Monocarboxylate Transporter Mediates Uptake of Lovastatin Acid in Rat Cultured Mesangial Cells

Nagasawa, Kohei; Nagai, Katsutoshi; Sumitani, Yuji; Moriya, Yuka; Takara, Kohji; Ohnishi, Noriaki; Yokoyama, Teruyoshi; Fujimoto, Sadaki

doi:10.1002/jps.10246

Cited by 28 publications

(16 citation statements)

References 33 publications

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“…Indeed, the involvement of MCTs in membrane transport has been demonstrated for a small range of drugs (salicylic acid, valproic acid, nateglinide, atorvastatin) (Nagasawa et al, 2002;Okamura et al, 2002), and the MCT1 transporter was recently exploited to increase absorption of a gabapentin prodrug (Cundy et al, 2004). The MCT5 isoform has been studied less thoroughly than MCT1; in a recent publication, it was labeled an "orphan transporter" (Halestrap and Meredith, 2004).…”

Section: Discussionmentioning

confidence: 99%

Expression of Thirty-six Drug Transporter Genes in Human Intestine, Liver, Kidney, and Organotypic Cell Lines

Hilgendorf

Ahlin²,

Seithel³

et al. 2007

Drug Metab Dispos

517

432

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ABSTRACT:This study was designed to quantitatively assess the mRNA expression of 36 important drug transporters in human jejunum, colon, liver, and kidney. Expression of these transporters in human organs was compared with expression in commonly used cell lines (Caco-2, HepG2, and Caki-1) originating from these organs to assess their value as in vitro transporter system models, and was also compared with data obtained from the literature on expression in rat tissues to assess species differences. Transporters that were highly expressed in the intestine included HPT1, PEPT1, BCRP, MRP2, and MDR1, whereas, in the liver, OCT1, MRP2, OATP-C, NTCP and BSEP were the main transporters. In the kidney, OAT1 was expressed at the highest levels, followed by OAT3, OAT4, MCT5, MDR1, MRP2, OCT2, and OCTN2. The best agreement between human tissue and the representative cell line was observed for human jejunum and Caco-2 cells. Expression in liver and kidney ortholog cell lines was not correlated with that in the associated tissue. Comparisons with rat transporter gene expression revealed significant species differences. Our results allowed a comprehensive quantitative comparison of drug transporter expression in human intestine, liver, and kidney. We suggest that it would be beneficial for predictive pharmacokinetic research to focus on the most highly expressed transporters. We hope that our comparison of rat and human tissue will help to explain the observed species differences in in vivo models, increase understanding of the impact of active transport processes on pharmacokinetics and distribution, and improve the quality of predictions from animal studies to humans.

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Section: Discussionmentioning

confidence: 99%

Expression of Thirty-six Drug Transporter Genes in Human Intestine, Liver, Kidney, and Organotypic Cell Lines

Hilgendorf

Ahlin²,

Seithel³

et al. 2007

Drug Metab Dispos

517

432

View full text Add to dashboard Cite

show abstract

“…Of the now 14 identified MCT members, MCT 1-4 have been shown to be proton-coupled monocarboxylate transporters, important in the transport of endogenous monocarboxylates, such as pyruvate, lactate and ketone bodies (1,2), as well as clinically relevant drugs, such as foscarnet (3), nateglinide (4) and lovastatin (5). Among these four MCTs, MCT1 is expressed nearly ubiquitously throughout the body, including erythrocytes, muscle, heart, kidney, intestine, liver and brain (2).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Interaction between the Flavonoid Luteolin and γ-Hydroxybutyrate in Rats: Potential Involvement of Monocarboxylate Transporters

Wang

Morris

2008

AAPS J

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Abstract. Monocarboxylate transporter 1 (MCT1) has been previously reported as an important determinant of the renal reabsorption of the drug of abuse, γ-hydroxybutyrate (GHB). Luteolin is a potent MCT1 inhibitor, inhibiting the uptake of GHB with an IC 50 of 0.41 μM in MCT1-transfected MDA-MB231 cells. The objectives of this study were to characterize the effects of luteolin on GHB pharmacokinetics and pharmacodynamics in rats, and to investigate the mechanism of the interaction using model-fitting methods. GHB (400 and 1,000 mg/kg) and luteolin (0, 4 and 10 mg/kg) were administered to rats via iv bolus doses. The plasma or urine concentrations of luteolin and GHB were determined by HPLC and LC/MS/MS, respectively. The pharmacodynamic parameter sleep time in rats after GHB administration was recorded. A pharmacokinetic model containing capacity-limited renal reabsorption and metabolic clearance was constructed to characterize the in vivo interaction. Luteolin significantly decreased the plasma concentration and AUC, and increased the total and renal clearances of GHB. Moreover, luteolin significantly shortened the duration of GHB (1,000 mg/kg)-induced sleep in rats (161±16, 131±14 and 121±5 min for control, luteolin 4 and 10 mg/kg groups, respectively, p<0.01). An uncompetitive inhibition model, with an inhibition constant of 1.1 μM, best described the in vivo pharmacokinetic interaction. The results of this study indicated that luteolin significantly altered the pharmacokinetics of GHB by inhibiting its MCT1-mediated transport. The interaction between luteolin and GHB may offer a potential clinical detoxification strategy to treat GHB overdoses.

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“…Monocarboxylate transporters belong to the SLC16A gene family and consist of 14 members that differ in terms of substrate specificities and affinities (Halestrap and Meredith, 2004). MCTs 1 to 4 have been demonstrated to be protoncoupled transporters (Halestrap and Meredith, 2004) with similar, but not identical, substrates, including the endogenous compounds, lactate and pyruvate (Garcia et al, 1994;Lin et al, 1998) and the exogenous compounds, foscarnet, nateglinide, simvastatin acid, lovastatin acid, and fluorescein (Tsuji A, 1993;Nagasawa et al, 2002;Okamura et al, 2002). However, the tissue distribution of MCT isoforms is quite different.…”

mentioning

confidence: 99%

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

Wang

Morris

2007

Drug Metab Dispos

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Monocarboxylate Transporter Mediates Uptake of Lovastatin Acid in Rat Cultured Mesangial Cells

Cited by 28 publications

References 33 publications

Expression of Thirty-six Drug Transporter Genes in Human Intestine, Liver, Kidney, and Organotypic Cell Lines

Expression of Thirty-six Drug Transporter Genes in Human Intestine, Liver, Kidney, and Organotypic Cell Lines

Pharmacokinetic Interaction between the Flavonoid Luteolin and γ-Hydroxybutyrate in Rats: Potential Involvement of Monocarboxylate Transporters

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

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