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.

中文翻译：

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Ro 23-9424（一种双作用头孢菌素）在动物体内的药代动力学。

Ro 23-9424是双作用头孢菌素，在7位具有氨基噻唑基甲氧基亚氨基型侧链，在3'位具有酯化的氟罗沙星。新化合物在体外和体内均具有广泛而有效的抗菌活性，这反映了β-内酰胺部分和喹诺酮部分的贡献。在动物中，酯键可能会被酶或非酶水解，从而产生去乙酰头孢噻肟和氟罗沙星的活性代谢产物。因此，Ro 23-9424在体内充当真正的双重作用头孢菌素或作为活性代谢产物的组合的程度是其药代动力学特性的函数。为了研究这些性质，将Ro 23-9424以20 mg / kg体重的单次静脉内剂量给予小鼠，大鼠，狗和狒狒。通过离子对高压液相色谱法测定定时的血浆样品，该方法可检测完整的Ro 23-9424和氟罗沙星。Ro 23-9424的药代动力学参数与头孢噻肟的已公布结果相似，而血浆中氟罗沙星的浓度较低，并且在所有物种中都相当恒定（约1-3微克/ ml），这表明完整分子的排泄是主要的Ro 23-9424的消除途径，如头孢噻肟。由于技术原因，未对Ro 23-9424的尿回收率进行定量，但在直接从膀胱中吸入的小鼠尿液中发现了高浓度（大于400微克/ ml）的完整Ro 23-9424。在所有物种中，Ro 23-9424完全消除后，血浆中的游离氟罗沙星浓度仍然很低，但是在狒狒的14天多剂量实验中，氟罗沙星并未过度积聚。因此，似乎体内可见的活性主要是由于完整的Ro 23-9424，尽管低水平的游离氟沙星也可能具有一定的治疗意义。