title: Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle.
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 (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.
authors.affiliation: Department of Occupational and Environmental Health, University of Iowa, College of Public Health, Iowa City, IA 52242-5000, USA. hans-joachim-lehmler@uiowa.edu
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Sandhya M
authors.initials: SM
authors.lastname: Vyas
authors.forename: Vivian A
authors.initials: VA
authors.lastname: Ojogun
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Knutson
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ludewig
mesh_terms: 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
chemical_list: D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D009539:Nicotinic Acids; D014677:Pharmaceutical Vehicles; D011355:Prodrugs; D009243:NAD; D009249:NADP; C003072:perflubron