title: Nasal membrane and intracellular protein and enzyme release by bile salts and bile salt-fatty acid mixed micelles: correlation with facilitated drug transport.
abstract: The effects of four bile salts, one fusidate derivative, and one mixed micellar formulation of bile salt-fatty acid combination on the nasal mucosal protein and enzyme release have been investigated in rats using an in situ nasal perfusion technique. Deoxycholate (NaDC) was found to possess the maximum protein solubilizing activity, followed by taurodihydrofusidate (STDHF), cholate, glycocholate (NaGC), and taurocholate (NaTC) in a descending order. The difference in protein solubilization of NaDC and NaGC was further characterized by the release of 5'-nucleotidase (5'-ND), a membrane-bound enzyme, and lactate dehydrogenase (LDH), an intracellular enzyme, in the perfusate. While both NaDC and NaGC caused comparable 5'-ND release from nasal membrane, intracellular LDH release was significantly higher with NaDC. The greater protein and LDH solubilizing effects of NaDC corresponded well with its faster rate of disappearance from the nasal perfusate. Therefore, the dihydroxy bile salt NaDC tends to cause intracellular damage and cell lysis, whereas the trihydroxy bile salt NaGC appears to produce primarily mucosal membrane perturbations. Linoleic acid in the form of soluble mixed micelles with glycocholate caused a further increase in nasal protein release. However, the rate and extent of nasal membrane protein release by the mixed micelles composed of 15 mM glycocholate and 5 mM linoleic acid were significantly lower than those caused by either deoxyholate or STDHF at the same concentrations. Nasal absorption of acyclovir, a non-absorbable hydrophilic model antiviral agent, was found to be enhanced in the presence of conjugated trihydroxy bile salts and bile salt-fatty acid mixed micelles.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Z
authors.initials: Z
authors.lastname: Shao
authors.forename: A K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism*; D000212:Acyclovir / Q000493:pharmacokinetics; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D005227:Fatty Acids / Q000494:pharmacology*; D005672:Fusidic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006000:Glycocholic Acid / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D005227:Fatty Acids; D008041:Linoleic Acids; D008565:Membrane Proteins; D005672:Fusidic Acid; D013656:Taurocholic Acid; C053824:tauro-24,25-dihydrofusidate; D019787:Linoleic Acid; D007770:L-Lactate Dehydrogenase; D015720:5'-Nucleotidase; D006000:Glycocholic Acid; D000212:Acyclovir