Christenson J G, Chan K K, Cleeland R, Dix-Holzknecht B, Farrish H H, Patel I H, Specian A
Roche Research Center, Nutley, New Jersey 07110.
Antimicrob Agents Chemother. 1990 Oct;34(10):1895-900. doi: 10.1128/AAC.34.10.1895.
Ro 23-9424 is a dual-action cephalosporin with an aminothiazolylmethoxyimino-type side chain at the 7 position and fleroxacin esterified at the 3' position. The new compound has broad and potent antibacterial activity in vitro and in vivo, reflecting contributions from both the beta-lactam moiety and the quinolone moiety. In animals, the ester bond potentially could be hydrolyzed enzymatically or nonenzymatically, to yield the active metabolites desacetylcefotaxime and fleroxacin. The extent to which Ro 23-9424 acts in vivo as a true dual-action cephalosporin, or acts as a combination of active metabolites, is therefore a function of its pharmacokinetic properties. To investigate these properties, Ro 23-9424 was administered as a single intravenous dose of 20 mg/kg of body weight to mice, rats, dogs, and baboons. Timed plasma samples were assayed by an ion-paired high-pressure liquid chromatography method that allowed detection of both intact Ro 23-9424 and fleroxacin. The pharmacokinetic parameters of Ro 23-9424 were similar to published results for cefotaxime, while concentrations of fleroxacin in plasma were low and fairly constant (about 1 to 3 micrograms/ml) in all species, suggesting that excretion of the intact molecule is a major route of elimination for Ro 23-9424, as it is for cefotaxime. For technical reasons, urinary recovery of Ro 23-9424 was not quantitated, but intact Ro 23-9424 was found in high concentrations (greater than 400 micrograms/ml) in mouse urine aspirated directly from the bladder. In all species, low concentrations of free fleroxacin in plasma persisted after the elimination of Ro 23-9424 was complete, but fleroxacin did not accumulate unduly in a 14-day multiple-dose experiment in baboons. Thus, it seems likely that the activity seen in vivo is primarily due to intact Ro 23-9424, although the low levels of free fleroxacin may also have some therapeutic significance.
Ro 23-9424是一种双效头孢菌素，其7位带有氨噻唑基甲氧基亚氨基型侧链，3'位与氟罗沙星酯化。这种新化合物在体外和体内均具有广泛而强效的抗菌活性，这反映了β-内酰胺部分和喹诺酮部分的共同作用。在动物体内，酯键可能会通过酶促或非酶促方式水解，生成活性代谢产物去乙酰头孢噻肟和氟罗沙星。因此，Ro 23-9424在体内作为真正的双效头孢菌素发挥作用，还是作为活性代谢产物的组合发挥作用，取决于其药代动力学特性。为了研究这些特性，给小鼠、大鼠、狗和狒狒静脉注射单剂量20 mg/kg体重的Ro 23-9424。通过离子对高压液相色谱法对定时采集的血浆样本进行检测，该方法能够检测完整的Ro 23-9424和氟罗沙星。Ro 23-9424的药代动力学参数与已发表的头孢噻肟结果相似，而在所有物种中，血浆中氟罗沙星的浓度都很低且相当恒定（约1至3微克/毫升），这表明完整分子的排泄是Ro 23-9424的主要消除途径，头孢噻肟也是如此。由于技术原因，未对Ro 23-9424的尿回收率进行定量，但在直接从膀胱抽取的小鼠尿液中发现了高浓度（大于400微克/毫升）的完整Ro 23-9424。在所有物种中，当Ro 23-9424的消除完成后，血浆中仍存在低浓度的游离氟罗沙星，但在狒狒的14天多剂量实验中，氟罗沙星并未过度蓄积。因此，尽管游离氟罗沙星水平较低可能也具有一定的治疗意义，但体内观察到的活性似乎主要归因于完整的Ro 23-9424。
