title: Mechanistic toxicokinetic model for gamma-hydroxybutyric acid: inhibition of active renal reabsorption as a potential therapeutic strategy.
abstract: gamma-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, along with two tissue and two ultrafiltrate compartments. The estimate of the Michaelis-Menten constant for renal reabsorption (K (m,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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Felmlee
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Dapeng
authors.initials: D
authors.lastname: Cui
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Roiko
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D000818:Animals; D019540:Area Under Curve; D006885:Hydroxybutyrates / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006885:Hydroxybutyrates; C111420:4-hydroxybutyric acid
references.citation: J Pharmacol Exp Ther. 1997 May;281(2):753-60
references.pmid: 9152382
references.citation: Pharm Res. 1997 Sep;14(9):1133-9
references.pmid: 9327438
references.citation: Life Sci. 2002 May 10;70(25):3059-67
references.pmid: 12138019
references.citation: J Pharmacol Exp Ther. 2010 Jun;333(3):764-71
references.pmid: 20215411
references.citation: J Pharm Sci. 1980 Mar;69(3):356-8
references.pmid: 7381722
references.citation: Drug Metab Dispos. 2007 Feb;35(2):201-8
references.pmid: 17108059
references.citation: Cereb Cortex. 2001 May;11(5):424-9
references.pmid: 11313294
references.citation: Neurosci Biobehav Rev. 1989 Winter;13(4):187-98
references.pmid: 2691926
references.citation: N Engl J Med. 2005 Jun 30;352(26):2721-32
references.pmid: 15987921
references.citation: Alcohol. 2000 Apr;20(3):257-62
references.pmid: 10869867
references.citation: South Med J. 2000 Jun;93(6):558-61
references.pmid: 10881768
references.citation: J Pharmacol Exp Ther. 1984 Jan;228(1):174-9
references.pmid: 6694100
references.citation: Eur J Pharmacol. 2001 Oct 12;428(3):315-21
references.pmid: 11689189
references.citation: Diabetologia. 1982 Apr;22(4):285-8
references.pmid: 7095329
references.citation: Pharm Res. 1993 Jul;10(7):1093-5
references.pmid: 8378254
references.citation: AAPS J. 2008;10(1):56-69
references.pmid: 18446506
references.citation: Pharm Res. 2007 Jun;24(6):1067-78
references.pmid: 17377745
references.citation: Med J Aust. 2008 Jun 16;188(12):709-11
references.pmid: 18558893
references.citation: Drug Metab Dispos. 1986 Mar-Apr;14(2):239-45
references.pmid: 2870900
references.citation: J Pharmacol Exp Ther. 1979 Jan;208(1):7-11
references.pmid: 759616
references.citation: J Pharmacol Exp Ther. 2005 Jun;313(3):1194-202
references.pmid: 15722403
references.citation: Mol Pharm. 2006 Nov-Dec;3(6):675-85
references.pmid: 17140255
references.citation: Thromb Res. 2001 May 1;102(3):255-60
references.pmid: 11369419
references.citation: Drug Metab Dispos. 2008 Nov;36(11):2244-51
references.pmid: 18719239
references.citation: Br J Clin Pharmacol. 1992 Sep;34(3):231-5
references.pmid: 1389947
references.citation: Acad Emerg Med. 2002 Jul;9(7):730-9
references.pmid: 12093716
references.citation: J Pharmacol Exp Ther. 2006 Aug;318(2):751-61
references.pmid: 16707723
references.citation: Am J Physiol. 1995 Jan;268(1 Pt 2):F175-8
references.pmid: 7840243
references.citation: Drug Metab Dispos. 2007 Aug;35(8):1393-9
references.pmid: 17502341
references.citation: Eur J Pharmacol. 1997 Feb 19;321(1):67-75
references.pmid: 9083788
references.citation: AAPS J. 2008;10(1):47-55
references.pmid: 18446505
references.citation: J Pharmacobiodyn. 1990 Feb;13(2):97-107
references.pmid: 2384854
references.citation: Prog Neurobiol. 1997 Feb;51(3):337-61
references.pmid: 9089792
references.citation: J Pharmacol Exp Ther. 2007 Mar;320(3):1252-60
references.pmid: 17138862
references.citation: Sleep. 1986;9(1 Pt 2):285-9
references.pmid: 3704454
references.citation: Pediatr Emerg Care. 2000 Dec;16(6):435-40
references.pmid: 11138892
references.citation: AAPS J. 2008;10(1):193-9
references.pmid: 18446519
references.citation: Eur J Clin Pharmacol. 1993;45(4):353-6
references.pmid: 8299669
references.citation: Toxicol Sci. 2003 Jun;73(2):270-8
references.pmid: 12700396
references.citation: Biochem J. 1999 Oct 15;343 Pt 2:281-99
references.pmid: 10510291
references.citation: J Pharm Pharm Sci. 2001 May-Aug;4(2):167-75
references.pmid: 11466174
references.citation: Drug Metab Dispos. 2009 Jul;37(7):1404-10
references.pmid: 19389857
references.citation: J Pharm Sci. 1970 Jun;59(6):765-72
references.pmid: 5463652
references.citation: Drug Metab Dispos. 1994 May-Jun;22(3):447-50
references.pmid: 8070323