Clinical Toxicology
`
`Research Anicle
`
`Morris et al. J Clinic Toxicol 2011 . 1,2
`http,; /dx.doi.org/10.4172/2161-0495.1000105
`
`Open Access
`
`Monocarboxylate Transporter Inhibition with Osmotic Diuresis Increases
`y -Hydroxybutyrate Renal Elimination in Humans: A Proof-of-Concept
`Study
`Marilyn E. Morris'*, Bridget L. Morse', Gloria J. Baciewicz2 , Matthew M. Tessena2 , Nicole M. Acquisto3, David J. Hutchinson• and Robert
`DiCenzo5
`
`'Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences. University at Buffalo, State University of New York, Buffalo, NY (Morris and
`Morse)
`'Department of Psychiatry, University of Rochester Medical Center, University of Rochester, Rochester. NY (Baciewicz and Tessena)
`'Departments of Pharmacy and Emergency Medicine, University of Rochester Medical Center, University of Rochester, Rochester, NY (Acquisto)
`'Department of Pharmacy Practice, School of Pharmacy, St. John Fisher College, Rochester, NY (Hutchinson)
`5Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY (DiCenzo)
`
`Abstract
`
`Background and objective: The purpose of the current study was to demonstrate proof-of-concept that
`monocarboxylate transporter (MCT) inhibition with L-lactate combined with osmotic diuresis increases renal
`clearance of y-hydroxybutyrate (GHB) in human subjects. GHB is a substrate for human and rodent MCTs, which
`are responsible for GHB renal reabsorption , and this therapy increases GHB renal clearance in rats.
`
`Methods: Ten healthy volunteers were administered GHB orally as sodium oxybate 50 mg/kg (4.5 gm maximum
`dose) on two different study days. On study day 1, GHB was administered alone. On study day 2, treatment of L-lactate
`0.125 mmol/kg and mannitol 200 mg/kg followed by L-lactate 0.75 mmol/kg/hr was administered intravenously 30
`minutes after GHB ingestion. Blood and urine were collected for 6 hours, analyzed for GHB, and pharmacokinetic
`and statistical analyses performed.
`
`Results: L-lactate/mannitol administration significantly increased GHB renal clearance compared to GHB alone,
`439 vs. 615 mllhr (P=0.001), and increased the percentage of GHB dose excreted in the urine, 2.2 vs. 3.3%
`(P=0.021 ). Total clearance was unchanged.
`
`Conclusions: MCT inhibition with L-lactate combined with osmotic diuresis increases GHB renal elimination in
`humans. No effect on total clearance was observed in this study due to the negligible contribution of renal clearance
`to total clearance at this low GHB dose. Considering the nonlinear renal elimination of GHB, further research in
`overdose cases is warranted to assess the efficacy of this treatment strategy for increasing renal and total clearance
`at high GHB doses.
`
`Keywords: y-hydroxybutyrate; Pharmacokinetics; Renal clearance;
`Monocarboxylate transporter
`
`Abbreviations: AUC: Area under the plasma concentration-time
`curve; Cl: Clearance; ClR: Renal clearance; CV: Coefficient of variation;
`F: Bioavailahility; GHB: y-hydroxyhutyrate; MCT: Monocarhoxylate
`transporter
`
`Introduction
`
`its precursors,
`Overdose of y-hydroxybutyrate (GHB) and
`y-butyrolactone and 1,4-butanediol, has recently been recognized as
`a significant issue in public health. From 1990-2000, over 7100 GHB
`overdoses including 65 deaths were reported in the U.S. [1], and in a
`recent publication, 209 GHB-associated deaths were reported in the
`U.S. from 1995-2005 [2]. Manifestations of GHB overdose include
`sedation, coma, hypothermia, bradycardia, and respiratory arrest [3-
`5]. Although abuse of GHB has been recognized, there currently exists
`no pharmacological treatment for the overdose of these compounds.
`Current treatment consists primarily of supportive care and mechanical
`ventilation in cases of significant respiratory depression [ 6,7].
