Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle.
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 (logK(p)=0.78 to >2.2), perfluoromethylcyclohexane-toluene (logK(p)=-2.62 to 0.13) and octanol-water (logK(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 1mM 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 > or =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.
Lehmler
Hans-Joachim
HJ
Department of Occupational and Environmental Health, University of Iowa, College of Public Health, Iowa City, IA 52242-5000, USA. hans-joachim-lehmler@uiowa.edu
Xu
Ling
L
Vyas
Sandhya M
SM
Ojogun
Vivian A
VA
Knutson
Barbara L
BL
Ludewig
Gabriele
G
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005466:Fluorocarbons / Q000008:administration & dosage*; D006801:Humans; D006842:Hydrocarbons, Brominated; D008168:Lung / Q000378:metabolism*; D009243:NAD / Q000032:analysis; D009249:NADP / Q000032:analysis; D009539:Nicotinic Acids / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility
D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D009539:Nicotinic Acids; D014677:Pharmaceutical Vehicles; D011355:Prodrugs; D009243:NAD; D009249:NADP; C003072:perflubron