PURPOSE: Since the absorption of ceftriaxone (CTO) in the intestine is restricted by its natural physiological characteristics, we developed a series of small synthetic compounds derived from bile acids to promote the absorption of CTO in the gastrointestinal tract. METHODS: Several bile acid derivatives were screened by measuring water solubility and partition coefficient of their complexes with CTO. The pharmacokinetic parameters of the selected CTO/HDCK ionic complex in monkeys were evaluated. The absorption pathway of CTO/HDCK complex was evaluated using Caco-2 cells and MDCK cells transfected with ASBT gene. RESULTS: HDCK enhanced the apparent membrane permeability of CTO 5.8-fold in the parallel artificial membrane permeability assay model. CTO/HDCK complex permeated Caco-2 cell via transcellular pathway, and interaction of the HDCK complex with ASBT was important to enhance uptake. When CTO/HDCK (equivalent to 50 mg/kg of ceftriaxone) formulated with lactose, poloxamer 407 and Labrasol was orally administered to monkeys, its maximum plasma concentration was 19.5 ± 1.8 μg/ml and oral bioavailability 28.5 ± 3.1%. CONCLUSIONS: The CTO/HDCK formulation could enhance oral bioavailability of CTO in non-human primates. This oral formulation could be an alternative to injectable CTO with enhanced clinical effects.
PURPOSE: Since the absorption of ceftriaxone (CTO) in the intestine is restricted by its natural physiological characteristics, we developed a series of small synthetic compounds derived from bile acids to promote the absorption of CTO in the gastrointestinal tract. METHODS: Several bile acid derivatives were screened by measuring water solubility and partition coefficient of their complexes with CTO. The pharmacokinetic parameters of the selected CTO/HDCK ionic complex in monkeys were evaluated. The absorption pathway of CTO/HDCK complex was evaluated using Caco-2 cells and MDCK cells transfected with ASBT gene. RESULTS: HDCK enhanced the apparent membrane permeability of CTO 5.8-fold in the parallel artificial membrane permeability assay model. CTO/HDCK complex permeated Caco-2 cell via transcellular pathway, and interaction of the HDCK complex with ASBT was important to enhance uptake. When CTO/HDCK (equivalent to 50 mg/kg of ceftriaxone) formulated with lactose, poloxamer 407 and Labrasol was orally administered to monkeys, its maximum plasma concentration was 19.5 ± 1.8 μg/ml and oral bioavailability 28.5 ± 3.1%. CONCLUSIONS: The CTO/HDCK formulation could enhance oral bioavailability of CTO in non-human primates. This oral formulation could be an alternative to injectable CTO with enhanced clinical effects.
Authors: G Beskid; J Unowsky; C R Behl; J Siebelist; J L Tossounian; C M McGarry; N H Shah; R Cleeland Journal: Chemotherapy Date: 1988 Impact factor: 2.544