Investigators assessing the bioavailability of a new drug administer it intravenously (IV) to a volunteer and measure plasma concentrations of the drug over time. After the drug is completely cleared from the volunteer's circulation, the investigators administer the same dose of the drug orally (PO) and again measure plasma concentrations of the drug over time. The data obtained are plotted on the graph shown below.
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Which of the following is the best determinant of oral bioavailability of this drug?
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Bioavailability refers to the fraction of administered drug that reaches the systemic circulation and is therefore available for eliciting the desired pharmacologic effect. A drug administered by the intravenous (IV) route has 100% bioavailability by definition. For other modes of drug administration (eg, oral [PO], intramuscular [IM], subcutaneous [SQ], transdermal [TD], rectal [PR]), the bioavailability is usually less than 100%.
The bioavailability of a drug for a given route of administration can be determined by plotting plasma drug concentrations over time for a given dose administered by both the IV route and the other route being studied (eg, PO). The area under the curve (AUC) of each plot represents the total systemic drug exposure for the given dose and route (Choice A). Bioavailability can then be determined by comparing the AUCs of each curve. In this case, PO bioavailability can be calculated by dividing the AUC of the PO curve by the AUC of the IV curve.
In the case of PO administration, bioavailability depends upon the drug's ability to cross the intestinal mucosa and can be influenced by gastric acidity and motility, the presence of food or other drugs in the gut, and first-pass metabolism by the intestine and liver.
(Choice C) The maximal concentration at the peak of the PO curve (ie, peak plasma level) is dose dependent and is not an indicator of drug bioavailability.
(Choice D) PO administration of a drug usually results in lower peak serum drug levels compared to IV administration, even when PO bioavailability is near 100%, due to delayed absorption from the gastrointestinal tract (versus near-instantaneous delivery of IV drugs). As a result, comparing peak PO to peak IV concentration levels is not an appropriate way to determine bioavailability.
Educational objective:
Bioavailability refers to the fraction of administered drug that reaches the systemic circulation. For a drug administered by any route other than intravenous (IV), bioavailability is usually less than 100%. Bioavailability can be determined by graphing plasma drug concentrations over time for a given dose administered by both the IV route and the other route being studied. Oral (PO) bioavailability is calculated by dividing the area under the PO curve by the area under the IV curve.