2007 Flavonoids modulate monocarboxylate transporter1-mediated transport of gamma-hydroxybutyrate in vitro and in vivo. Drug Metab Dispos

The objective of this study was to determine the effects of fla-vonoids on the in vitro monocarboxylate transporter 1 (MCT1)-mediated transport and in vivo disposition of the drug of abuse, -hydroxybutyrate (GHB). The uptake of GHB in rat MCT1 gene-transfected MDA-MB231 cells was significantly decreased in the presence of the flavonoids apigenin, biochanin A, chrysin, diose-min, fisetin, genistein, hesperitin, kaempferol, luteolin, morin, na-rigenin, phloretin, and quercetin, but was not affected by the fla-vonoid glycosides phloridzin and rutin. The IC50 values for luteolin, morin, and phloretin were 0.41 0.14, 6.41 2.01, and 2.57 0.48 M, with the inhibition mechanism for luteolin being competitive. [3H]Kaempferol and [3H]biochanin A did not exhibit MCT1-medi-ated uptake, suggesting that these flavonoids are not substrates for MCT1. The combination of luteolin and phloretin inhibited the uptake of GHB in a synergistic manner; however, the combination of luteolin and morin was antagonistic. GHB 1000 mg/kg was administered to rats by i.v. bolus, with or without the concomitant administration of luteolin 10 mg/kg i.v. After luteolin treatment, the renal and total clearances of GHB were significantly increased, probably because of inhibition of the MCT1-mediated renal reab-sorption of GHB, and the sleep time significantly decreased (121 5 min versus 165 10 min) compared with control rats. Overall, the results of this study indicate that flavonoids from food or herbal products may significantly alter the pharmacokinetics and phar-macodynamics of MCT substrates. Nonlinear pharmacokinetics of the drug of abuse, -hydroxybutyric acid (GHB), occurs in animals (Lettieri and Fung, 1979; Shumate an