The Role of Monocarboxylate Transporter 2 and 4 in the Transport of γ-Hydroxybutyric Acid in Mammalian Cells

Wang, Qi; Morris, Marilyn E.

doi:10.1124/dmd.107.014852

Cited by 52 publications

(55 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In Ehrlich tumour cells the Michaelis-Menten constant, K m , of transport kinetics has been found to be 20 mM at 37 o C and pH 7.2 (Spencer and Lehninger, 1976) and, with a different technique, 5.34 mM in the same conditions (Carpenter and Halestrap, 1994). In the mammary carcinoma MDA-MB231, high affinity (MCT2) and low affinity (MCT4) transporters have been evidenced (Wang and Morris, 2007), with a prevalent flux through MCT4 (K m = 21.3 mM). The K m values have been found to be highly pH dependent, with K m decreasing with acidity (Dimmer et al, 2000).…”

Section: Accepted Manuscript 2 a Simple Mathematical mentioning

confidence: 94%

Necrotic core in EMT6/Ro tumour spheroids: Is it caused by an ATP deficit?

Bertuzzi

Fasano

Gandolfi

et al. 2010

Journal of Theoretical Biology

View full text Add to dashboard Cite

Section: Accepted Manuscript 2 a Simple Mathematical mentioning

confidence: 94%

Necrotic core in EMT6/Ro tumour spheroids: Is it caused by an ATP deficit?

Bertuzzi

Fasano

Gandolfi

et al. 2010

Journal of Theoretical Biology

View full text Add to dashboard Cite

“…Acetoacetate [88] 216 000 N.R N.R Atorvastatin [90] 33 a DL-a-Hydroxybutyrate [88] 56 000 Cerivastatin [90] 96 a D-b-Hydroxybutyrate [88] 130 000 Fluvastatin [90] 32 a L-b-Hydroxybutyrate [88] 824 000 Lovastatin acid [90] 44 a g-Hydroxybuturate [91] Pravastatin [90] >1 000 a…”

Section: Substrates and Inhibitorsmentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

show abstract

“…Functional characterization of MCT isoforms has been extended to seven isoforms (MCT1- 4,6,8,10) with the seven remaining MCT family members being classified as orphan MCTs (MCT5, 7,9,[11][12][13][14]. Table II provides a summary of currently identified substrates and inhibitors of functionally characterized MCT isoforms from humans and rats.…”

Section: Structure Function and Regulation Of Monocarboxylate Transpmentioning

confidence: 99%

“…For example, functional characterization of MCT6 indicated that it was involved in the transport of bumetanide, and not endogenous monocarboxylates (3). Furthermore, GHB has been demonstrated to be both a substrate and inhibitor for a number of MCT isoforms (10)(11)(12)53).…”

Section: Role Of Mcts In Drug Dispositionmentioning

confidence: 99%

“…The impact of MCT substrate/ inhibitor specificity and tissue distribution needs to be further examined with respect to drug substrates, and the overall influence of MCTs on drug disposition. The present review focuses on the proton-coupled MCTs and aims to summarize our current understanding of their structure, function and regulation as well as their role in drug disposition using γ-hydroxybutyrate (GHB; a known MCT substrate) (10)(11)(12) as a specific example.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

Morris

Felmlee

2008

AAPS J

Self Cite

184

146

View full text Add to dashboard Cite

Abstract. The transport of monocarboxylates, such as lactate and pyruvate, is mediated by the SLC16A family of proton-linked membrane transport proteins known as monocarboxylate transporters (MCTs). Fourteen MCT-related genes have been identified in mammals and of these seven MCTs have been functionally characterized. Despite their sequence homology, only MCT1-4 have been demonstrated to be proton-dependent transporters of monocarboxylic acids. MCT6, MCT8 and MCT10 have been demonstrated to transport diuretics, thyroid hormones and aromatic amino acids, respectively. MCT1-4 vary in their regulation, tissue distribution and substrate/inhibitor specificity with MCT1 being the most extensively characterized isoform. Emerging evidence suggests that in addition to endogenous substrates, MCTs are involved in the transport of pharmaceutical agents, including γ-hydroxybuytrate (GHB), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), salicylic acid, and bumetanide. MCTs are expressed in a wide range of tissues including the liver, intestine, kidney and brain, and as such they have the potential to impact a number of processes contributing to the disposition of xenobiotic substrates. GHB has been extensively studied as a pharmaceutical substrate of MCTs; the renal clearance of GHB is dose-dependent with saturation of MCT-mediated reabsorption at high doses. Concomitant administration of GHB and L-lactate to rats results in an approximately two-fold increase in GHB renal clearance suggesting that inhibition of MCT1-mediated reabsorption of GHB may be an effective strategy for increasing renal and total GHB elimination in overdose situations. Further studies are required to more clearly define the role of MCTs on drug disposition and the potential for MCTmediated detoxification strategies in GHB overdose.

show abstract

The Role of Monocarboxylate Transporter 2 and 4 in the Transport of γ-Hydroxybutyric Acid in Mammalian Cells

Cited by 52 publications

References 39 publications

Necrotic core in EMT6/Ro tumour spheroids: Is it caused by an ATP deficit?

Necrotic core in EMT6/Ro tumour spheroids: Is it caused by an ATP deficit?

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

Contact Info

Product

Resources

About