Extent and Rate of Bioavailability

BIOAVAILABILITY It is important to distinguish between the rate and extent of drug absorption and the amount of drug that ultimately reaches the systemic circulation. This depends not only on the administered dose but also on the fraction of the dose (F) that is absorbed and escapes any first-pass elimination. This fraction is the drug's bioavailability.

If the hepatic blood clearance for the drug is large relative to hepatic blood flow, the extent of availability will be low when the drug is given orally (e.g., lidocaine or propranolol). This reduction in availability is a function of the physiological site from which absorption takes place, and no modification of dosage form will improve the availability under conditions of linear kinetics. Incomplete absorption and/or intestinal metabolism following oral dosing will, in practice, reduce this predicted maximal value of F. When drugs are administered by a route that is subject to firstpass loss, the equations presented above that contain the terms dose or dosing rate also must include the bioavailability term F. For example, Equation (1—2) is modified to

where the value of F is between 0 and 1. The value of F varies widely for drugs administered by mouth and successful therapy can still be achieved for some drugs with F values as low as 0.03 (e.g., etidronate).

RATE OF ABSORPTION Although the rate of drug absorption does not, in general, influence the average steady-state concentration of the drug in plasma, it may still influence drug therapy. If a drug is absorbed rapidly (e.g., a dose given as an intravenous bolus) and has a small "central" volume, the concentration of drug initially will be high. It will then fall as the drug is distributed to its "final" (larger) volume (Figure 1-3B). If the same drug is absorbed more slowly (e.g., by slow infusion), it will be distributed while it is being administered, and peak concentrations will be lower and will occur later. Controlled-release preparations are designed to provide a slow and sustained rate of absorption in order to produce smaller fluctuations in the plasma concentration-time profile during the dosage interval compared with more immediate-release formulations. Since the beneficial, nontoxic effects of drugs are based on knowledge of an ideal or desired plasma concentration range, maintaining that range while avoiding large swings between peak and trough concentrations can improve therapeutic outcome.

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