Abstract
The drug of abuse γ-hydroxybutyrate (GHB) displays nonlinear renal clearance, which has been attributed to saturable renal reabsorption by monocarboxylate transporters (MCTs) present in the kidney. MCT1 is also present in red blood cells (RBCs); however, the significance of this transporter on the blood/plasma partitioning of GHB is unknown. The purpose of this research was to characterize the transport of GHB across the RBC membrane and assess GHB blood/plasma partitioning in vivo in the presence and absence of a competitive MCT inhibitor, l-lactate. In vitro experiments were performed using freshly isolated rat erythrocytes at pH values of 6.5 and 7.4. Inhibition with p-chloromercuribenzene sulfonate and 4,4′-diisothiocyanostilbene-2,2′-disulfonate were used to determine the contribution of MCT1 and band 3, respectively, on GHB uptake. For in vivo experiments, rats were administered GHB (400–1500 mg/kg) with and without l-lactate. In vitro experiments demonstrated that GHB is transported across the RBC membrane primarily by MCT1 at relevant in vivo concentrations. The Km for MCT1 was lower at pH 6.5 than that at pH 7.4, 2.2 versus 17.0 mM, respectively. The in vivo blood/plasma partitioning of GHB displayed linearity across all concentrations. l-Lactate coadministration increased GHB renal clearance but had no effect on the blood/plasma ratio. Unlike its MCT-mediated transport in the intestine and kidneys, GHB blood/plasma partitioning appears to be linear and is unaffected by l-lactate. These findings can be attributed, at least in part, to differences in physiologic pH at different sites of MCT-mediated transport.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA023223]; and by a fellowship from Pfizer Global Research and Development (to B.L.M.).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- GHB
- γ-hydroxybutyrate
- MCT
- monocarboxylate transporter
- RBC
- red blood cell
- pCMBS
- p-chloromercuribenzene sulfonate
- DIDS
- 4,4′-diisothiocyanostilbene-2,2′-disulfonate
- GHB-d6
- deuterated GHB
- AE
- anion exchanger
- AUC
- area under the curve
- B/P
- blood/plasma
- CL
- clearance
- CLm
- metabolic clearance
- CLR
- renal clearance
- HPLC
- high-performance liquid chromatography
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- rMCT1
- rat MCT1
- SMCT
- sodium-coupled monocarboxylate transporter.
- Received June 20, 2011.
- Accepted October 5, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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