Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: role of passive diffusion in the direct nose-to-brain uptake of small molecules

Karunya K Kandimalla; Maureen D Donovan

doi:10.1016/j.ijpharm.2005.06.012

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Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: role of passive diffusion in the direct nose-to-brain uptake of small molecules

Journal article

Peer reviewed

Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: role of passive diffusion in the direct nose-to-brain uptake of small molecules

Karunya K Kandimalla and Maureen D Donovan

International journal of pharmaceutics, Vol.302(1-2), pp.133-144

09/30/2005

DOI: 10.1016/j.ijpharm.2005.06.012

PMID: 16105724

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Abstract

Hydroxyzine and triprolidine have both been reported to reach the CNS following nasal administration. The objective of this study was to investigate their in vitro permeation across bovine olfactory mucosa in order to further characterize the biological and physicochemical parameters that influence direct nose-to-brain transport. In vitro experiments were conducted using Sweetana-Grass (Navicyte) vertical diffusion cells to evaluate the effect of directionality, donor concentration and pH on the permeation of hydroxyzine and triprolidine across excised bovine olfactory mucosa. These studies demonstrated that the Jm-s (mucosal-submucosal flux) and Js-m (submucosal-mucosal flux) of hydroxyzine and triprolidine across the olfactory mucosa were linearly dependent upon the donor concentration without any evidence of saturable transport. Hydroxyzine inhibited the efflux of P-gp substrates like etoposide and chlorpheniramine across the olfactory mucosa. Both hydroxyzine and triprolidine reduced the net flux (Js-m-Jm-s) of etoposide with IC50 values of 39.2 and 130.6 microM, respectively. The lipophilicty of these compounds, coupled with their ability to inhibit P-gp, enable them to freely permeate across the olfactory mucosa. Despite the presence of a number of protective barriers such as efflux transporters and metabolizing enzymes in the olfactory system, lipophilic compounds such as hydroxyzine and triprolidine can access the CNS primarily by passive diffusion when administered via the nasal cavity.

Animals

Biological Transport - drug effects

Cattle

Chlorpheniramine - pharmacokinetics

Chlorpheniramine - pharmacology

Diffusion - drug effects

Dose-Response Relationship, Drug

Etoposide - pharmacokinetics

Etoposide - pharmacology

Hydrogen-Ion Concentration

Hydroxyzine - chemistry

Hydroxyzine - pharmacokinetics

In Vitro Techniques

Molecular Structure

Olfactory Mucosa - drug effects

Olfactory Mucosa - metabolism

Permeability - drug effects

Solubility

Triprolidine - chemistry

Triprolidine - pharmacokinetics

Details

Title: Subtitle: Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: role of passive diffusion in the direct nose-to-brain uptake of small molecules
Creators: Karunya K Kandimalla - University of Iowa
Maureen D Donovan - University of Iowa
Resource Type: Journal article
Publication Details: International journal of pharmaceutics, Vol.302(1-2), pp.133-144
DOI: 10.1016/j.ijpharm.2005.06.012
PMID: 16105724
ISSN: 0378-5173
eISSN: 1873-3476
Language: English
Date published: 09/30/2005
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984366026002771

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