The various ways by which improvement of stability of drug in the GIT has a positive impact on bioavailability are discussed below.
BIOAVAILABILITY ENHANCEMENT THROUGH ENHANCEMENT OF DRUG STABILITY
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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