Effect of pharmaceuticals and natural products on multidrug resistance mediated transport in Caco-2 and MDCKII-MDR1 drug transport models Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/8910jx39j

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  • This thesis details my investigation of some pharmaceuticals and natural products on the transport of drugs which are substrates of P-glycoprotein (P-gp), such as cyclosporin A (CSA) and digoxin by using Caco-2 and MDCKII-MDR1 drug transport models. Three objectives were performed to address this goal. The first objective was to investigate if ketoconazole (KT) can modulate Pgp, thereby, altering cellular uptake and apparent permeability (Papp) of multidrugresistance (MDR) substrates, such as CSA and digoxin, across Caco-2, MDCKIIMDR1, and MDCKII-wild type drug transport models. 3H-CSA/3H-digoxin transport experiments were performed with and without co-exposure to KT. KT was found to inhibit the Papp efflux of CSA and digoxin in Caco-2 cells. In MDCKII-MDR1 cells, KT reduced the Papp efflux of CSA and increased the Papp absorption of digoxin. The drug-diet interaction of KT with flavonoids, epigallocatechin gallate (EGCG) and xanthohumol, was evaluated as well. EGCG and xanthohumol were able to reduce the Papp efflux of KT. In the uptake studies, EGCG and xanthohumol exhibited biphasic responses in KT uptake. Our results suggest that KT may modulate the Papp of P-gp substrates by interacting with MDR1 protein. EGCG and xanthohumol can modulate the transport and uptake of KT. The second objective was to investigate if specific flavonoids such as EGCG, epicatechin gallate (ECG), and xanthohumol can modulate the cellular uptake and the permeability of CSA and digoxin across the Caco-2 and MDCKIIMDR1 cell transport models. 3H-CSA/3H-digoxin transport and uptake experiments were performed with and without co-exposure of 30 μM xanthohumol, EGCG and ECG. EGCG and ECG inhibited the permeability efflux of CSA in Caco-2 cells, but not in MDCKII-MDR1 cells, which suggests EGCG and ECG may modulate other efflux transporters other than MDR1. Xanthohumol was able to inhibit the uptake of CSA, but increased the uptake of digoxin; xanthohumol inhibited the efflux permeability of CSA, but not digoxin in both Caco-2 and MDCKII-MDR1 cells. These data suggests that xanthohumol may increase the bioavailability of CSA by inhibiting MDR1-mediated efflux, whereas digoxin may share substrate specificity with other transporters such as multidrug resistance associated protein 2 (MRP2), or interact with MDR1 at a different site than xanthohumol. Oregon Grape Root (OGR), Mahonia aquifolia, is native to the West coast of North America. Berberine as an alkaloid found in the OGR as well as berbamine have been reported to have significant anticancer activity. The last objective of my studies was to evaluate if berberine and berbamine can modulate P-gp, thereby, altering the Papp of P-gp substrates across Caco-2 and MDCKIIMDR1 drug transport models. OGR extract inhibited the efflux of CSA and digoxin with significant inhibition seen at low concentration of 0.1 mg/ml. Berberine and berbamine significantly reduced the efflux Papp of CSA, whereas berberine did not have a measurable effect on the Papp of digoxin in the Caco-2 cells. In the MDCKII-MDR1 cells, berberine and berbamine inhibited both the efflux Papp of CSA and digoxin. Our data suggests that OGR extract, berberine, and berbamine can inhibit P-gp thereby may increase the bioavailability of drugs that are substrates of P-gp.
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