Journal
PHARMACEUTICAL RESEARCH
Volume 30, Issue 4, Pages 959-967Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-012-0932-0
Keywords
ceftriaxone; deoxycholic acid; enhancer; ionic complex; oral delivery
Funding
- Converging Research Center Program of the National Research Foundation of Korea (NRF) [2012K001398]
- World Class University (WCU) program of the National Research Foundation of Korea (NRF) [R31-2008-000-10103-0]
- Ministry of Education, Science and Technology in Korea
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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. 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. 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 mu g/ml and oral bioavailability 28.5 +/- 3.1%. 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.
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