Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2

Amo, Eva M. del; Urtti, Arto; Yliperttula, Marjo

doi:10.1016/j.ejps.2008.06.015

Cited by 275 publications

(223 citation statements)

References 80 publications

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“…The authors argued that 18 F-DOPA uptake occurs via both the LAT1 and the LAT2 systems, whereas 18 F-FET is mainly transported by LAT2 (29,32). However, the in vivo relevance of this phenomenon for the pharmacokinetics of 18 F-DOPA versus those of 18 F-FET remains unknown (33). Additionally, the transport mechanism of 18 F-FET may be more complex.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Amino Acid Tracers¹⁸F-FET and¹⁸F-DOPA in High-Grade Glioma Patients

et al. 2014

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Section: Discussionmentioning

confidence: 99%

Comparison of the Amino Acid Tracers¹⁸F-FET and¹⁸F-DOPA in High-Grade Glioma Patients

et al. 2014

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“…It is known to be a substrate for OCTN1 (SLC22A4, Na + -independent) in the apical membrane of the enterocytes (31). It is also a substrate of the System L (SLC7) family of amino acid transporters; LAT1 light chain (with 4F2hc heavy chain, Na + -independent family) in the apical membranes of brain, placenta, and tumors (32,42) and LAT2 light chain (with 4F2hc heavy chain, Na + -independent family) in the basolateral membrane of the enterocytes (42). Its absorption is entirely dependent on active transporters (43).…”

Section: Gabapentinmentioning

confidence: 99%

Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine

Bolger

Lukáčová

Woltosz

2009

AAPS J

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Abstract. The purpose of this study was to develop simulation and modeling methods for the evaluation of pharmacokinetics when intestinal influx and efflux transporters are involved in gastrointestinal absorption. The advanced compartmental absorption and transit (ACAT) model as part of the computer program GastroPlus™ was used to simulate the absorption and pharmacokinetics of valacyclovir, gabapentin, and talinolol. Each of these drugs is a substrate for an influx or efflux transporter and all show nonlinear dose dependence within the normal therapeutic range. These simulations incorporated the experimentally derived gastrointestinal distributions of transporter expression levels for oligopeptide transporters PepT1 and HPT1 (valacyclovir); System L-amino acid transporter LAT2 and organic cation transporter OCTN1 (gabapentin); and organic anion transporter (OATP1A2) and P-glycoprotein (talinolol). By assuming a uniform distribution of oligopeptide transporter and by application of the in vitro K m value for valacyclovir, the simulations accurately reproduced the experimental nonlinear dose dependence. For gabapentin, LAT2 distribution produced simulation results that were much more accurate than OCTN1 distributions. For talinolol, an influx transporter distribution for OATP1A2 and the efflux transporter P-glycoprotein distributed with increasing expression in the distal small intestine produced the best results. The physiological characteristics of the small and large intestines used in the ACAT model were able to accurately account for the positional and temporal changes in concentration and carrier-mediated transport of the three drugs included in this study. The ACAT model reproduced the nonlinear dose dependence for each of these drugs.

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“…It should be noted that this poor-prognosis MDR gene signature probably reflects a biologic state of the HCC rather than being the sole cause of the poor prognosis, since the patients who were the source of the analyzed HCC samples were not treated with chemotherapeutic agents; however, the presence of these drug-resistance mechanisms in poor-prognosis HCC makes it difficult to design chemotherapy that might be effective against these cancers. On the other hand, this 103-gene signature not only confirms the expression of known markers of HCC such as TOP2A (Wong et al, 2009), which is a target for topoisomerase inhibitors, but also highlights new markers including the solute carriers SLC2A5/ GLUT5, SLC16A3/MCT, SLC7A11, and the melphalan transporter SLC7A5/LAT1 (del Amo et al, 2008). It is possible that these uptake transporters might facilitate cellular entry of certain yet unidentified drug species, therefore facilitating therapy.…”

Section: Discussionmentioning

confidence: 76%

A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy

et al. 2015

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Despite improvements in the management of liver cancer, the survival rate for patients with hepatocellular carcinoma (HCC) remains dismal. The survival benefit of systemic chemotherapy for the treatment of liver cancer is only marginal. Although the reasons for treatment failure are multifactorial, intrinsic resistance to chemotherapy plays a primary role. Here, we analyzed the expression of 377 multidrug resistance (MDR)-associated genes in two independent cohorts of patients with advanced HCC, with the aim of finding ways to improve survival in this poor-prognosis cancer. Taqman-based quantitative polymerase chain reaction revealed a 45-gene signature that predicts overall survival (OS) in patients with HCC. Using the Connectivity Map Tool, we were able to identify drugs that converted the gene expression profiles of HCC cell lines from ones matching patients with poor OS to profiles associated with good OS. We found three compounds that convert the gene expression profiles of three HCC cell lines to gene expression profiles associated with good OS. These compounds increase histone acetylation, which correlates with the synergistic sensitization of those MDR tumor cells to conventional chemotherapeutic agents, including cisplatin, sorafenib, and 5-fluorouracil. Our results indicate that it is possible to modulate gene expression profiles in HCC cell lines to those associated with better outcome. This approach also increases sensitization of HCC cells toward conventional chemotherapeutic agents. This work suggests new treatment strategies for a disease for which few therapeutic options exist.

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Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2

Cited by 275 publications

References 80 publications

Comparison of the Amino Acid Tracers¹⁸F-FET and¹⁸F-DOPA in High-Grade Glioma Patients

Comparison of the Amino Acid Tracers¹⁸F-FET and¹⁸F-DOPA in High-Grade Glioma Patients

Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine

A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy

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Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2

Cited by 275 publications

References 80 publications

Comparison of the Amino Acid Tracers18F-FET and18F-DOPA in High-Grade Glioma Patients

Comparison of the Amino Acid Tracers18F-FET and18F-DOPA in High-Grade Glioma Patients

Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine

A Gene Expression Signature Associated with Overall Survival in Patients with Hepatocellular Carcinoma Suggests a New Treatment Strategy

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Comparison of the Amino Acid Tracers¹⁸F-FET and¹⁸F-DOPA in High-Grade Glioma Patients

Comparison of the Amino Acid Tracers¹⁸F-FET and¹⁸F-DOPA in High-Grade Glioma Patients