The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e., F< 100%). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora. Disease states affecting liver metabolism or gastrointestinal function will also have an effect.
Other factors may include, but are not limited to:
* Physical properties of the drug (hydrophobicity, pKa, solubility)
* The drug formulation (immediate release, excipients used, manufacturing methods, modified release – delayed release, extended release, sustained release, etc.)
* Whether the formulation is administered in a fed or fasted state
* Gastric emptying rate
* Circadian differences
* Interactions with other drugs/foods:
** Interactions with other drugs (e.g., antacids, alcohol, nicotine)
** Interactions with other foods (e.g., grapefruit juice, pomello, cranberry juice, brassica vegetables)
* Transporters: Substrate of efflux transporters (e.g. P-glycoprotein)
* Health of the gastrointestinal tract
* Enzyme induction/inhibition by other drugs/foods:
** Enzyme induction (increased rate of metabolism), e.g., Phenytoin induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4
** Enzyme inhibition (decreased rate of metabolism), e.g., grapefruit juice inhibits CYP3A → higher nifedipine concentrations
* Individual variation in metabolic differences
** Age: In general, drugs are metabolized more slowly in fetal, neonatal, and geriatric populations
** Phenotypic differences, enterohepatic circulation, diet, gender
* Disease state
** E.g., hepatic insufficiency, poor renal function
Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In clinical trials, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.