Metabolism with extravascular administration

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. 

Methadone is firmly bound to protein in various tissues, including brain, and accumulates gradually with repeated administration. When administration is stopped, low plasma concentrations are maintained by slow release from extravascular binding sites this process probably accounts for the relatively mild but protracted withdrawal syndrome. Rifampin and phenytoin accelerate methadone metabolism and can precipitate withdrawal symptoms. 

An active substance generally exerts its effect through defined molecular interactions with a receptor. As a prerequisite, the substance needs to be dissolved and reach the receptor. For a local effect, the substance is usually administered in close proximity to the desired target and should penetrate into body tissues as little as possible. However, when a systemic effect is desired, the substance has to reach the blood circulation system for distribution. For extravascular administration routes, this requires membrane passage and may expose the substance to various pre systemic elimination mechanisms, including metabolism and efflux transporters such as P-glycoprotein. 

For this calculation, it is unnecessary to assume that Vd and/or kei are the same for the two studies. It is only necessary that fe be the same in both studies. This is usually a valid assumption unless the drug undergoes a significant amount of first-pass metabolism in the gut wall or liver following oral administration or a significant amount of decomposition at an intra muscular (IM) injection site. When this occurs, the availability of the extravascular dosage form may appear to be low, but the fault will not lie with the formulation. The bioavailability will be a true reflection of the therapeutic efficacy of the drug product, and reformulation may not increase bioavailability. 

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