DOI

10.17077/etd.kt3jqulu

Document Type

Thesis

Date of Degree

Summer 2018

Access Restrictions

Access restricted until 08/31/2019

Degree Name

MS (Master of Science)

Degree In

Pharmacy

First Advisor

Maureen D. Donovan

First Committee Member

Guohua An

Second Committee Member

Ramprakash Govindarajan

Abstract

Over recent decades, intranasal drug delivery has received considerable attention. The intranasal route is a non-invasive route that provides rapid drug absorption with a quick onset of action and enhanced bioavailability by avoiding hepatic first-pass metabolism and GIT degradation. The unique anatomical connections between the nasal cavity and the CNS provided by the olfactory and trigeminal nerves also makes the nasal route an interesting administration site for the purpose of CNS targeting.

Epithelial transporters in the nasal mucosa modulate the uptake and efflux of substrates and their subsequent systemic absorption and/or CNS targeting. Ribavirin, a nucleoside-analog antiviral drug compound, inhibits the replication of various strains of viral encephalitis, a progressive and fatal CNS disorder, in cell culture. However, it has been reported that ribavirin was ineffective in the treatment of encephalitis following intramuscular, subcutaneous, or intraperitoneal injection. These findings suggest that ribavirin is unable to cross the blood brain barrier. The nasal route, which shows promise in targeting drugs to the brain via the olfactory region might be a potential administration route for ribavirin in the treatment of encephalitis. Ribavirin may also be a potential substrate for uptake via nucleoside transporters in the nasal mucosa. The objective of this study was to measure the permeation of ribavirin across the nasal mucosa in vitro and to evaluate the role of nucleoside transporter-mediated uptake and P-gp-mediated efflux in the total permeability of ribavirin across the nasal respiratory and olfactory tissues.

The permeation of ribavirin across the nasal mucosa was investigated using bovine nasal tissues. Both respiratory and olfactory nasal tissues were exposed to ribavirin-containing solutions (concentration range 50µM - 20mM), and a non-linear uptake of ribavirin was observed in the olfactory mucosa. These results suggest the contribution of saturable transporters, specifically nucleoside transporters, in the nasal uptake of ribavirin. A linear increase in permeation with increasing ribavirin concentration was observed across the respiratory nasal mucosa which suggests a lower activity of the nucleoside transporters in these tissues. To further evaluate the role of nucleoside transporters on ribavirin intranasal uptake, NBMPR (nitrobenzyl mercaptopurine ribonucleoside) was used as an equilibrative nucleoside transporter (ENT) inhibitor. When bovine nasal tissues were exposed to solutions containing ribavirin and NBMPR, ribavirin flux was decreased by 45% suggesting that ENTs play an important role in the nasal uptake of ribavirin.

The effect of P-gp-mediated-efflux on ribavirin uptake was also studied. Two inhibitors were used to evaluate the role of general energy-dependent transporters (sodium azide) and the specific role of P-glycoprotein (verapamil). Sodium azide (known to inhibit ATP synthesis and deplete cellular ATP) only resulted in a slight increase in ribavirin flux across the nasal respiratory and olfactory tissues. However, the flux of ribavirin across the respiratory nasal tissues increased significantly when 50 uM of verapamil (specific P-gp inhibitor) was included. These findings may be attributed to the effect of sodium azide to inhibit cellular ATP synthesis, and thus it might affect other transporters such as concentrative nucleoside transporters (CNTs) that utilize ATP indirectly to transport ribavirin across the cell membrane. Knowledge of the contributions of nucleoside transporters and P-gp in the nasal uptake of ribavirin is valuable in the evaluation of the potential absorption and subsequent distribution of drugs across the nasal mucosa. Reducing P-gp-mediated efflux and enhancing nucleoside transporter activity may enable the nasal administration of ribavirin to treat encephalitis.

Pages

xiii, 71 pages

Bibliography

Includes bibliographical references (pages 66-71).

Copyright

Copyright © 2018 Zainab Ibrahim Bakri

Available for download on Saturday, August 31, 2019

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