`
`GHB is currently used in the form of sodium oxybate (Xyrem"')
`for the treatment of excessive daytime sleepiness and cataplexy in
`patients with narcolepsy in the U.S. and in Europe. Clinical studies
`with sodium oxybate demonstrate dose-dependent pharmacokinetics,
`even at low,
`therapeutic doses
`[8,9]. Similar pharmacokinetic
`properties are reported in rats, in which nonlinearity has been
`
`attributed to several concentration-dependent processes including
`saturable metabolism, oral absorption, and renal reabsorption [10-12].
`Saturable renal reabsorption in rats can be accounted for by saturable
`transport by monocarboxylate transporters (MCTs), of which GHB is
`a substrate [10,13]. In the kidney, MCTs act to conserve endogenous
`monocarboxylates, such as lactate, from being cleared into the urine,
`and serve a similar role in the conservation of GHB. Increasing GHB
`renal elimination by inhibition of these transporters represents a
`potential therapeutic strategy for the treatment of GHB overdose. This
`strategy has been validated using rat kidney membrane vesicles and in
`vivo rat studies to demonstrate that administration of MCT inhibitors
`inhibits GHB transport in the kidney and effectively increases GHB
`
`•corresponding author: Marilyn E, Morris, University at Buffalo, 527 Hochstetler
`Hall Buffalo, NY 14260, Tel: (716) 645-4839; Fax: (716) 645-3693: E-mail:
`memorris@buffalo.edu
`
`Received October 01, 2011; Accepted November 03, 2011 : Published November
`10, 2011
`
`Citation: Morris ME, Morse BL, Baciewicz GJ, Tessena MM, Acquisto NM. et al.
`(2011) Monocarboxylate Transporter Inhibition with Osmotic Diuresis Increases
`y-Hydroxybutyrate Renal Elimination in Humans· A Proof-of-Concept Study. J
`Clinic Toxicol1 :105. doi: 1 0.4172/2161-0495.1000105
`
`Copyright:© 2011 Morris ME, et al. This is an open-access article distributed under
`the terms of the Creative Commons Attribution License, which permits unrestricted
`use, distribution, and reproduction in any medium, provided the original author and
`source are credited
`
`J Clinic Toxicol
`ISSN, 2161- 0495 JCT, an open access journal
`
`Ranbaxy Ex. 1029
`IPR Petition - USP 8, 772,306
`
`Volume 1 • Issue 2 • 1000105
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`Page 1
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`

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`Citation: Morris ME, Morse BL, Baciewicz GJ, Tessena MM, Acquisto NM, et al. (201 1) Monocarboxylate Transporter Inhibition with Osmotic
`Diuresis Increases y-Hydroxybutyrate Renal Elimination in Humans: A Proof-of-Concept Study. J Clinic Toxicol1:105. doi: 10.4172/2161-
`0495.1 000105
`
`total and renal clearance at high GHB doses [10,13- 15]. Using a human
`kidney cell line, MCT inhibitors similarly inhibited the transport of
`GHB in human tissue [16].
`
`Although well-established in rodents, the role of MCTs in the
`renal elimination of GHB in humans has not been demonstrated in
`vivo. The purpose of this study was to provide proof-of-concept that
`administration of an MCT inhibitor, L-lactate, combined with osmotic
`diuresis increases the renal clearance of GHB in human subjects.
`
`Materials and Methods
`
`Study design and selection of participants
`
`This was a prospective, open-label, crossover study performed
`at a university hospital from 2009-2011. ]bis study was approved by
`the institutional review boards at the sponsoring institutions. Healthy
`male and female volunteers, ages 21 -55, were recruited for the study.
`A screening visit was used to determine subjects in good health
`considering medical history, physical examination, and laboratory
`tests. Women of child-bearing age were administered a pregnancy test
`at the screening visit and were required to use an acceptable method
`of contraception throughout the study. Exclusion criteria included
`evidence of organ dysfunction as determined by physical examination
`and laboratory results, history of drug or alcohol abuse within 6 months
`prior to the study, allergy to study medications, known succinic semi(cid:173)
`aldehyde dehydrogenase deficiency, women who were pregnant, breast(cid:173)
`feeding or unwilling to use an acceptable method of contraception, and
`prescription or non-prescription drug use within I week prior to the
`study, excluding oral contraceptives or other medications approved by
`the investigator.
