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Modulation of nose-to-brain delivery of a P-glycoprotein (MDR1) substrate model drug (quinidine) in rats.
Brain Res Bull. 2020 Jul; 160:65-73.BR

Abstract

During the last decades several new drug formulations were developed to target the central nervous system (CNS) from the nasal cavity. However, in these studies less attention was paid to the possible drug-drug interactions in case of multi-drug therapy. In our pilot study first we compared a nasal solution and a nasal gel to demonstrate their distribution in the nasal cavity (3D printed rat skull model and histology). Due to the aspiration induced high mortality at administration of nasal solution the study was continued only with the gel formulation of quinidine. The aim of our experiments was to identify the possible functional role of P-glycoprotein (P-gp) in the drug absorption in nasal cavity and to test drug-drug interactions at nose-to-brain delivery. Therefore, a P-gp substrate model drug, quinidine was tested by intranasal (IN) administration in presence of PSC-833 (specific P-gp inhibitor) given intravenously (IV) or IN and adrenaline (IN) at low (50 ng) or high (20 μg) dose. In control animals the brain penetration of quinidine was at the level of detection limit, but in combination therapy with IV PSC-833 the brain levels increased dramatically, similarly to high dose IN adrenalin, where due to vasoconstriction peripheral distribution was blocked. These results indicate that P-gp has an important role in drug absorption and efflux at nasal cavity, while adrenaline is also able to modify the penetration profile of the P-gp substrate model drug at nasal application as it decreases nose-to-blood absorption, letting more quinidine to reach the brain along with the nasal nerves.

Authors+Show Affiliations

Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary. Electronic address: lucaannabors@outlook.com.Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary. Electronic address: agnesbajza@hotmail.com.University of Veterinary Medicine, Department of Pathology, Budapest, Hungary. Electronic address: mandoki.mira@univet.hu.Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary. Electronic address: tasi.benedek.jozsef@hallgato.ppke.hu.Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary. Electronic address: cserey.gyorgy@itk.ppke.hu.Research Centre for Natural Sciences, Instrumentation Centre, Budapest, Hungary. Electronic address: imre.timea@ttk.hu.Research Centre for Natural Sciences, Instrumentation Centre, Budapest, Hungary. Electronic address: szabo.pal@ttk.hu.Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary. Electronic address: erdo.franciska@itk.ppke.hu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32344126

Citation

Bors, Luca Anna, et al. "Modulation of Nose-to-brain Delivery of a P-glycoprotein (MDR1) Substrate Model Drug (quinidine) in Rats." Brain Research Bulletin, vol. 160, 2020, pp. 65-73.
Bors LA, Bajza Á, Mándoki M, et al. Modulation of nose-to-brain delivery of a P-glycoprotein (MDR1) substrate model drug (quinidine) in rats. Brain Res Bull. 2020;160:65-73.
Bors, L. A., Bajza, Á., Mándoki, M., Tasi, B. J., Cserey, G., Imre, T., Szabó, P., & Erdő, F. (2020). Modulation of nose-to-brain delivery of a P-glycoprotein (MDR1) substrate model drug (quinidine) in rats. Brain Research Bulletin, 160, 65-73. https://doi.org/10.1016/j.brainresbull.2020.04.012
Bors LA, et al. Modulation of Nose-to-brain Delivery of a P-glycoprotein (MDR1) Substrate Model Drug (quinidine) in Rats. Brain Res Bull. 2020;160:65-73. PubMed PMID: 32344126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulation of nose-to-brain delivery of a P-glycoprotein (MDR1) substrate model drug (quinidine) in rats. AU - Bors,Luca Anna, AU - Bajza,Ágnes, AU - Mándoki,Míra, AU - Tasi,Benedek József, AU - Cserey,György, AU - Imre,Tímea, AU - Szabó,Pál, AU - Erdő,Franciska, Y1 - 2020/04/26/ PY - 2020/01/21/received PY - 2020/04/07/revised PY - 2020/04/16/accepted PY - 2020/4/29/pubmed PY - 2020/4/29/medline PY - 2020/4/29/entrez KW - 3D printed model KW - Blood-brain barrier KW - Efflux transporters KW - Intranasal drug administration KW - Nose-to-brain delivery KW - P-glycoprotein SP - 65 EP - 73 JF - Brain research bulletin JO - Brain Res. Bull. VL - 160 N2 - During the last decades several new drug formulations were developed to target the central nervous system (CNS) from the nasal cavity. However, in these studies less attention was paid to the possible drug-drug interactions in case of multi-drug therapy. In our pilot study first we compared a nasal solution and a nasal gel to demonstrate their distribution in the nasal cavity (3D printed rat skull model and histology). Due to the aspiration induced high mortality at administration of nasal solution the study was continued only with the gel formulation of quinidine. The aim of our experiments was to identify the possible functional role of P-glycoprotein (P-gp) in the drug absorption in nasal cavity and to test drug-drug interactions at nose-to-brain delivery. Therefore, a P-gp substrate model drug, quinidine was tested by intranasal (IN) administration in presence of PSC-833 (specific P-gp inhibitor) given intravenously (IV) or IN and adrenaline (IN) at low (50 ng) or high (20 μg) dose. In control animals the brain penetration of quinidine was at the level of detection limit, but in combination therapy with IV PSC-833 the brain levels increased dramatically, similarly to high dose IN adrenalin, where due to vasoconstriction peripheral distribution was blocked. These results indicate that P-gp has an important role in drug absorption and efflux at nasal cavity, while adrenaline is also able to modify the penetration profile of the P-gp substrate model drug at nasal application as it decreases nose-to-blood absorption, letting more quinidine to reach the brain along with the nasal nerves. SN - 1873-2747 UR - https://www.unboundmedicine.com/medline/citation/32344126/Modulation_of_nose-to-brain_delivery_of_a_P-glycoprotein_(MDR1)_substrate_model_drug_(quinidine)_in_rats L2 - https://linkinghub.elsevier.com/retrieve/pii/S0361-9230(20)30045-9 DB - PRIME DP - Unbound Medicine ER -
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