Received for publication August 4, 2006.
Revised November 6, 2006.
Accepted for publication November 8, 2006.

Flavonoids modulate Monocarboxylate transporter-1 mediated transport of -hydroxybutyrate in vitro and in vivo

Abstract

The objective of this study was to determine the effects of flavonoids 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, diosmetin, fisetin, genistein, hesperitin, kaempferol, luteolin, morin, narigenin, phloretin and quercetin, but was not affected by the flavonoid 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 µM, with the inhibition mechanism for luteolin being competitive. ³H-kaempferol and ³H-biochanin A did not exhibit MCT1-mediated 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 iv bolus, with or without the concomitant administration of luteolin 10 mg/kg iv. Following luteolin treatment, the renal and total clearances of GHB were significantly increased, likely due to inhibition of the MCT1-mediated renal reabsorption 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 pharmacodynamics of MCT substrates.

Key words: membrane transport, organic anion transport, pharmacokinetics, renal transport, toxicokinetics, transporters