`
`On study day I, subjects were administered sodium oxybate 50 mg/
`kg (4.5 gm maximum dose) orally in water. Subjects were instructed
`to fast overnight until they were served breakfast 2 hours after drug
`administration and to withhold caffeine ingestion on study days.
`On study day 2, subjects were administered sodium oxybate 50 mg/
`kg (4.5 gm maximum dose) orally, and treatment was administered
`intravenously at 30 m inutes after GHB ingestion. Treatment consisted
`of a 0.125 mmol!kg L-lactate bolus over 10 minutes and a 200 mg/kg
`bolus of mannitol over 3 - 5 minutes, followed by a 0.75 mmol!kg/
`hr L-lactate infusion for the duration of the study. The L-lactate bolus
`and infusion were administered as sodium lactate 1/6 M solution for
`infusion. Mannitol was administered as a 20% solution in normal
`saline. In some subjects the study days were conducted in opposite
`order. Regardless of order, a washout period of at least I week was
`required between study days.
`
`Data collection
`
`Blood samples were taken on both study days directly before and
`at 10, 15, 20, 25, 30, 45, 60, 90, 120, 150, 180, 210,240, and 360 minutes
`after GHB administration. A spot urine was collected predose and
`urine samples were collected at intervals of 0-30, 30-60, 60-120, 120-
`180, 180-240, and 240-360 minutes after GHB administration. GHB
`plasma and urine concentrations were determined using an LC/MS/
`MS assay [17,18]. Urine volume at urine collection intervals were
`recorded and multiplied by urine concentrations to determine the total
`amount of GHB recovered at each urine collection interval. On study
`day 2, plasma lactate concentrations were also taken at baseline and at
`180 minutes after GHB administration. Plasma lactate concentrations
`were determined by a colorimetric lactate oxidase assay. Vital signs
`and adverse events were continuously monitored on both study days.
`On study day 2, an electrocardiogram was recorded via telemetry from
`
`J Clinic T oxicol
`ISSN t 2161-0495 JCT, an open access journal
`
`Page 2 of 4
`
`time zero to 6 hours after study drug administration and a physical
`examination was performed prior to release.
`
`Data and statistical analysis
`
`by
`determined
`were
`parameters
`Pharmacokinetic
`noncompartmental analysis using WinNonlin 5.2 (Pharsight Corp.,
`Palo Alto, CA). Primary outcome measurements included GHB renal
`clearance (Cl") and the percentage of GHB excreted unchanged in the
`urine. Other outcome measurements included total clearance (CLIF),
`area under the plasma-concentration time curve (AUC), and maximum
`plasma concentration (C
`). Individual AUCs were determined by
`the trapezoidal method, ;here the measured plasma concentrations
`represented >95% the total AUC. Cl!F was determined as Dose/AUC.
`Cl" was determined by AJAUC where A, represents the amount of
`GHB recovered unchanged in the urine. Paired t-tests were used to
`determine statistically significant differences in mean pharmacokinetic
`parameters between study days. Statistical analyses were performed
`using Sigma Plot 10.0 (Systat Software, Inc., San Jose, CA). In this study,
`a 20% change in Cl" was considered significant. Considering previous
`reports of 25% coefficient of variation (CV) values in GHB clearance
`[19] using a=0.05 and power of 0.8, 12 subjects were determined
`necessary to detect significant differences in measured pharmacokinetic
`parameters.
`
`Results
`
`A total of 21 subjects voluntarily gave informed consent for the
`study. Of these, 15 subjects completed the screening visit and 10
`subjects completed both study days and were included in the statistical
`analyses. Primary outcome measurements were met with this sample
`size; therefore recruitment was concluded. Demographics and baseline
`characteristics of the 10 subjects are given in Table 1. No significant
`differences in renal or liver function tests were detected between study
`days.
