Drug transporters in the nasal epithelia and their contribution in drug delivery

Al-Ghabeish, Manar

doi:10.17077/etd.9mkkvyzi

Cited by 7 publications

(19 citation statements)

References 96 publications

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“…12, 13 Investigations of uptake transporter activities have also used Western blotting and immunohistochemistry to confirm the expression of OCT2, OCTN2, LAT1, LAT2, CNT3, and ENT1 in cows. 10, 12, 14–16 Further in vivo investigations have shown that OCT2 and OCTN2 are able to modulate the transfer of drugs across the nasal mucosa and the activity of these transporters significantly enhances nose to brain transport of substrate drug compounds.…”

Section: Introductionmentioning

confidence: 99%

Microarray Determination of the Expression of Drug Transporters in Humans and Animal Species Used for the Investigation of Nasal Absorption

et al. 2015

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Purpose Mice and rats are commonly used to investigate in vivo nasal drug absorption, yet their small nasal cavities limit their use for in vitro investigations. Bovine tissue explants have been used to investigate drug transport through the nasal respiratory and olfactory mucosae, yet limited information is available regarding the similarities and differences among these animal models compared to humans. The aim of this study was to compare the presence of a number of important drug transporters in the nasal mucosa of these species. Methods DNA microarray results for nasal samples from humans, rats and mice were obtained from GenBank, while DNA microarray and RT-PCR were performed on bovine nasal explants. The drug transporters of interest include multidrug resistance, cation, anion, peptide, and nucleoside transporters. Results Each of the species (mouse, rat, cow and human) shows similar patterns of expression for most of the important drug transporters. Several transporters were highly expressed in all the species, including MRP1, OCTN2, PEPT2 and y+LAT2. Conclusion While some differences in transporter mRNA and protein expression were observed, the transporter expression patterns were quite similar among the species. The differences suggest that it is important to be aware of any specific differences in transporter expression for a given compound being investigated, yet the similarities support the continued use of these animal models during preclinical investigation of intranasally administered therapeutics.

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Section: Introductionmentioning

confidence: 99%

Microarray Determination of the Expression of Drug Transporters in Humans and Animal Species Used for the Investigation of Nasal Absorption

et al. 2015

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“…For example, FLT is reported to be a substrate for at least 4 nucleoside transporters, two of which are known to be expressed in the nasal mucosa. (21, 25) Based on the reported substrate interactions of other nucleoside-like drug compounds, additional transporters, especially efflux transporters may also play an important role in determining the overall distribution of intranasally administered compounds. The evaluation of in vivo disposition patterns is complicated by the activity of a variety of transporters, some identified and others unknown, on distribution, along with a lack of information regarding exact tissue concentrations and target concentrations that result in the saturation of a transporter.…”

Section: Discussionmentioning

confidence: 99%

“…(20) ENT1 and CNT3 have been demonstrated to be expressed in the nasal mucosa and are present primarily on the apical surface of the respiratory and olfactory epithelia in the nasal cavity. (9, 21) Using cell-based techniques, Paproski, et al demonstrated that alovudine (FLT analog) was a substrate for ENT1, ENT2, CNT1 and CNT3. (22) The equilibrative transporters were also shown to have lower affinities but greater capacities for alovudine transport than the concentrative nucleoside transporters.…”

Section: Introductionmentioning

confidence: 99%

Demonstration of Nucleoside Transporter Activity in the Nose-to-Brain Distribution of [18F]Fluorothymidine Using PET Imaging

Ponto

Huang

Walsh

et al. 2017

AAPS J

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Purpose To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [18F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1–3) substrate, using PET to measure local tissue concentrations. Methods Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 minutes. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. Results FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT exposure following both IN and IV administration, suggesting that NBMPR decreases the clearance rate of FLT from the brain. When FLT and NBMPR were co-administered IN, there was a decrease in the OB AUC while an increase in the brain AUC was observed. The decrease in OB exposure was likely the result of inhibition of ENT1 uptake activity in the nose-to-brain transport pathway. Conclusion FLT distribution patterns show that nucleoside transporters, including ENT1, play a key role in the distribution of transporter substrates between the nasal cavity and the brain via the OB.

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“…Another proposed pathway for drug absorption after intranasal administration is the direct transport of drugs to the CNS known as "nose-to-brain delivery" via the olfactory and trigeminal nerves 17 . It was observed early in the last century that viruses like poliomyelitis and stomatitis can enter to the brain via the nose 16,18 . Later, this pathway was reported in a study by Reiss et al who showed that stomatitis virus can enter to the brain via the olfactory nerves 19 .…”

Section: VImentioning

confidence: 99%

“…In addition, the volume of the nasal cavity limits the volume of the dose that can be administered to ~ 100-150 μl. While absorption from the nasal cavity does bypass hepatic first pass metabolism, the activity of the metabolizing enzymes found in the nasal mucosa can also decrease the amount of drug available for uptake 16 .…”

Section: VImentioning

confidence: 99%

In vitro assessment of the transport of Poly D, L Lactic-Co-Glycolic Acid (PLGA) nanoparticles across the nasal mucosa

Albarki

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Drug transporters in the nasal epithelia and their contribution in drug delivery

Abstract: I sincerely appreciate all the help and support from my family and friends in Jordan and Egypt and the ones I met in Iowa. Finally, my parents, my brother Ziad and sister Haneen, I would like to thank them all for their love and never ending support.

Cited by 7 publications

References 96 publications

Microarray Determination of the Expression of Drug Transporters in Humans and Animal Species Used for the Investigation of Nasal Absorption

Microarray Determination of the Expression of Drug Transporters in Humans and Animal Species Used for the Investigation of Nasal Absorption

Demonstration of Nucleoside Transporter Activity in the Nose-to-Brain Distribution of [18F]Fluorothymidine Using PET Imaging

In vitro assessment of the transport of Poly D, L Lactic-Co-Glycolic Acid (PLGA) nanoparticles across the nasal mucosa

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