Extravascular administration drug absorption

Absolute bioavailability is a measure of the true extent of systemic absorption of an extravascularly administrated drug. Along with clearance and volume of distribution, absolute bioavailability is one of the important parameters to characterize PK. Low bioavailability of a drug can be caused by incomplete dissolution when administrated as a solid, inability to permeate membranes, and metabolic instability (first-pass metabolism). Despite the importance of absolute bioavailability, it is not routinely assessed due to the cost and toxicology requirements for such a study in a conventional study design, which requires an intravenous reference. Safety issues may arise due to solubility limitation and toxicity associated with Cmax effect. As a result, it is necessary to conduct a preclinical toxicological study with an IV formulation to ensure adequate human safety and potential problem. Bioavailability determined from animal models is not always predictive of that in human. 

For all commonly used routes of administration except intravenous, the drug must dissolve in body fluids and diffuse through one or more membranes to enter the plasma. Thus, all routes except intravenous are classed as extravascular routes, and absorption is defined as appearance of the drug in plasma. 

When a drug reaches the systemic circulation, either after intravenous administration or after absorption following extravascular administration, it can be distributed in the elements of blood (erythrocytes, etc.) or bind to plasma proteins. Blood transports the drug to different organs where it diffuses at different rates. The drug not bound to plasma proteins will diffuse in the extravascular compartments and tissues where it can then bind to other proteins or other tissue components. 

Figure 2.5 Stages in drug absorption from an extravascular administration site (stomach, small intestine, intramuscular injection). Only drug in solution is absorbed. If the rate of dissolution (K2) is less than the rate of absorption (K3) then the rate at which drug is released from the dosage form controls absorption. This permits modified or sustained-release formulations, but can also lead to bioequivalence problems.

The noncompartmental analysis of pharmacokinetic data after extravascular drug administration, when coupled with that of IV dosing, can yield additional relevant pharmacokinetic parameters, particularly regarding absorption processes. For example, the systemic availability F), which represents the net fraction of the drug dose reaching the systemic circulation after extravascular administration, is defined as ... 

Once a drug is in the systemic circulation (immediately for intravenous administration and after the absorption step in extravascular administration), it is distributed simultaneously to all tissues including the organ responsible for its elimination. The distinction between elimination and distribution is often difficult. When such a distinction is either not desired or is difficult to obtain, disposition is the term used. In other words, disposition is defined as all the processes that occur subsequent to the absorption of the drug. Hence, by definition, the components of the disposition phase are distribution and elimination. 

One sure way is to have an rmambiguous value of the drug s elimination half life (and therefore of the elimination rate constant) determined from a study in which the drug is administered intravenously. Another strong indication that the regular model is the correct model is the situation where the extravascular administration is of a type that should not have any kind of slow, extended absorption. An example of this is an immediate release tablet or a capsule. This type of dosage form should not have an absorption half life that is slower than its elimination half life. 

Figure 7.15 represents plasma concentration versus time data following the administration of an identical dose of a drug by intravascular or extravascular routes. The absorption of drug from the extravascular route can be described as slow but virtually complete. Since peak time is long and peak plasma concentration is much lower than the initial plasma concentration for an intravenous bolus, this can be attributed to slower absorption. The (AUC)q for the intravascular and extravascular routes may be identical. If this assumption is applicable, then the extent of drug absorption is identical. 

Figure 7.19 represents the rate of excretion against average time profile following the administration of an identical dose of a drug via an intravascular or extravascular route. The absorption of drug from the extravascular route can be described as rapid and complete. This profile is the same as that presented in Fig. 7.14. The time at which maximum rate of elimination occurs is very short and the maximum elimination rate for the oral dose is almost identical to that for an intravenously administered dose.

This expression, which relies on fairly rapid absorption such that each subsequent dose is administered in the post-absorptive phase, can be readily employed to determine the extent of accumulation following extravascular administration of a drug as long as dosing interval and the elimination rate constant of the drug are available. Note the similarity between Eq. 12.27 for multiple oral dosing and Eqs 11.29,11.33 and 11.34 for multiple intravenous bolus administration. 

After extravascular administration, a drug must be transferred from the site of absorption, through a cell... 

The relationship indicates that in the case of extravascular administration, the level of the drug in plasma first increases gradually, but when the rate of drug elimination becomes equal to that of absorption a maximum is finally achieved and afterwards only a decline is observed (Fig. 6). The time of occurrence of this r is independent from the dose, depending only on the rate constant for absorption and elimination as it is shown by the formula ... 

Thus, amount of drug in the body following administration of an extravascular dose is a constant [(Dgka)/(ka — kei) multiplied by the difference between two exponential terms—one representing elimination [exp(—keit) and the other representing absorption [exp(—kat). ... 

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... 

Systemic effects are more likely to occur with long-acting anesthetics if an excessive dose is used, if absorption into the blood stream is accelerated for some reason, or if the drug is accidentally injected into the systemic circulation rather than into extravascular tissues.17 40 Other factors that can predispose a patient to systemic effects include the type of local anesthetic administered, as well as the route and method of administration.3 Therapists and other health care professionals should always be alert for signs of the systemic effects of local anesthetics in patients. Early symptoms of CNS toxicity include ringing/buzzing... 

The absorption of protein drugs from extravascular sites is dependent on the size of the molecule. Upon subcutaneous administration, small molecules with molecular weights less than 1 kD predominantly enter the systemic circulation via blood capillaries, whereas subcutaneously administered proteins with molecular weights greater than 16kD enter the systemic circulation predominantly via the lymphatic system. The extent of the lymphatic recovery after subcutaneous administration is a linear function of molecular weight (Figure 3.2-1) [1-5]. 

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