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KMID : 0370219930370060638
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Yakhak Hoeji
1993 Volume.37 No. 6 p.638 ~ p.646
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Physicochemical Properties, Stabilities and Pharmacokinetics of Cephalosporin 3’’-Quinolone Dithiocarbamate
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나성범/La SB
공재양/김완주/지웅길/Kong JY/Kim WJ/Jee UK
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Abstract
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A cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and bicyclic quinolone dithicarbamate at the 3’’ position was synthesized. It has broad and potent antivacterial activity in vitro. The antibacterial spectrum reflects contributions of both the cephalosporin moiety and the quinolone moiety. Thus, this compound was named DACD implying a dualaction cephalosporin derivative. In this paper, the physicochemical properties (lipid-water partition, pKa), stability and pharmacokinetics of DACD were determined and compared with cefotaxime 3’’-norfloxacin dithiocarbamate (CENO). Stability tests were studied in pH 1.20, 6.80 and 8.00 buffers and in the presence of AB type human plasma, rat liver homogenate and its beta-lactamase. The pharmacokinetic parameters of DACD were evaluated in mice after a single intravenous dose of 40mg/kg. The results are as follows. The lipid-water partition coefficient of DACD was higher than that of CENO. The calculated pKa values of CENO and DACD, were 6.82 +/- 0.03, 7.53 +/- 0.21, respectively. In the hydrolysis test, half-lives (t1/2) of CENO and DACD was 66.0 hr and 80.0 hr in pH 6.80 buffer, 190 hr and 91.4 hr in pH 8.00 buffer. CENO and DACD were rapidly hydrolyzed in human plasma and in rat liver homogenate. Half-lives (t1/2) of CENO and DACD were 1.29 hr and 1.15 hr in hyman plasma, 0.62 hr and 0.71 hr rat liver homogenate. In beta-lactamase stability test, CENO and DACD were very stable to the beta-lactamases obtained from three different strains. Half-life (t1/2) and areas under the curve (AUC) in mice were 2.33 hr and 15.97 (mg.h/l), respectively.
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