Absorption, bioavailability, routes of delivery and volume of distribution

At a glance

• Absorption is the movement of drug from the site of administration into plasma. Most drugs cross membranes by passive diffusion of the un-ionised, lipid-soluble form.
• Bioavailability (F) is the fraction of a dose that reaches the systemic circulation unchanged. Oral F falls with poor absorption, gut wall metabolism (CYP3A4), efflux by P-glycoprotein and hepatic first-pass extraction.
• Volume of distribution (Vd) links the amount of drug in the body to the plasma concentration. It sets the loading dose and predicts whether dialysis will remove a drug.
• Protein binding matters when albumin is low or binding sites are displaced: total levels mislead, and the free level is what acts.
• Paper 1 asks you to calculate F, Vd or a loading dose, explain an oral-to-IV dose ratio, or explain why a drug level is misleading.

Absorption and routes

Membrane transport

Weak acids are un-ionised in acid and weak bases in alkali (Henderson-Hasselbalch). Aspirin (pKa 3.5) is largely un-ionised in the stomach, but most absorption still happens in the small bowel because its surface area is enormous. The same principle explains ion trapping: alkalinising urine to pH 7.5 to 8.5 ionises salicylate in the tubule so it can't be reabsorbed.

Carrier systems matter for some drugs. Levodopa competes with dietary large neutral amino acids for the gut and blood-brain barrier transporter, which is why a high-protein meal blunts its effect in Parkinson disease.

What lowers oral bioavailability

Mechanism	Example	Clinical consequence
Poor absorption	Bisphosphonates (F under 1%); oral vancomycin (essentially 0% through intact mucosa)	Alendronate on an empty stomach with water; oral vancomycin works in the gut lumen (C. difficile), but severe colitis lets some through
Chelation in the gut	Calcium, iron, magnesium with tetracyclines, quinolones, levothyroxine	Separate doses by 2 to 4 hours
Needs gastric acid	Itraconazole capsules, ketoconazole, iron salts	PPIs reduce absorption
Gut wall CYP3A4	Ciclosporin, felodipine, simvastatin	Grapefruit juice inhibits gut CYP3A4 and raises levels
P-glycoprotein efflux	Digoxin, dabigatran	Verapamil, amiodarone raise levels; rifampicin lowers them
Hepatic first pass	Morphine (F about 30%), propranolol, GTN (near 0 orally)	Oral doses much larger than IV; GTN given sublingually

Route and formulation

• Sublingual, buccal, rectal (partly), transdermal, inhaled and parenteral routes avoid portal first pass. Sublingual GTN works in 1 to 3 minutes; swallowed GTN barely works.
• Transdermal fentanyl takes 12 to 24 hours to reach steady effect and keeps releasing from a skin depot after removal, so serum levels take roughly 17 to 27 hours to halve (labels differ; the current US label gives 20 to 27 hours). Fever and heat increase absorption.
• Modified-release preparations flatten peaks and allow less frequent dosing. Crushing them can deliver the whole dose at once.
• Intramuscular absorption depends on perfusion and is unreliable in shock.
• In cirrhosis with portosystemic shunting, high-extraction drugs bypass the liver, so oral bioavailability rises sharply (see cirrhosis).

Worked example: bioavailability

A drug given as 100 mg IV produces an AUC of 20 mg.h/L. A 200 mg oral dose produces an AUC of 12 mg.h/L.

F = (12 / 20) × (100 / 200) = 0.6 × 0.5 = 0.30. An oral dose of about 3.3 times the IV dose gives the same exposure.

Generics and bioequivalence

Under ICH M13A (finalised in 2024 and in force from 2025 for immediate-release oral solids, adopted by the TGA; the 2010 EMA guideline still covers products outside its scope), the TGA accepts a generic when the 90% confidence interval of the generic-to-reference ratio for AUC and Cmax lies within 80 to 125%. Narrow therapeutic index drugs (ciclosporin, tacrolimus, antiepileptics, levothyroxine) are the ones where brand switching may need a level or a check of thyroid function.

Distribution

Volume of distribution

Vd = amount of drug in body / plasma concentration. It is an apparent volume, not a real one.