`
`Pharmacokinetic parameters determined for both study days are
`given in Table 2. As shown, administration of L-lactate and mannitol
`significantly increased GHB renal clearance and the percentage of
`GHB dose excreted in the urine. Individual changes in renal clearance
`are displayed in Figure 1. GHB plasma AUC and total clearance were
`unchanged between study days. Administration of L-lactate on study
`day 2 increased the plasma lactate level from 0.9±0.2 mM at baseline
`to 2.6±0.8 mM at 180 minutes (mean±SD, P<0.001) . Adverse effects
`were similar between study days and were limited to light sedation,
`headache, dizziness, and nausea/vomiting. No effects on heart rate,
`blood pressure, or ECG were observed.
`
`Characteristic
`N
`Age, yr
`Gender, female
`Weight, kg
`Race, Caucasian
`Race, African American
`
`Number or Mean (range)
`10
`24 (21-30)
`5
`74 (53-120)
`9
`
`Scr (mg/dl)
`BUN (mg/dl)
`AST (IU/L)
`ALT (IU/L)
`
`Study Day 1 Mean (SD)
`0.86 (0.1)
`12 (2)
`30 (12)
`24 (16)
`
`Study Day 2 Mean (SD)
`0.84 (0.1)
`12 (2)
`40 (29)
`30 (22)
`
`Study Day 1 represents day of administration of GHB alone. Study Day 2 represents
`day of administration of GHB + lactate/manmtol
`
`Table 1: Baseline Characteristics of Study Population.
`
`Volume 1 • Issue 2 • 1000105
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`

`
`Citation: Morris ME, Morse BL, Baciewicz GJ, Tessena MM, Acquisto NM, et al. (201 1) Monocarboxylate Transporter Inhibition with Osmotic
`Diuresis Increases y-Hydroxybutyrate Renal Elimination in Humans: A Proof-of-Concept Study. J Clinic Toxicol1:105. doi: 10.4172/2161-
`0495.1 000105
`
`GHB + Lactate/mannitol P-value
`Pharmacokinetic Parameter GHB
`AUG (ug/ml·hr)
`183 (52)
`0.593
`191 (71)
`20.4 (6 .6)
`0.983
`20.4 (7.7)
`CI/F (L/hr)
`0.533
`111 (31)
`102 (27)
`em, (ug/ml)
`2.2% (1.2) 3.2% (1 .6)
`% dose excreted in urine
`0.021
`439 (222)
`615 (263)
`0.001
`Cl" (mllhr)
`
`Results are from administration of GHB 50 mg/kg orally to 10 healthy volunteers
`alone and with L-lactate/mannitol. Data are presented as mean ± SO. CI/F=total
`oral clearance, cm,=maxim~m plasma _concentra~ion, CIR=rena! cl~arance. Paired
`t-tests were used to detect s1gn1f1cant differences 1n pharmacok1net1c parameters
`
`Table 2: Effect of L-lactate/mannitol administration on GHB pharmacokinetics.
`
`1400
`
`1200
`
`1000
`~ .....
`.s:::.
`:::J
`
`800
`
`.s
`0::
`0
`
`600
`
`400
`
`200
`
`0
`
`... - .....
`
`.·
`
`·-.~ •
`_.
`.. _....
`.-
`..-:::::....--;;-;:-,.
`-~
`.......
`..,-
`.....
`......
`!:-7"""'""--------...
`'7----
`
`- - - ---<1
`
`GHB
`
`GHB+
`L-lactate/mannitol
`
`Figure 1: Individual renal clearances in 10 healthy volunteers administered
`GHB 50 mg/kg alone and with L-lactate/mannitol. Renal clearance (CIR) of
`each subject is represented by individual symbols. Heavy dashed line represents
`mean.
