title: Influence of enhancers on the absorption and on the pharmacokinetics of cefodizime using in-vitro and in-vivo models.
abstract: In the development of novel antibiotics, more and more compounds have been found that cannot be absorbed orally and, therefore, must be administered intravenously or intramuscularly. Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability has received much attention in pharmaceutical research. Cefodizime, a novel third-generation cephalosporin with significant advantages in the parenteral treatment of common infections, was used as a model drug. Cefodizime behaves as a highly hydrophilic compound, as shown from its extremely low partition coefficient. The effect of cationic absorption enhancers (hexadecyldimethylbenzylammonium chloride, N-hexadecylpyridinium bromide, dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide) on the lipophilicity of cefodizime was investigated by means of the n-octanol/water system. Results showed that the counter-ions had a positive influence on the solubility of cefodizime. These results on partitioning coefficients in the n-octanol/buffer system were confirmed using an in-vitro transport model with artificial and biological membranes (Caco-2-cells). Furthermore, the physiological compatibility of the absorption enhancers was investigated using the active D-glucose transport. The pharmacokinetic profile of cefodizime was evaluated in rabbits after intraduodenal administration with and without an absorption enhancer.
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Department of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Yahya
authors.initials: Y
authors.lastname: Mrestani
authors.forename: Beate
authors.initials: B
authors.lastname: Bretschneider
authors.forename: Albert
authors.initials: A
authors.lastname: Härtl
authors.forename: Matthias
authors.initials: M
authors.lastname: Brandsch
authors.forename: Reinhard H H
authors.initials: RH
authors.lastname: Neubert
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport; D002021:Buffers; D018938:Caco-2 Cells; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007408:Intestinal Absorption; D008567:Membranes, Artificial; D010539:Permeability; D011817:Rabbits; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D002021:Buffers; D008567:Membranes, Artificial; D013501:Surface-Active Agents; D002439:Cefotaxime; D020003:1-Octanol; C033356:cefodizime