Bioavailability is one of the principal pharmacokinetic properties of a drug. It represents the percentage or fraction of an administered drug that reaches systemic circulation. In terms of efficacy, there should be a demonstrable bioavailability of the drug in therapeutic doses at the target site.
Given this importance, bioavailability studies are conducted on prospective drugs to consider therapeutic use. Under the broader umbrella of pharmacokinetics, the bioavailability of drugs is studied with the ADME (Absorption, Distribution, Metabolism, and Excretion) process. This is also represented as ADMET or ADME-Tox when toxicological studies are involved.
Three primary variables affect the bioavailability of a drug. These are Cmax, Tmax, and AUC. Cmax represents the maximum concentration of the drug in the systemic circulation. Tmax represents the time taken from the dosage to Cmax. When plotted as a concentration-time graph, AUC (Area Under Curve) presents another useful factor.
Bioequivalence may be studied for generic drugs or different forms of administration of a drug. In a comparison between a drug and a reference drug, bioequivalence is established by similar bioavailability. Factors like similar bioavailability, Cmax, Tmax, AUC, and comparable therapeutic effects establish bioequivalence. Since it is unlikely that both formulations will have the same characteristics, the bioavailability of the test drug within 80% to 125% of the reference drug is acceptable.
Major Factors Affecting Bioavailability Studies
Absorption and Distribution
Bioavailability for a drug delivered intravenously is 100% and it is achieved practically at the same time as administration. For drugs administered through other means (e.g. orally), bioavailability will be lower. Additionally, there will be a time gap between administration and the drug reaching the systemic circulation.
A drug administered orally also has to face other risks. These include being denatured by gastric acid, binding to food, or changing with the first-pass metabolism in the liver.
Apart from the pharmacological factors mentioned here, pharmaceutical (physiochemical) factors play a role in absorption and distribution too. Particle size and salt form are important considerations. For example, a drug administered in a solution form will be available faster than a coated tablet.
The relevant factors in this process may be listed as:
Physiological factors (gastric motility, blood flow, etc.)
Food effects on the drug
Metabolism and Excretion
Once the drug is in the systemic circulation, bioavailability studies see the method of removal of the drug of the body. Small-molecules can undergo metabolism in the liver, forming metabolites. In some cases, metabolites are inert and their formation leads to reduced bioavailability. However, some metabolites can be pharmacologically active. In some cases, they may be more active than the drug itself.
The role of enzymes in metabolism has to be considered, especially the Cytochrome P450. Drug interaction plays an important role as many drugs can increase or decrease the activity of CYP isozymes. This can affect the metabolism and clearance of drugs.
With the effects of the Cytochrome P450 superfamily, there are also chances for DDI (drug-drug interaction) or interaction with other substances. This can affect the bioavailability of a drug, with different results. In some cases, it can cause increased bioavailability, leading to overdose or potentially toxic effects. On the negative side, it can render the drug with low bioavailability to reduced use.
Compounds and their metabolites are removed from the body via excretion. This can be done through urine or in feces.
Overall, the relevant factors for the bioavailability of drugs are:
Effect of efflux transporters on drug metabolism
Cytochrome P450 (CYP450 isozymes)
Possibility of drug-drug interaction