Pharmacokinetic interaction between the flavonoid luteolin and gamma-hydroxybutyrate in rats: potential involvement of monocarboxylate transporters.
Monocarboxylate transporter 1 (MCT1) has been previously reported as an important determinant of the renal reabsorption of the drug of abuse, gamma-hydroxybutyrate (GHB). Luteolin is a potent MCT1 inhibitor, inhibiting the uptake of GHB with an IC(50) of 0.41 microM in MCT1-transfected MDA-MB231 cells. The objectives of this study were to characterize the effects of luteolin on GHB pharmacokinetics and pharmacodynamics in rats, and to investigate the mechanism of the interaction using model-fitting methods. GHB (400 and 1,000 mg/kg) and luteolin (0, 4 and 10 mg/kg) were administered to rats via iv bolus doses. The plasma or urine concentrations of luteolin and GHB were determined by HPLC and LC/MS/MS, respectively. The pharmacodynamic parameter sleep time in rats after GHB administration was recorded. A pharmacokinetic model containing capacity-limited renal reabsorption and metabolic clearance was constructed to characterize the in vivo interaction. Luteolin significantly decreased the plasma concentration and AUC, and increased the total and renal clearances of GHB. Moreover, luteolin significantly shortened the duration of GHB (1,000 mg/kg)-induced sleep in rats (161 +/- 16, 131 +/- 14 and 121 +/- 5 min for control, luteolin 4 and 10 mg/kg groups, respectively, p < 0.01). An uncompetitive inhibition model, with an inhibition constant of 1.1 microM, best described the in vivo pharmacokinetic interaction. The results of this study indicated that luteolin significantly altered the pharmacokinetics of GHB by inhibiting its MCT1-mediated transport. The interaction between luteolin and GHB may offer a potential clinical detoxification strategy to treat GHB overdoses.
Wang
Xiaodong
X
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, 517 Hochstetter Hall, Amherst, New York 14260, USA.
Wang
Qi
Q
Morris
Marilyn E
ME
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005419:Flavonoids / Q000493:pharmacokinetics; D047311:Luteolin / Q000493:pharmacokinetics*; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012978:Sodium Oxybate / Q000493:pharmacokinetics*
D005419:Flavonoids; D027501:Monocarboxylic Acid Transporters; D012978:Sodium Oxybate; D047311:Luteolin