Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent.
A. Determination of bioavailability
Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection in which all of the agent rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). This curve reflects the extent of absorption of the drug.
[Note: By definition, this is 100 percent for drugs delivered IV.] Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection
Figure Determination of the bioavailability of a drug. (AUC = area under curve.)
B. Factors that influence bioavailability
1. First-pass hepatic metabolism:
When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation . If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propranolol or lidocaine, undergo significant biotransformation during a single passage through the liver.
2. Solubility of the drug:
Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin.
3. Chemical instability:
Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes.
4. Nature of the drug formulation:
Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.
Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two related drugs with a significant difference in bioavailability are said to be bioinequivalent.
D. Therapeutic equivalence
Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety.
[Note: Clinical effectiveness often depends on both the maximum serum drug concentrations and on the time required (after administration) to reach peak concentration. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.]
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