bioavailability

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In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability decreases (due to incomplete absorption and first-pass metabolism). Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.

Definition

Bioavailability is a measurement of the rate and extent of a therapeutically active drug that reaches the systemic circulation and is available at the site of action.^[1] It is denoted by the letter F.

Absolute bioavailability

Absolute bioavailability compares the bioavailability (estimated as the area under the curve, or AUC) of the active drug in systemic circulation following non-intravenous administration (i.e., after oral, rectal, transdermal, subcutaneous, or sublingual administration), with the bioavailability of the same drug following intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be dose normalized if different doses are used; consequently, each AUC is corrected by dividing the corresponding dose administered.

In order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (IV) and non-intravenous administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the oral route (po) is given below.

Therefore, a drug given by the intravenous route will have an absolute bioavailability of 1 (F=1) while drugs given by other routes usually have an absolute bioavailability of less than one.

Although knowing the true extent of systemic absorption (referred to as absolute bioavailability) is clearly useful, in practise it is not determined as frequently as one may think. The reason for this is that its assessment requires an intravenous reference, that is, a route of administration that guarantees that all of the administered drug reaches the systemic circulation. Such studies come at considerable cost, not least of which is the necessity to conduct preclinical toxicity tests to ensure adequate safety, as well as there being potential problems due to solubility limitations. ^[2]

There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailbility information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between the pharmacodynamics and the pharmacokinetics at therapeutic doses. In all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously.^[3]

Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution (V) and clearance (CL).^[3]

Relative bioavailability

This measures the bioavailability (estimated as area under the curve, or AUC) of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as relative bioavailability.

Factors influencing 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.

See also

• ADME-Tox
• Lipinski's Rule of 5
• Biopharmaceutics Classification System
• Caco-2

http://www.nottingham.ac.uk/nursing/sonet/rlos/bioproc/metabolism/default.html http://www.xceleron.com/metadot/index.pl?iid=2724

References

1. ^ Shargel, L.; Yu, A.B. (1999). Applied biopharmaceutics & pharmacokinetics (4th ed.). New York: McGraw-Hill. ISBN 0-8385-0278-4
2. ^ The use of Isotopes in the Determination of Absolute Bioavailability of Drugs in Humans. Graham Lappin, Malcolm Rowland, R. Colin Garner. Expert Opin. Drug Metab. Toxicol. (2006) 2(3)
3. ^ ^{a b} Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics. Graham Lappin, Lloyd Stevens. Expert Opin. Drug Metab. Toxicol. (2008) 4(8):1021-1033