Bioavailability Enhancement Through Enhancement of Drug Stability

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Chapter: Biopharmaceutics and Pharmacokinetics : Bioavailability and Bioequivalence

The various ways by which improvement of stability of drug in the GIT has a positive impact on bioavailability are discussed below.


The various ways by which improvement of stability of drug in the GIT has a positive impact on bioavailability are discussed below.


1. Enteric Coating: Enteric-coated systems utilize polymeric coatings that are insoluble in the gastric media and therefore, prevent or retard drug release in the stomach. Such systems release the drug in the alkaline milieu of intestine. Bioavailability of drugs that are unstable in the gastric milieu, for e.g. erythromycin, penicillin V, pancreatin and benzimidizoles such as omeprazole can be improved by enteric coating.


2. Complexation: Complexation, in certain instances, can be used to increase the stability of drug in the GI milieu, particularly those of ester drugs and thus enhance their oral availability. Generally speaking, β-cyclodextrins are potential carriers for achieving such objectives but other complexing agents, such as caffeine, sodium salicylate, sodium benzoate, and nicotinamide, may also be used.


3. Use of Metabolism Inhibitors: Co-administration of a drug with low bioavailability and its metabolism inhibitor, which can selectively inhibit any of the contributing processes, would result in increased fractional absorption and hence a higher bioavailability. In fact, this approach seems to be a promising alternative to overcome the enzymatic barriers to oral delivery of metabolically labile drugs such as peptides and proteins. Current novel approaches in this area include:

·            Bioadhesive delivery systems that can reduce the drug degradation between the delivery system and absorbing membrane by providing intimate contact with GI mucosa.

·            Controlled-release microencapsulated systems that can provide simultaneous delivery of a drug and its specific enzyme inhibitor at the desired site for required period of time.

·            Immobilization of enzyme inhibitors on mucoadhesive delivery systems.

Interestingly, the intestinal wall metabolism (prehepatic metabolism) may also be inhibited by co-administration of certain drugs and diet, which act by selectively inhibiting an enzyme present in enterocytes. An illustrative example is that of cyclosporin, which undergoes extensive intestinal metabolism, resulting in low bioavailability ranging between 30–40%. Studies have shown that co-administration of ketoconazole and grapefruit juice, which contains the inhibitory components, can significantly decrease the presystemic metabolism (both act via selective inhibition of intestinal, not hepatic, CYP3A4) and consequently increase the oral bioavailability of cyclosporin. In a differential manner, however, ketoconazole moderately inhibits P-gp, whereas grapefruit juice activates P-gp-mediated efflux of cyclosporine, which is a well-characterized substrate of P-gp, thereby partially counteracting the CYP3A4-inhibitory effects of grapefruit juice.

Grapefruit juice is reported to be a powerful inhibitor of enzyme CYP3A4 and is known to enhance the bioavailability of several drugs. It could be argued that extraction of such components from grapefruit juice (thought to be flavonoids) and their inclusion as excipient in the dosage form would lead to not only more complete but also more consistent systemic levels by counteracting inconsistencies brought about by enzyme inhibitors in food and drink.

Co-administration of a drug that can selectively inhibit an enzyme in the liver may lead to increased bioavailability of another drug. For example, co-administration of erythromycin can result in inhibition of hepatic metabolism and thereby significantly increase the oral bioavailability of cyclosporin. As a matter of fact, this attribute of erythromycin appears to be selective, which permits a noninvasive measurement of the in vivo hepatic CYP3A4 activity, popularly known as erythromycin breath test. Many examples also exist related to the inhibitory effects of diet on hepatic first-pass metabolism.

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