Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle

Hans-Joachim Lehmler; Ling Xu; Sandhya M Vyas; Vivian A Ojogun; Barbara L Knutson; Gabriele Ludewig

doi:10.1016/j.ijpharm.2007.11.011

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Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle

Journal article

Peer reviewed

Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle

Hans-Joachim Lehmler, Ling Xu, Sandhya M Vyas, Vivian A Ojogun, Barbara L Knutson and Gabriele Ludewig

International journal of pharmaceutics, Vol.353(1), pp.35-44

2008

DOI: 10.1016/j.ijpharm.2007.11.011

PMCID: PMC2408535

PMID: 18164563

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Abstract

This study explores perfluorooctyl bromide (PFOB) as a potential vehicle for the pulmonary delivery of a series of prodrugs of nicotinic acid using cell culture studies. The prodrugs investigated have PFOB–water (log K p = 0.78 to >2.2), perfluoromethylcyclohexane–toluene (log K p = −2.62 to 0.13) and octanol–water (log K p = 0.90–10.2) partition coefficients spanning several orders of magnitude. In confluent NCI-H358 human lung cancer cells, the toxicity of prodrugs administered in culture medium or PFOB depends on the medium of administration, with EC20's above 8 mM and 2.5 mM for culture medium and PFOB, respectively. Short-chain nicotinates administered both in PFOB and medium increase cellular NAD/NADP levels at 1 mM nicotinate concentrations. Long-chain nicotinates, which could not be administered in medium due to their poor aqueous solubility, increased NAD/NADP levels if administered in PFOB at concentrations ≥10 mM. These findings suggest that even highly lipophilic prodrugs can partition out of the PFOB phase into cells, where nicotinic acid is released and converted to NAD. Thus, PFOB may be a novel and biocompatible vehicle for the delivery of lipophilic prodrugs of nicotinic acid and other drugs directly to the lung of laboratory animals and humans.

Cell culture

Drug delivery

Fluorocarbon

Lung

Details

Title: Subtitle: Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle
Creators: Hans-Joachim Lehmler - Department of Occupational and Environmental Health, University of Iowa, College of Public Health, Iowa City, IA 52242-5000, USA
Ling Xu - Department of Occupational and Environmental Health, University of Iowa, College of Public Health, Iowa City, IA 52242-5000, USA
Sandhya M Vyas - Department of Occupational and Environmental Health, University of Iowa, College of Public Health, Iowa City, IA 52242-5000, USA
Vivian A Ojogun - Chemical and Materials Engineering Department, University of Kentucky, Lexington, KY 40506-0046, USA
Barbara L Knutson - Chemical and Materials Engineering Department, University of Kentucky, Lexington, KY 40506-0046, USA
Gabriele Ludewig - Department of Occupational and Environmental Health, University of Iowa, College of Public Health, Iowa City, IA 52242-5000, USA
Resource Type: Journal article
Publication Details: International journal of pharmaceutics, Vol.353(1), pp.35-44
DOI: 10.1016/j.ijpharm.2007.11.011
PMID: 18164563
PMCID: PMC2408535
NLM abbreviation: Int J Pharm
ISSN: 0378-5173
eISSN: 1873-3476
Publisher: Elsevier B.V
Language: English
Date published: 2008
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
Record Identifier: 9983997479902771

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