Transporter-mediated flavonoid-drug interactions: In vitro and in vivo
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Flavonoid-drug interactions have been increasingly observed due to the popular use of flavonoid-containing products for disease prevention and health promotion. However, our current understanding of the mechanisms underlying most of these interactions is related predominantly to the modulation of drug metabolizing enzymes. In order to better understand and predict the potential pharmacokinetic interactions of flavonoids with conventional medicines, the interactions of flavonoids with drug transporters important in drug disposition were investigated in this dissertation. The transporters of interest in this dissertation include the uptake transporters, organic anion transporting polypeptide OATP1B1 and monocarboxylate transporter 1 (MCT1), and the efflux transporters, breast cancer resistance protein (BCRP) and P-glycoprotein. Many of the tested flavonoids significantly inhibited the uptake of the OATP1B1 substrate [ 3 H]dehydroepiandrosterone sulfate (DHEAS) in a concentration-dependent manner in HeLa OATP1B1-expressing cells, with biochanin A being one of the most potent inhibitors with an IC 50 of 11.3 ± 3.22 μM. A kinetic study revealed that biochanin A inhibited [ 3 H]DHEAS uptake in a noncompetitive manner with a Ki of 10.2 ± 1.89 μM. This is consistent with our finding that biochanin A is not a substrate for OATP1B1. The flavonoid luteolin has been reported to be a potent MCT1 inhibitor. In chapter 3, we characterized the effects of luteolin on the pharmacokinetics and pharmacodynamics of the MCT1 substrate γ-hydroxybutyrate (GHB) in rats. Luteolin significantly decreased the plasma concentration and AUC, and increased the total and renal clearances of GHB in a dose-dependent manner. Moreover, luteolin significantly shortened the duration of GHB-induced sleep in rats. A pharmacokinetic model that incorporated capacity-limited renal reabsorption and metabolic clearance was constructed to characterize the in vivo interaction and revealed that luteolin significantly altered the pharmacokinetics of GHB by uncompetitively inhibiting its MCT1-mediated transport, with an inhibition constant of 1.1 μM. The flavonoid chrysin has been reported to be a potent inhibitor of BCRP. The pharmacokinetic interaction between chrysin and the BCRP substrate nitrofurantoin in rats was characterized in chapter 4. Oral and intravenous coadministration of chrysin significantly increased the AUC of nitrofurantoin. Moreover, the cumulative hepatobiliary excretion of nitrofurantoin was significantly decreased by approximately 75% following the coadministration of chrysin. The flavonoid 7,8-benzoflavone was more potent than chrysin in inhibiting BCRP-mediated transport, and a 50 mg/kg oral dose significantly increased the AUC of nitrofurantoin. The investigation of the pharmacokinetics of 7,8-benzoflavone following the administration of oral and intravenous doses revealed nonlinear pharmacokinetics, likely due to its capacity-limited metabolism and BCRP-mediated elimination. The studies addressing BCRP inhibition mechanisms indicated that flavonoids, such as biochanin A and kaempferol and/or their metabolites, inhibited BCRP-mediated transport by acting as BCRP substrates. Different from the BCRP-mediated flavonoid-drug interactions, the flavonoid biochanin A inhibited P-glycoprotein-mediated efflux in vitro , but had minimal effects on the pharmacokinetics of P-glycoprotein substrates doxorubicin and cyclosporine A, indicating other transporters or metabolizing enzymes might be important in the in vivo disposition of doxorubicin and cyclosporine A. In summary, this dissertation characterized the flavonoid-drug interactions mediated by the uptake and efflux transporters. This research is of significance due to the widespread use of dietary supplements containing flavonoids, and provides new information on the pharmacokinetics and pharmacodynamics of this important class of dietary compounds.