`
`Discussion
`
`Although GHB abuse has resulted in an increasing incidence of
`overdose case reports and fatalities, treatment for these cases remains
`limited to supportive measures. Treatment with antidotes including
`flumazenil, naloxone, and physostigmine has been attempted, with
`little effect on clinical course [6]. Administration ofGABAB antagonists
`has been demonstrated etTective for treating overdose in rodent studies
`[20,21 ]; however, these agents are not currently available for use in
`humans. This study was performed to assess the ability of a clinically
`available treatment strategy ofL-lactate and mannitol to increase GHB
`renal elimination. The treatment strategy including MCT inhibition
`and osmotic diuresis was chosen based upon results of previous animal
`studies [10,14,15]. L-lactate was chosen as the MCT inhibitor based
`upon its ability to increase renal and total clearances of GHB in rats
`along with its demonstrated safety in humans at the effective doses
`[15,22,23]. The addition of mannitol as an osmotic diuretic was based
`upon animal experiments demonstrating an increased effect with the
`combination of L-lactate and mannitol compared to L-lactate alone
`[15]; however, the contribution of mannitol to overall effects on GHB
`toxicokinetics remains uncertain. L lactate effectively increased GHB
`renal and total clearance in animal studies in the absence of mannitol
`[10,1 5], as has also been demonstrated with other MCT inhibitors [14].
`Ongoing animal studies are being conducted to determine the benefit of
`mannitol co-administration on the improvement of GHB toxicokinetic
`and toxicodynamic endpoints with MCT inhibitors.
`
`J Clinic T oxicol
`ISSN t 2161-0495 JCT, an open access journal
`
`Page 3 of 4
`
`Although the renal clearance of GHB was increased in this study,
`there was no effect of treatment on total clearance. At low, therapeutic
`GHB doses, such as that studied currently, the primary route of
`elimination is metabolism by GHB dehydrogenase to form succinic
`semialdehyde, which is then metabolized by succinic semialdehyde
`dehydrogenase to succinic acid, which enters the Krebs cycle at is
`excreted as carbon dioxide [9]. Renal excretion represents a minor
`route of elimination at low doses, as illustrated in this study with
`only approximately 2% of the total dose excreted into the urine. In
`both humans and rats, GHB metabolism is saturable [8,10,11 ], and
`contributes less to overall clearance as doses are increased [ 10 ]. In rats,
`nonlinear GHB renal clearance has also been well-characterized, and,
`in contrast with metabolism, the contribution of renal elimination
`to total clearance increases with dose [ 10 ]. In clinical studies, the
`urinary recovery of GHB has also been demonstrated to increase with
`dose [9], suggesting similar nonlinear renal elimination in humans.
`Accordingly, extremely high urine concentrations have been reported
`in overdose cases [24-26]. At low GHB doses, when renal elimination is
`negligible, even a significant increase in renal clearance with treatment
`administration would not be expected to significantly affect total
`clearance, as was observed in this study. However, in clinical GHB
`overdose, due to both concentration-dependent renal reabsorption and
`saturation of metabolism, renal clearance may contribute significantly
`to total drug elimination, allowing the increase in renal clearance
`demonstrated in this study to translate to increased total clearance, a
`concept which has been demonstrated in our animal studies of GHB
`overdose. In animal studies, the increase in clearance and decrease
`in GHB plasma concentrations with MCT inhibition also resulted in
`improvement in the toxicodynamic endpoint of sedation [14,15]. In
`the current study, the low dose and lack of effect on total clearance
`limited the pharmacodynamic evaluation possible with this study,
`as changes in total AUC would be necessary to expect differences
`in pharmacodynamic endpoints. Animal studies are in progress to
`further assess the effect of a clinically relevant dose of L-lactate with
`and without mannitol on toxicodynamic endpoints of GHB overdose
`including sedation, respiratory depression, and fatality.
`
`Although this study demonstrated a statistically significant increase
`in renal clearance with L-lactate/mannitol administration, this increase
`in renal clearance of approximately 40% is modest compared to that
`observed in animal studies [10,15]. Since L-lactate is a competitive
`inhibitor of MCTs, increasing the L-lactate dose may have greater
`effects on GHB renal clearance. The dose of L-lactate administered
`in this clinical study is moderate, and higher infusion rates have been
`administered safely to human subjects [23]. Animal studies are being
`conducted to compare a similar L-lactate/mannitol regimen as that
`administered in this study with high-dose L-lactate/mannitol regimens.
