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Drug Metabolism and Disposition Fast Forward
First published on August 21, 2008; DOI: 10.1124/dmd.108.022996

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Received for publication June 20, 2008.
Revised August 19, 2008.
Accepted for publication August 20, 2008.

Effect of L-lactate and D-mannitol on {gamma}-Hydroxybutyrate Toxicokinetics and Toxicodynamics in Rats

Qi Wang 1, Xiaodong Wang 1, Marilyn E. Morris 1*

1 University at Buffalo, State University of New York

* Address correspondence to: E-mail: memorris{at}buffalo.edu

Abstract

Overdoses of {gamma}-hydroxybutyrate (GHB), a drug of abuse, result in coma, respiratory arrest, and death. The objective of this study was to evaluate a potential GHB detoxification strategy by inhibiting the monocarboxylate transporter (MCT)-mediated renal reabsorption of GHB in rats, using the MCT substrate L-lactate. The use of the osmotic diuretic D-mannitol alone or combined with L-lactate was also explored. GHB (208 mg·hr-1kg-1) was infused iv for 3 hours in the absence or presence of L-lactate (60.5, 121, and 302.5 mg·hr-1kg-1), D-mannitol (0.5 g/kg), or L-lactate (60.5 mg·hr-1kg-1) combined with D-mannitol (0.5 g/kg). GHB in plasma and urine samples was determined along with blood pH, electrolytes, glucose, and L-lactate. Administration of L-lactate, or the combination of L-lactate and D-mannitol, but not D-mannitol alone, significantly increased the renal and total clearances of GHB in rats. Blood pH and electrolyte concentrations exhibited small changes with GHB, GHB/lactate and GHB/mannitol treatments, although most values remained within their normal range. The concomitant administration of Lactated Ringer's solution (28 mM L-lactate) at 300 µl/min with mannitol (0.5 g/kg) resulted in a significant increase in GHB clearance and a decrease in sleep time following an iv dose of 1 g/kg. Overall, our results indicated that 1) the use of the MCT inhibitor L-lactate can increase the renal and total clearances of GHB, and 2) the combination of Lactated Ringer's solution and D-mannitol significantly alters GHB toxicokinetics and toxicodynamics, and represents a potential clinical detoxification strategy for the treatment of GHB overdoses.


Key words: drug transport, pharmacokinetics, renal transport, toxicokinetics, transporters


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
D. Cui and M. E. Morris
The Drug of Abuse {gamma}-Hydroxybutyrate Is a Substrate for Sodium-Coupled Monocarboxylate Transporter (SMCT) 1 (SLC5A8): Characterization of SMCT-Mediated Uptake and Inhibition
Drug Metab. Dispos., July 1, 2009; 37(7): 1404 - 1410.
[Abstract] [Full Text] [PDF]


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