Oral Delivery of Ionic Complex of Ceftriaxone with Bile Acid Derivative in Non-human Primates

• Published in: Pharmaceutical research Vol. 30; no. 4; pp. 959 - 967
• Main Authors: Jeon, Ok-Cheol, Hwang, Seung Rim, Al-Hilal, Taslim A., Park, Jin Woo, Moon, Hyun Tae, Lee, Seulki, Park, Jae Hyung, Byun, Youngro
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2013; Springer; Springer Nature B.V
• Subjects: Acids; Administration, Oral; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacokinetics; Bile; Bile Acids and Salts - chemistry; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Caco-2 Cells; Ceftriaxone - chemistry; Ceftriaxone - metabolism; Ceftriaxone - pharmacokinetics; Cell Line; Dogs; Drug Carriers - chemistry; Drug delivery systems; Haplorhini; Humans; Medical Law; Medical sciences; Organic Anion Transporters, Sodium-Dependent - genetics; Organic Anion Transporters, Sodium-Dependent - metabolism; Permeability; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Research Paper; Solubility; Symporters - genetics; Symporters - metabolism; Transfection; ceftriaxone; enhancer; deoxycholic acid; ionic complex; oral delivery; β-Lactams; Monkey; Oral administration; Ceftriaxone; Deoxycholic acid; Cephalosporin derivatives; Vertebrata; Antibiotic; Mammalia; Bile acid; Primates; Antibacterial agent
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-012-0932-0

ABSTRACT 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.