`
`Limitations
`
`The primary limitation of this study was the low GHB dose used,
`which reflects therapeutic dosing and not that in overdose cases. This
`excluded the evaluation of possible effects of treatment on total GHB
`clearance or pharmacodynamic endpoints. Due to the short half-life
`of GHB at the low dose used, treatment was administered 30 minutes
`after GHB administration in this study; in the clinic, treatment is
`not likely to be available this quickly after GHB ingestion. However,
`following overdoses, delayed peak plasma concentrations may occur,
`perhaps hours after ingestion as observed in animal studies [ 11 ], which
`may provide the opportunity for treatment at later time points. Finally,
`with the administration of L-lactate and mannitol concomitantly in
`this study, effects ofMCT inhibition or osmotic diuresis alone on GHB
`renal clearance cannot be determined.
`
`Volume 1 • Issue 2 • 1000105
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`Page 3
`
`

`
`Citation: Morris ME, Morse BL, Baciewicz GJ, Tessena MM, Acquisto NM, et al. (201 1) Monocarboxylate Transporter Inhibition with Osmotic
`Diuresis Increases y-Hydroxybutyrate Renal Elimination in Humans: A Proof-of-Concept Study. J Clinic Toxicol1:105. doi: 10.4172/2161-
`0495.1 000105
`
`Conclusions
`
`1his ptlot study demonstrates the proof-of-concept that MCT
`inhibition with L-lactate in combination with osmotic diuresis
`increases GHB renal elimination in humans. Administration of
`L-lactate and mannitol may represent a practical potential strategy for
`GHB overdose due to the clinical availability and low risk associated
`with these agents. Further research in GHB overdose cases is needed
`to determine the efficacy of this treatment strategy for increasing GHB
`total clearance and improving clinical course during GHB intoxication.
`
`Acknowledgments
`
`This research was supported by the National Institutes of Health National
`Institute on Drug Abuse [grant DA023223] to MEM and by a fellowsh ip from Pfizer
`Global Research and Development to BLM.
`
`Sodium oxybate (Xyrem®) was provided by Jazz Pharmaceuticals, Inc. , Palo
`Alto, CA.
`
`The authors would like to acknowledge Alyse DiCenzo for protocol conduct
`and data management during the study.
`
`References
`
`1. Shannon M, Quang LS (2000) Gamma-hydroxybutyrate, gamma-butyrolactone,
`and 1 ,4-butanediol: a case report and review of the literature. Pediatr Emerg
`Care 16:435-440.
`
`2. Zvosec DL, Smith SW, Porrata T, Strobl AQ, Dyer JE (2010) Case series of
`226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am
`J Emerg Med 29:319-332 .
`
`3. Caldicott DG, Chow FY, Burns BJ, Felgate PO, Byard RW (2004) Fatalities
`associated with the use of gamma-hydroxybutyrate and its analogues in
`Australasia. Med J Aust 181 :310-313.
`
`4. Chin RL, Sporer KA, Cullison B, Dyer JE, Wu TO (1998) Clinical course of
`gamma-hydroxybutyrate overdose. Ann Emerg Med 31 :716-722.
`
`5. Li J, Stokes SA, Woeckener A (1998) A tale of novel intoxication: seven cases
`of gamma-hydroxybutyric acid overdose. Ann Emerg Med 31:723-728.
`
`6. Mason PE, Kerns WP (2002) Gamma hydroxybutync acid (GHB) intoxication.
`Acad Emerg Med 9:730-739.
`
`7. Okun MS, Boothby LA, Bartfield RB, Doering PL (2001) GHB: an important
`pharmacologic and clinical update. J Pharm Pharm Sci 4:167-175.
`
`8. Palatini P, Tedeschi L, Frison G, Padrini R, Zordan R, et al.(1993) Dose(cid:173)
`dependent absorption and elimination of gamma-hydroxybutyric acid in healthy
`volunteers. Eur J Clin Pharmacol 45:353-356.
`
`9. Food and Drug Administration. Xyrem application, Clinical Pharmacology
`Biopharmaceutics Review. Orphan Medical Inc. , 2002. Available at http://www.
`accessdata. fda . gov/drugsatfda _ docs/nda/2002/21-1 96 _X yrem.cfm.
`
`10. Morris ME, Hu K, Wang Q (2005) Renal clearance of gamma-hydroxybutyric
`acid in rats: increasing renal elimination as a detoxification strategy. J
`Pharmacol Exp Ther 313:1194-1202.
