Bioavailability

Bioavailability means the extent and rate to which a drug becomes available in the general circulation. The extent is measured by the fraction (F) of the administered dose which reaches intact the general circulation. When the drug is administered by the intravascular route, F = 1 and the relevant rate is that of the injection. When extravascular routes are used, for instance, the oral route, F< 1 and depends on the absorbed fraction of the ingested dose and on the lost part of the dose metabolized in the gut during absorption or in the liver before reaching the general blood flow. These latter possibilities are named first-pass effects (intestinal and/or hepatic).

The amount of drug M that reaches the general circulation is given by eqn [16]. Thus:

The rate of absorption is estimated by two parameters, Cmax and tmax, with Cmax being related to: (1) total plasma clearance; (2) the fraction of dose that reaches the general circulation without being metabolized; (3) the rate of absorption; and (4) the rates of distribution and elimination. As for tmax, it depends on: (1) the rate of absorption; and (2) the rates of distribution and elimination.

After oral administration, bioavailability may be estimated by comparison with either the intravascular route, yielding the absolute bioavailability, or with another pharmaceutical form of the drug by the same route, yielding the relative bioavailability. Absolute bioavailability can be measured after intravascular administration:

or after oral administration:

If the doses used for both routes are identical, assuming a linear and identical kinetics (i.e., a constant CL), then:

This test is of interest for several reasons. When a drug has not been previously investigated by the i.v. route, the i.v. results allow the calculation of CL and VD and can lead to a basic understanding of the drug's kinetics. Moreover, they yield the characteristics of oral absorption, which are needed when oral administration follows i.v. injection. A typical example of such a test is given in Figure 6.

The relative bioavailability (Frel) is used to compare two different pharmaceutical forms, one serving as a reference:

_ AUCteSt [431

This equation may be used if the respective doses of the two pharmaceutical forms are the same and if the clearance is constant. It also allows a comparison of Cmax and tmax.

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