Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid: Inhibition of Active Renal Reabsorption as a Potential Therapeutic Strategy

γ-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance  and capacity-limited  metabolism.   The  objectives  of  this  study  were  to  construct  a  mechanistic  toxicokinetic  (TK) model  describing  saturable renal  reabsorption and  capacity-limited  metabolism  of GHB  and  to predict the  effects  of  inhibition   of  renal   reabsorption  on  GHB   TK  in  the  plasma  and  urine.   GHB   was administered by iv bolus (200–1,000 mg/kg) to male Sprague-Dawley rats and plasma and urine samples were  collected  for  up  to  6 h  post-dose. GHB  concentrations were  determined by LC/MS/MS.  GHB plasma  concentration and  urinary  excretion  were  well-described  by a TK model  incorporating plasma and kidney compartments, alongwith two tissue and two ultrafiltrate compartments. The estimate  of the Michaelis-Menten constant  for renal reabsorption (Km,R) was 0.46 mg/ml which is consistent  with in vitro estimates  of monocarboxylate transporter  (MCT)-mediated uptake  of GHB  (0.48 mg/ml).  Simulation studies assessing inhibition  of renal  reabsorption of GHB  demonstrated increased  time-averaged renal
clearance  and GHB  plasma AUC,  independent of the inhibition  mechanism  assessed.Co-administration of GHB (600 mg/kg iv) and L-lactate  (330 mg/kg iv bolus plus 121 mg/kg/h iv infusion), a known inhibitor of MCTs, resulted  in a significant  decrease  in GHB  plasma AUC  and an increase  in time-averaged renal clearance,   consistent   with  the   model   simulations.  These   results   suggest   that   inhibition   of  renal reabsorption of GHB  is a viable therapeutic strategy  for the treatment of GHB  overdoses.  Furthermore, the  mechanistic  TK  model  provides  a useful  in silico tool  for  the  evaluation of potential therapeutic strategies.

 

Melanie A. Felmlee, Qi Wang, Dapeng Cui, Samuel A. Roiko, Marilyn E. Morris
September 1, 2010
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