Question 1

What is absolute bioavailability?

Accepted Answer

Absolute bioavailability (F) is the fraction of an administered dose that reaches the systemic circulation intact, expressed as a percentage or as a decimal fraction. It is calculated by comparing the systemic exposure (area under the concentration-time curve, AUC) after the test route to the AUC after intravenous (IV) administration — which by definition delivers 100% of the dose to systemic circulation. The formula is: F = (AUC_extravascular / AUC_IV) × (Dose_IV / Dose_extravascular) × 100%. The dose correction is necessary because oral and IV doses are rarely identical. For example, if 500 mg oral ibuprofen produces an AUC of 60 mg·h/L and 200 mg IV ibuprofen produces an AUC of 50 mg·h/L, then: F = (60/50) × (200/500) = 0.48 = 48%. Absolute bioavailability is measured in clinical pharmacology studies during drug development, typically in Phase I. It requires IV formulation development which can be challenging for poorly soluble drugs. It is distinct from relative bioavailability, which compares two non-IV formulations against each other.

Question 2

How does absolute bioavailability differ from relative bioavailability?

Accepted Answer

Absolute bioavailability requires IV reference data to calculate the true fraction reaching systemic circulation. Relative bioavailability compares two extravascular formulations (or routes) without an IV reference — expressing exposure from Test as a fraction of exposure from Reference. Relative bioavailability formula: F_rel = (AUC_Test / AUC_Reference) × (Dose_Reference / Dose_Test) × 100%. Bioequivalence studies use relative bioavailability — a generic is deemed bioequivalent if its AUC and Cmax fall within 80–125% of the reference product (90% CI for the log-transformed ratio). Absolute bioavailability is required for: (1) calculating bioavailability-adjusted oral doses when only IV PK data exist; (2) population PK models for drugs given by multiple routes; (3) PK/PD modelling of drugs where the route changes clinical efficacy. If absolute bioavailability is not measured (no IV formulation available), it can sometimes be estimated from the urinary recovery of unchanged drug (if complete renal elimination is assumed) or from PBPK modelling.

Question 3

What factors reduce absolute oral bioavailability?

Accepted Answer

Oral bioavailability (F) is determined by the sequential product of three terms: F = fa × fg × fh, where fa is the fraction absorbed from the gastrointestinal lumen, fg is the fraction surviving gut-wall metabolism, and fh is the fraction surviving hepatic first-pass extraction. Factors reducing fa: poor aqueous solubility (BCS Class II/IV drugs — dissolution rate-limited), low membrane permeability (BCS Class III/IV), degradation in gastric acid (e.g., omeprazole original formulation, requiring enteric coating), enzymatic degradation (peptides, proteins — hence why insulin requires injection), incomplete absorption, and efflux by intestinal P-gp/BCRP. Factors reducing fg: CYP3A4 in enterocytes metabolises drugs like cyclosporin, felodipine, buspirone, midazolam — accounting for 20–50% first-pass extraction in the gut wall before hepatic extraction. Factors reducing fh: hepatic extraction ratio (EH = CLh / Qh). High-extraction drugs (EH > 0.7): morphine, lidocaine, propranolol, verapamil, nitrates — extensive first-pass reduces F to 10–40%. Low-extraction drugs (EH < 0.3): warfarin, diazepam, theophylline — minimal first-pass. First-pass effects are also saturable — dose-dependent bioavailability occurs for some high-extraction drugs at therapeutic doses.

Question 4

What are common examples of drugs with notably high or low oral bioavailability?

Accepted Answer

Oral bioavailability varies enormously across drug classes. Very high bioavailability (>90%): amoxicillin (~90%), metronidazole (~99%), fluconazole (~94%), metformin (~50–60% at low doses, lower at higher doses), diazepam (~100%), warfarin (~97%), atenolol (~50% — reduced but consistent), levodopa (~>80% intestinal, but substantial dopa-decarboxylase first-pass). Very low bioavailability (<20%): morphine (~25–35% oral F), GTN/nitroglycerin (~1–2% — hence sublingual/transdermal preferred), colchicine (~45%), vancomycin (~<5% oral — this is intentional for C. difficile treatment, targeting gut lumen), acyclovir (~15–30%, dose-dependent saturable absorption), dabigatran etexilate (~6–7% — converted by esterases in gut wall and liver), rivaroxaban (~80–100% at 10 mg dose, ~66% at 20 mg with food — BCS II). Variable/formulation-dependent bioavailability: carbamazepine (suspension > tablet), atorvastatin (~14% typical F, range 9–25%), tacrolimus (~25%, high variability due to P-gp and CYP3A4 in gut and liver, requiring TDM). Understanding F is essential for calculating oral maintenance dose from IV reference data: Oral dose = IV dose / F.

Parameter	Site	Key determinants	Example drugs
fa	GI lumen → blood	Solubility (BCS), permeability, P-gp/BCRP efflux, acid stability	Vancomycin (fa~0; oral for C.diff), dabigatran (fa very low)
fg	Enterocyte	CYP3A4, UGT in gut wall	Felodipine, cyclosporin, midazolam (30–50% gut extraction)
fh	Liver	Hepatic extraction ratio EH = CLh/Qh	Morphine EH~0.7, GTN EH~0.99, warfarin EH~0.01

Absolute bioavailability

F = f_a × f_g × f_h — three sequential barriers

Frequently asked questions

F = fa × fg × fh — three sequential barriers

Frequently asked questions

F = f_a × f_g × f_h — three sequential barriers