Factors affecting bioavailability?

The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e. F<1). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation,

Such 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.)

If the drug is administered in a fed or fasted state

Gastric emptying rate

Circadian differences

Enzyme induction/inhibition by other drugs/foods:

Interactions with other drugs (e.g. antacids, alcohol, nicotine)

Interactions with other foods (e.g. grapefruit juice, pomello, cranberry juice)

Transporters: Substrate of an efflux transporter? (e.g. P-glycoprotein)

Health of the GI tract

Enzyme induction/inhibition by other drugs/foods:

Enzyme induction (increase rate of metabolism). e.g. Phenytoin (antiepileptic) induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4

Enzyme inhibition (decrease rate of metabolism). e.g. grapefruit juice inhibits CYP3A --> higher nifedipine concentrations

Individual Variation in Metabolic Differences

Age: In general, drugs 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). Whether a drug is taken with or without food will 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.

Relative bioavailability is extremely sensitive to drug formulation. Relative bioavailability is one of the measures used to assess bioequivalence between two drug products, as it is the Test/Reference ratio of AUC. The maximum concentration of drug in plasma or serum (Cmax) is also usually used to assess bioequivalence. When Tmax is given, it refers to the time it takes for a drug to reach Cmax.