Development of hemiacetal esterified levofloxacin to prevent chelation with metal-containing drugs
| Autor: | Masahiro Iwaki, Yoshikazu Ishii, Toru Otori, Sumio Matzno, Mayumi Nishikata, Tetsutaro Kimachi, Keiji Nishiwaki, Mai Asahide, Kenji Matsuyama, Ryuta Tominaga, William Figoni, Atushi Kawase |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Drug Compounding 030106 microbiology Administration Oral Biological Availability Pharmaceutical Science Aluminum Hydroxide Levofloxacin Microbial Sensitivity Tests In Vitro Techniques Intestinal absorption Rats Sprague-Dawley 03 medical and health sciences Hydrolysis chemistry.chemical_compound 0302 clinical medicine Oral administration Intestine Small Animals Organic chemistry Drug Interactions Prodrugs Chelation Chelating Agents Pharmacology Aluminium hydroxide Prodrug Anti-Bacterial Agents Gastrointestinal Microbiome Bioavailability Intestinal Absorption chemistry 030220 oncology & carcinogenesis Hemiacetal Nuclear chemistry |
| Zdroj: | Journal of Pharmacy and Pharmacology. 68:1527-1534 |
| ISSN: | 2042-7158 0022-3573 |
| DOI: | 10.1111/jphp.12642 |
| Popis: | Objectives To avoid the chelate formation between levofloxacin (LVFX) and aluminium hydroxide in gastrointestinal tract, an ethoxycarbonyl 1-ethyl hemiacetal ester of levofloxacin (LVFX-EHE) was synthesised as a prodrug. Methods The effects of aluminium hydroxide on the bioavailability of LVFX following oral administration of LVFX-EHE were investigated in rats. Furthermore, the effects of aluminium hydroxide on small intestinal absorption of LVFX and LVFX-EHE when subjected to a hydrolysis experiment using in situ everted gut sac were investigated, and the minimal inhibitory concentrations (MICs) of LVFX and LVFX-EHE for various intestinal bacteria were measured. Key findings When LVFX-EHE was co-administered with and without aluminium hydroxide, the AUC0–4 h values of LVFX hydrolysed from LVFX-EHE were similar to that of LVFX alone. In everted gut sac experiments, LVFX-EHE was efficiently absorbed even in the presence of aluminium ions after 1 h of incubation, whereas the absorption of LVFX decreased significantly in the presence of aluminium ions. MIC values of LVFX-EHE were far higher than LVFX. Conclusions This study suggests the benefit of ethoxycarbonyl 1-ethyl hemiacetal esterification of the carboxyl group of new quinolone as a prodrug which is able to avoid chelate formation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text