Vd	Interpretation	Examples
About 0.05 L/kg (plasma)	Large molecule confined to plasma	Heparin, monoclonal antibodies
About 0.1 to 0.2 L/kg	Highly albumin-bound drug in plasma and some interstitial fluid	Warfarin (0.14 L/kg), many NSAIDs
About 0.2 to 0.3 L/kg (extracellular fluid)	Polar drug that doesn't enter cells	Gentamicin and other aminoglycosides
About 0.6 L/kg (total body water)	Small water-soluble drug	Ethanol, lithium (0.7 L/kg)
Much greater than 1 L/kg	Extensive tissue binding	Digoxin (about 7 L/kg), amiodarone (about 60 L/kg), TCAs, chloroquine

Vd changes with disease. Polar drugs such as aminoglycosides have a larger Vd in sepsis, oedema, ascites and burns, so standard doses give low peaks and larger loading doses are needed. Lipophilic drugs accumulate in fat in obesity; gentamicin is dosed on adjusted body weight in obese patients. Older people have more fat and less water, so diazepam's Vd rises and its half-life lengthens.

Worked example: loading dose

Target gentamicin peak 20 mg/L, Vd 0.25 L/kg, weight 70 kg, F = 1 (IV).

Loading dose = 0.25 × 70 × 20 = 350 mg (5 mg/kg). Septic Vd is about 0.3 to 0.4 L/kg. At 0.4 L/kg the same peak needs 0.4 × 70 × 20 = 560 mg (8 mg/kg), which is why sepsis doses sit at 7 mg/kg or more.

Dialysability

Haemodialysis clears drug from plasma. A drug with a huge Vd has almost none in plasma, so dialysis barely touches the total body load. Dialysis works for lithium, salicylate, toxic alcohols, metformin (lactic acidosis), valproate and theophylline, and is useless for digoxin, TCAs and amiodarone.

The simple rule has exceptions:

• Salicylate and valproate are highly albumin bound at therapeutic levels (valproate about 90%). In overdose the binding saturates, the free fraction rises and dialysis clears them well.
• Metformin has a Vd above 1 L/kg (it accumulates in red cells and tissues), but it is unbound and small. In metformin-associated lactic acidosis, dialysis removes the drug and corrects the acidosis together.

Pitfall: don't rule out dialysis for valproate or metformin just because their therapeutic-dose Vd or binding fails the textbook criteria.

Protein binding

• Acidic drugs bind albumin (phenytoin, valproate, warfarin). Basic drugs bind alpha-1 acid glycoprotein (lidocaine, propranolol), which rises after MI, surgery and in inflammation.
• Only free drug crosses membranes, acts and is cleared.
• Low albumin (nephrotic syndrome, cirrhosis, critical illness) or uraemic displacement raises the free fraction. For phenytoin, total level then underestimates the active drug. Request a free level, or correct the total (Sheiner-Tozer).
• Displacement interactions alone rarely matter for long, because the extra free drug is cleared. They matter for drugs with a narrow therapeutic index and when clearance is also inhibited (valproate displacing and inhibiting phenytoin metabolism).

Pitfall: a "therapeutic" total phenytoin in a patient with albumin of 20 g/L and nystagmus is likely toxic.

How it's tested

• Calculate F from AUCs, or Vd from dose and C0.
• Explain why oral morphine, propranolol or GTN needs a different dose from the parenteral route.
• Predict whether haemodialysis will help a poisoned patient, from Vd and binding.
• Explain a toxic patient with a normal total level, or a patient on levothyroxine whose TSH rose after starting iron or calcium.
• Explain why aminoglycoside doses are larger in sepsis or ascites (Vd), and see clearance, half-life and steady state for the maintenance side.

Pitfalls

• Vd sets the loading dose. Clearance sets the maintenance dose. Exam stems often swap these.
• A large Vd does not mean the drug is in a particular tissue, only that plasma concentrations are low relative to body load.
• First-pass metabolism is avoided by sublingual and transdermal routes, but only partly by the rectal route (the upper rectal veins drain to the portal system).
• Grapefruit inhibits gut CYP3A4, so it raises oral but not IV levels of affected drugs.
• Oral vancomycin is not a substitute for IV vancomycin outside the gut. In severe C. difficile colitis, especially with renal impairment, enough crosses inflamed mucosa to give measurable and occasionally toxic serum levels on prolonged high doses.