Many orally administered drugs must overcome several barriers before
reaching their target site. The first major obstacle to cross is the intestinal epithelium.
Although lipophilic compounds may readily diffuse across the apical plasma membrane,
their subsequent passage across the basolateral membrane and into blood is by no
means guaranteed. Efflux proteins located at the apical membrane, which include P-glycoprotein
(P-gp, MDR1) and Multidrug Resistance-associated Protein (MRP2), may
drive compounds from inside the cell back into the intestinal lumen, preventing their
absorption into the blood. Intestinal P-gp is localised to the villus tip enterocytes, i.e. the
main site of absorption for orally administered compounds and in close proximity to the
lumen. P-gp is therefore ideally positioned to limit the absorption of compounds by
driving efflux back into the lumen. Drugs may also be modified by intracellular phase I
and phase II metabolizing enzymes. This process may not only render the drug
ineffective, but it may also produce metabolites that are themselves substrates for P-gp
and/or MRP2. Drugs that reach the blood are then passed to the liver, where they are
subjected to further metabolism and biliary excretion, often by a similar system of ATP binding
cassette (ABC) transporters and enzymes to that present in the intestine. Thus
a synergistic relationship exists between intestinal drug metabolizing enzymes and
apical efflux transporters, a partnership that proves to be a critical determinant of oral
bioavailability. Aim: The aim of this study was to investigate the effect of selected
methoxy flavonoids (3-methoxyflavone, 5-methoxyflavone, 6-methoxyflavone and 7-
methoxyflavone) on the mean ratio of Rhodamine123 (Rho 123) transport across rat
intestine (jejunum) and to investigate structure activity relationships (SAR) of the
selected flavonoids with reference to inhibition of P-gp. Methods: 3-Methoxyflavone, 5-
methoxyflavone, 6-methoxyflavone and 7-methoxyflavone were evaluated at a
concentration of 10μM and 20μM as modulators of Rho 123 transport across rat
jejunum. The Sweetana-Grass diffusion cells were used to determine the transport of
Rho 123. Each modulator was studied bidirectionally with two cells measuring transport
in the apical to basolateral direction (AP/BL) and two cells measuring transport in the
basolateral to apical direction (BUAP). The rate of transport was expressed as the
apparent permeability coefficient (Papp)and the extent of active transport was expressed
by calculating the ratio of BUAP to AP/BL. Each modulators Papp ratio was then
compared with that of the control. Results: 3-Methoxyflavone decreased the Papp
ratio from 3.34 (control) to 1.66 (10μM) and 1.33 (20μM) and showed statistical
significant differences. 7-Methoxyflavone decreased the Papp ratio to 1.94 (10μM) and
1.55 (20μM) but only showed a statistical significant difference at 10μM. 5-
Methoxyflavone decreased the Papp ratio to 2.41 (10μM) and 1.71 (20μM) and 6-
methoxyflavone decreased the Papp to 3.03 (10μM) and 2.49 (20μM). Both 5- and 6-
methoxyflavone showed no statistical significant differences from the control. The
structure activity relationships with reference to P-gp inhibition clearly indicated that the
C3 and C7 positioning of the methoxy-group on the A ring played a major role in the
inhibition of Rho 123 transport. Conclusion: All the selected modulators showed
inhibition of Rho 123 transport across the jejunum. This should affect the bioavailability
of the substrates of P-gp and other active transporters. In summary, this study describe
the inhibitory interaction of selected flavonoids with P-gp. Structure activity relationships
were identified describing the inhibitory potency of the flavonoids based on methoxy
groups positioning. The inhibitory potency results were 3-methoxyflavone > 7-
methoxyflavone > 5-methoxyflavone> 6-methoxyflavone / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2005.
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/784 |
| Date | January 2005 |
| Creators | Dodd, Stanley Anthony |
| Publisher | North-West University |
| Source Sets | North-West University |
| Detected Language | English |
| Type | Thesis |
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