IV) dose is 100% bioavailable (F = 1) because it is placed directly into the blood. Every other route must be absorbed across one or more biological membranes, so F is usually less than 1.

Routes of administration and bioavailability implications

The DHA exam loves route–bioavailability logic: if a drug is destroyed by first-pass metabolism (GTN, lidocaine, propranolol), the correct answer is usually the route that avoids the gut and liver.

Membrane Transport and Drug Ionization

Most drugs cross membranes by passive diffusion — movement down a concentration gradient, without a carrier, without energy, and without saturability. The rate is described by Fick's law of diffusion:

Rate of diffusion = (C₁ − C₂) × surface area × partition coefficient ÷ membrane thickness

This explains why the small intestine, with its enormous villous surface area, absorbs even partially ionized drugs efficiently, and why highly lipophilic drugs (high partition coefficient) diffuse fastest.

Ionization and the Henderson-Hasselbalch equation

Only the unionized (uncharged) species is lipophilic enough to diffuse across lipid membranes; the ionized species is water-soluble and membrane-impermeant. The ratio of the two forms depends on the drug's pKa and the surrounding pH, given by the Henderson-Hasselbalch equation:

• For a weak acid: pH = pKa + log([A⁻]⁄[HA])
• For a weak base: pH = pKa + log([B]⁄[BH⁺])

Worked example — aspirin (weak acid, pKa 3.5) in gastric fluid (pH 2.0):

1. Ratio of ionized to unionized = 10^(pH − pKa) = 10^(2.0 − 3.5) = 10^(−1.5) ≈ 0.032
2. So for every 1 ionized molecule there are about 31 unionized — roughly 97% is in the absorbable, unionized HA form.

A weak base shows the mirror image: morphine (pKa ≈ 8) is mostly ionized in gastric acid and is absorbed mainly from the small intestine.

Ion trapping

Where a pH gradient exists across a membrane, drug distributes until the unionized concentrations equalize — but the total (ionized + unionized) concentration becomes higher on the side where ionization is favoured. The drug is effectively trapped on that side. This is the concept behind urinary alkalinization to enhance salicylate elimination (Section 14.3) and explains why basic drugs can concentrate in acidic fluids such as breast milk relative to plasma.

Carrier-mediated processes matter for a minority of drugs: facilitated diffusion (carrier, no energy, saturable, down-gradient) and active transport (carrier, ATP-dependent, saturable, can work against a gradient — e.g., levodopa via the LAT1 amino-acid transporter). Efflux transporters such as P-glycoprotein (P-gp) pump absorbed drug back into the gut lumen and limit oral bioavailability.

First-Pass (Presystemic) Metabolism

Drugs absorbed from the stomach and small intestine enter the hepatic portal vein and pass through the liver before reaching the systemic circulation. Enzymes in the gut wall (notably CYP3A4, working alongside P-glycoprotein) and in hepatocytes can metabolize a large fraction of the dose on this first pass. Oral bioavailability can be decomposed as:

F = fraction absorbed × fraction escaping gut-wall metabolism × fraction escaping hepatic extraction

Classic high-first-pass drugs:

• Glyceryl trinitrate (GTN) — given sublingually (or transdermally/IV) precisely because the oral route would inactivate it almost completely.
• Propranolol — extensive hepatic extraction; oral doses are much larger than IV doses for the same effect.
• Lidocaine (lignocaine) — such a high hepatic extraction ratio that oral dosing cannot achieve useful plasma levels; therefore given IV for ventricular arrhythmias.
• Morphine — oral bioavailability only about 25–30%, which is why the oral-to-parenteral potency ratio is roughly 3:1.

Measuring bioavailability: AUC, Cmax and Tmax

A plasma concentration–time curve after a single dose yields three descriptors:

• AUC (area under the curve): total systemic exposure — used to calculate F.
• Cmax (peak concentration): reflects the rate and extent of absorption; linked to peak effects and toxicity.
• Tmax (time to peak): reflects the rate of absorption only.

Worked example — absolute bioavailability:

F = (AUC_oral × Dose_IV) ÷ (AUC_IV × Dose_oral)

A 10 mg oral tablet gives AUC = 400 µg·h/L; a 5 mg IV dose gives AUC = 500 µg·h/L.

1. Numerator: 400 × 5 = 2000
2. Denominator: 500 × 10 = 5000
3. F = 2000 ÷ 5000 = 0.40 (40%)

Bioequivalence: two products (e.g., generic versus innovator) are bioequivalent when the 90% confidence interval for the ratio of their log-transformed AUC and Cmax lies entirely within 80–125%. Bioequivalent products are considered therapeutically interchangeable — the 80–125% band is a frequent licensing-exam number.

Food and formulation effects

• Grapefruit juice irreversibly inhibits intestinal CYP3A4, increasing the bioavailability of felodipine, simvastatin and many other 3A4 substrates (the effect persists 24–72 hours; even one glass can matter).
• Dairy products and antacids: di- and trivalent cations (Ca²⁺, Mg²⁺, Al³⁺, Fe³⁺) chelate tetracyclines and fluoroquinolones, forming insoluble, unabsorbable complexes — separate administration by at least 2 hours.
• Gastric emptying is the rate-limiting step for most oral absorption: food usually delays emptying (lower, later Cmax); prokinetics such as metoclopramide accelerate it; opioids and anticholinergics slow it.
• Formulation: enteric coatings delay release past the stomach; modified-release (MR) products flatten Cmax and prolong Tmax — crushing them can cause dangerous dose dumping.