Large Neutral Amino Acid Transporter Enables Brain Drug Delivery via Prodrugs

Gynther, Mikko; Laine, Krista; Ropponen, Jarmo; Leppänen, Jukka; Mannila, Anne; Nevalainen, Tapio; Savolainen, Jouko; Järvinen, Tomi; Rautio, Jarkko

doi:10.1021/jm701175d

Cited by 149 publications

(132 citation statements)

References 30 publications

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“…26 Male Sprague-Dawley rats weighing 220 ± 20 g (Dashuo Biotechnology, Chengdu, China) were anesthetized using intraperitoneal chloral hydrate (400 mg/kg), and the right carotid artery was perfused with Krebs- 10 mmol/L HEPES, and 20 IU/mL heparin, pH 7.4) containing DIBU or prodrug (80 μmol/L). Perfusion was performed for 30 seconds at a flow rate of 4.9 mL/min.…”

Section: In Situ Rat Brain Perfusion With Prodrugsmentioning

confidence: 99%

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

Zhou

Jiang

et al. 2015

J Cereb Blood Flow Metab

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The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energyindependent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H + /OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs.

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Section: In Situ Rat Brain Perfusion With Prodrugsmentioning

confidence: 99%

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

Zhou

Jiang

et al. 2015

J Cereb Blood Flow Metab

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“…Further, various attempts were made in the literature to enhance the delivery of poorly permeable drugs by making them substrates for a particular transporter through prodrug derivatization (Gynther et al, 2008;Peura et al, 2011). A key example of transporter-guided prodrug delivery is valacylovir, an L-valine ester of acyclovir, which has 3-to 5-fold greater oral bioavailability compared with the parent, acyclovir (Weller et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

2012

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Since there is paucity of information on solute transporters in human ocular tissues, the aim of this study was immunohistochemical and functional characterization of peptide transporters (PEPT), organic cation transporters (OCTs), neutral and basic amino acid transporters (ATB 0,+ ), and monocarboxylate transporters (MCTs) in human ocular barriers. Immunohistochemical localization of transporters was achieved using 5-mm-thick paraffin-embedded sections of whole human eyes. In vitro transport studies were carried out across human cornea and sclera-choroid-retinal pigment epithelium (SCRPE) using a cassette of specific substrates in the presence and absence of inhibitors to determine the role of transporters in transtissue solute delivery. Immunohistochemistry showed the expression of PEPT-1, PEPT-2, ATB 0,+

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“…GCV's PS product was 0.91 Â 10 24 6 0.27 Â 10 24 ml/s per g (mean 6 S.E.M. ; n = 4), which is lower than the PS product of urea, a small polar molecule used as a reference molecule for poor BBB permeation (Killian and Chikhale, 2001;Gynther et al, 2008). Furthermore, in the study of Liu et al (2004), the PS product of 28 drug-like molecules was determined and only two of these molecules had lower PS products than GCV.…”

Section: Resultsmentioning

confidence: 90%

“…The tumor and a part of the healthy brain tissue from the right brain hemisphere were removed for GCV concentration analysis. The in situ rat perfusion technique has been described in detail previously (Gynther et al, 2008). Nonspecific Tissue Binding.…”

Section: Methodsmentioning

confidence: 99%

Brain Pharmacokinetics of Ganciclovir in Rats with Orthotopic BT4C Glioma

et al. 2014

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Ganciclovir (GCV) is an essential part of the Herpes simplex virus thymidine kinase (HSV-tk) gene therapy of malignant gliomas. The purpose of this study was to investigate the brain pharmacokinetics and tumor uptake of GCV in the BT4C rat glioma model. GCV's brain and tumor uptakes were investigated by in vivo microdialysis in rats with orthotopic BT4C glioma. In addition, the ability of GCV to cross the blood-brain barrier and tumor vasculature was assessed with in situ rat brain perfusion. Finally, the extent to which GCV could permeate across the BT4C glioma cell membrane was assessed in vitro. The areas under the concentration curve of unbound GCV in blood, brain extracellular fluid (ECF), and tumor ECF were 6157, 1658, and 4834 mM×min, respectively. The apparent maximum unbound concentrations achieved within 60 minutes were 46.9, 11.8, and 25.8 mM in blood, brain, and tumor, respectively. The unbound GCV concentrations in brain and tumor after in situ rat brain perfusion were 0.41 and 1.39 nmol/g, respectively. The highly polar GCV likely crosses the fenestrated tumor vasculature by paracellular diffusion. Thus, GCV is able to reach the extracellular space around the tumor at higher concentrations than that in healthy brain. However, GCV uptake into BT4C cells at 100 mM was only 2.1 pmol/mg of protein, and no active transporter-mediated disposition of GCV could be detected in vitro. In conclusion, the limited efficacy of HSV-tk/GCV gene therapy may be due to the poor cellular uptake and rapid elimination of GCV.

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Large Neutral Amino Acid Transporter Enables Brain Drug Delivery via Prodrugs

Cited by 149 publications

References 30 publications

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

RETRACTION: Immunohistochemical and Functional Characterization of Peptide, Organic Cation, Neutral and Basic Amino Acid, and Monocarboxylate Drug Transporters in Human Ocular Tissues

Brain Pharmacokinetics of Ganciclovir in Rats with Orthotopic BT4C Glioma

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