Add time:08/11/2019         Source:sciencedirect.com

To obtain quantitative information for the rational design of an orally active prodrug of cefotiam (7β-(2-(2-aminothiazol-4-yl) acetamido)-3-(((1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl)thio)methyl)ceph-3-em-4-carboxyhc acid; CTM), 16 acyloxyliethyl esters of CTM were prepared and their oral bioavailability (BA) in mice was measured as well as the water solubility, lipophilicity, hydrolysis rate to CTM, and isomerization to Δ2-CTM, which were thought important factors influencing their oral BA. The plasma CTM levels after oral administration of the esters were higher than those observed after oral dosing of CTM and the relative bioavailability was improved 2–9-fold. Four esters had iBA of more than 40% including 2-propylvaleryloxymethyl ester 1 showing the best BA, 53.8%. The water solubility of these esters at pH 4.5 were between 1.31 and 3.46 mg/ml. The lipophilicity was closely related to the Hansch's substituent lipophilic constant (π value) of R. In a homogenate of mice small intestine, the esters were hydrolyzed to CTM and Δ2-CTM. The esters were also unstable and converted to Δ2-CTM rapidly in a buffer of pH 7.4. The hydrolysis and isomerization of the CTM ester could be parallel reactions. Analysis of the quantitative structure-absorption correlation revealed a good linear relation between the Taft's steric constant (Es value) of the ester moiety R and the hydrolysis rate of the ester to CTM in a 1% homogenate of mice small intestine at 37° C. Also, a close correlation was observed among the Es value, π value of R, and the BA or peak plasma level of CTM. Significant contribution of the steric hindrance of the ester moiety to the BA or Cmax was recognized for the first time in designing an orally active prodrug of a cephalosporin. An optimization of the promoiety (R) of acyloxymethyl ester of CTM revealed that an R with Es value near −2 and π value between 2 and 4, i.e. alkyl group having carbon atoms between 4 and 8, are necessary to give a good BA after oral administration to mice.

We also recommend Trading Suppliers and Manufacturers of (Z)-2-(2-AMINOTHIAZOL-4-YL)-2-ACETYLOXYIMINOACETIC ACID (cas 110130-88-6). Pls Click Website Link as below: cas 110130-88-6 suppliers