`
`J Clinic T oxicol
`ISSN, 2151- 0495 JCT. an open access journal
`
`Page 4 of 4
`
`11 . Lettieri JT, Fung HL(1979) Dose-dependent pharmacokinetics and hypnotic
`effects of sodium gamma-hydroxybutyrate in the rat. J Pharmacol Exp Ther
`208"7-11 .
`
`12. Arena C, Fung HL (1980) Absorption of sodium gamma-hydroxybutyrate and
`its prod rug gamma-butyrolactone: relationship between in vitro transport and in
`vivo absorption. J Pharm Sci 69:356-358.
`
`13. Wang Q, Darling IM. Morris ME (2006) Transport of gamma-hydroxybutyrate
`in rat kidney membrane vesicles· Role of monocarboxylate transporters. J
`Pharmacol Exp Ther 318: 751-761.
`
`14. Wang X, Wang Q, Morris ME (2008) Pharmacokinet1c interaction between the
`flavonoid luteolin and gamma-hydroxybutyrate in rats: potential involvement of
`monocarboxylate transporters. AAPS J 10: 47-5 5.
`
`15. Wang Q, Wang X, Morris ME (2008) Effects of L-lactate and D-mannitol on
`gamma-hydroxybutyrate toxicokinetics and toxicodynamics in rats. Drug Metab
`Dispos 36:2244-2251 .
`
`16. Wang Q, Lu Y, Morris ME (2007) Monocarboxylate transporter (MGT) mediates
`the transport of gamma-hydroxybutyrate in human kidney HK-2 cells. Pharm
`Res 24:1067-1078.
`
`17 Felmlee MA, Roiko SA, Morse BL, Morris ME (2010) Concentration-effect
`relationships for the drug of abuse gamma-hydroxybutyric acid. J Pharmacol
`Exp Ther 333:764-771 .
`
`18. Felmlee MA, Wang Q, Cui D, Roiko SA, Morris ME (2010) Mechanistic
`toxicokinetic model for gamma-hydroxybutyric acid: inhibition of active renal
`reabsorption as a potential therapeutic strategy. AAPS J 12:407-416.
`
`19. Abanades S, Farre M, Segura M, P1chim S, Barral D, et al .(2006) Gamma(cid:173)
`hydroxybutyrate (GHB) in humans: pharmacodynamics and pharmacokinetics.
`Ann NY Acad Sci1074: 559-576.
`
`20. Carai MA, Colombo G, Gessa GL (2005) Resuscitative effect of a gamma(cid:173)
`aminobutyric acid B receptor antagonist on gamma-hydroxybutyric acid
`mortality in mice. Ann Emerg Med 45: 614-619
`
`21 . Carai MA, Colombo G, Brunetti G, Melis S, Serra S, et al. (2001) Role of
`GABA(B) receptors in the sedative/hypnotic effect of gamma-hydroxybutyric
`acid. Eur J Pharmacol428: 315-321.
`
`22. Revelly JP, Tappy L. Martinez A, Bollmann M, Cayeux MC, et al. (2005) Lactate
`and glucose metabolism in severe sepsis and cardiogenic shock. Grit Care
`Med 33" 2235-2240.
`
`23. Miller BF, Failor JA, Jacobs KA, Horning MA, Navazio F, et al. (2002) Lactate
`and glucose interactions dunng rest and exercise in men: effect of exogenous
`lactate infusion. J Physiol 544: 963-975.
`
`24. Kintz P, Villain M, Pelissier AL, Cirimele V, Leonetti G (2005) Unusually high
`concentrations in a fatal GHB case. J Anal Toxicol 29: 582-585.
`
`25. Mazarr-Proo S, Kerrigan S (2005) Distribution of GHB in tissues and fluids
`following a fatal overdose J Anal Toxicol 29: 398-400.
`
`26. Kugelberg FC , Holmgren A, Eklund A, Jones AW (2010) Forensic toxicology
`findings in deaths involving gamma-hydroxybutyrate. lnt J Legal Med 124:1-6.
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`Volume 1 • Issue 2 • 1000105
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