PT  - JOURNAL ARTICLE
AU  - Qi Wang
AU  - Marilyn E. Morris
TI  - Flavonoids Modulate Monocarboxylate Transporter-1-Mediated Transport of γ-Hydroxybutyrate in Vitro and in Vivo
AID  - 10.1124/dmd.106.012369
DP  - 2007 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 201--208
VI  - 35
IP  - 2
4099  - http://dmd.aspetjournals.org/content/35/2/201.short
4100  - http://dmd.aspetjournals.org/content/35/2/201.full
SO  - Drug Metab Dispos2007 Feb 01; 35
AB  - 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, γ-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, diosemin, 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 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 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. The American Society for Pharmacology and Experimental Therapeutics