Extravascular administration concentration

Fig. 39.9. Time courses of plasma concentration Cp in a one-compartment model for extravascular administration, with different contingencies of (a) the transfer constant of absorption k p, (b) the transfer constant of elimination kpt and (c) the volume of distribution Vp.

Thus after 6 hours the semilog plot of Cp versus time shown in Fig. 10 becomes a straight line and kei can be determined from the slope. Therefore, the overall elimination rate constant for a drug may be accurately determined from the tail of a semilog plot of plasma concentration versus time following extravascular administration if ka is at least five times larger than kei. 

Serial drug concentrations following single dose extravascular administration of different doses given as a solution (not as a formulated tablet, capsule, etc.) at amounts low enough so as to not precipitate in the gastrointestinal tract. 

The time-course of plasma drug concentrations following extravascular administration is often irregular, and simple analytical solutions for calculating Af/C and AUMC, such as Equations (3.2-4) and (3.2-5), are not readily available. For these cases, numerical integration methods may be used to evaluate the integrals in Equations (3.2-1) and (3.2-2), such that ... 

Absolute bioavailability of a drug is the systemic availability of the drug after extravascular administration of the drug and is measured by comparing the area under the drug concentration-time curve after extravascular administration to that after IV administration, provided the and Vd are independent of the route of administration. Extravascular administration of the drug comprises routes such as oral, rectal, subcutaneous, transdermal, nasal, etc. 

This approach can be expanded to include other routes of administration such as IV infusion (of duration 7) and extravascular administrations such as oral, intramuscular, subcutaneous, or topical. Schemes and equations for these models are shown in Table 12.1. The integrated equations in Table 12.1 can be used to calculate drug concentrations after a single IV bolus, IV infusion, or oral dose as shown in Eigures 12.2 through 12.4. 

Figure 1.10 A typical semilogarithmic plot of plasma concentration (Cp) versus time following the extravascular administration of a dose of a drug that is rapidly distributed in the body.

The only difference between Eq. 11.17 (for an intravenous solution) and Eq. 12.19 (for extravascular administration) is the incorporation of the term F, the absolute bioavailability of a drug. Should the drug be completely absorbed following extravascular administration, Eqs 11.17 and 12.19 will be exactly the same therefore, identical "average" steady-state concentrations would be expected for an identical dosage regimen. 

Figure 12.5 Plasma concentration (Cp) versus time following repetitive extravascular administration of a drug by either a series of maintenance doses (D (1 or an initial loading dose followed by a series of maintenance doses (D ) (2—4). 1, series of maintenance doses (i.e. no loading dose) 2, loading dose 1.5 times maintenance dose 3, loading dose twice maintenance dose 4, loading dose three times the maintenance dose, r, dosing interval t /2, drug half life.

Methadone is a p receptor agonist with special properties that make it particularly useful as a maintenance agent. Rehably absorbed orally, it does not reach peak concentration until about 4 hours after administration and maintains a large extravascular reservoir (Kreek 1979). These properties minimize acute euphoric effects. The reservoir results in a plasma half-life of 1—2 days, so there are usually no rapid blood level drops that could lead to withdrawal syndromes between daily doses. Effective blood levels are in the range of 200-500 ng/mL. Trough levels of 400 ng/mL are considered optimal (Payte and Khouri 1993). There is wide variability among individuals in blood levels with identical doses (Kreek 1979), and some have inadequate levels even with doses as high as 200 mg/day (Tennant 1987 Tenore 2003). 

Fig. 39.7. (a) Two-compartment catenary model for extravascular (oral or parenteral) administration of a single dose D which is completely absorbed. The transfer constant of absorption is (b) Time courses of the amount in the extravascular compartment Xa, the concentration in the plasma compartment Cp and the content in the elimination pool X. ... 

The IM and SC routes are by far the most frequently used extravascular parenteral routes of drug administration in farm animals. The less frequently used parenteral routes have limited application, in that they aim at directly placing high concentrations of antimicrobial agent close to the site of infection. These routes of administration include intra-articular or subconjuctival injection and intra-mammary or intra-uterine infusion. These local routes differ from the major parenteral routes in that absorption into the systemic circulation is not a prerequisite for delivery of drug to the site of action. The combined use of systemic and local delivery of drug to the site of infection represents the optimum approach to... 

In practice, it is unlikely to have compartmental models with initial conditions unless there are residual concentrations obtained from previous administrations. Drugs are administered either by extravascular, or intravascular in single or repeated experiments. Extravascular routes are oral, or intramuscular routes, and intravascular are the constant-rate short- and long-duration infusions. 

FIGURE 5-2. Area under the concentration-time curve (AUC) after the administration of an extravascular dose. The AUC is a function of the fraction of drug dose that enters the systemic circuiation and clearance. AUCs measured after intravenous and extravascular doses can be used to determine bioavailability for the extravascular dose. 

If the clearance is plasma drug concentration-dependent, and either intravenous exposure is limited by blood stream solubility or the drug has very low bioavailability, there could be an error in the estimation of absolute bioavailability. For more on these PK parameters, see Chapter 3. Additionally, extravascular and intravenous administrations are performed at two different time periods any changes of metabolism in the study subject may also affect the calculated absolute bioavailability. 

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