PHARMACOKINETICS OF PRULIFLOXACIN .1. ABSORPTION, DISTRIBUTION AND EXCRETION IN RATS, DOGS AND MONKEYS AFTER A SINGLE ADMINISTRATION

The pharmacokinetics of prulifloxacin o-1-methyl-7-[4-(5-methyl-2-oxo- 1,3-dioxolen-4-yl) -oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, CAS 123447-62-1, NM441) a quinolone antibacterial prodrug, was i nvestigated after i.v. (C-14-NM394, CAS 112984-60-8) or oral (C-14-NM4 41) administration to rats, dogs and monkeys. 1. C-14-NM441 was absorb ed mainly from the upper small intestine and then metabolized to NM394 partly in the intestinal membrane but mainly in the portal blood and liver. Thus NM441 was not detected in the systemic circulation. 2. Aft er i.v. administration of C-14-NM394 (5 mg/kg), the plasma concentrati on of radioactivity decreased biexponentially, and the elimination hal f-life in rats, dogs and monkeys was 4.2, 5.8 and 7.0 h, respectively. After oral administration of C-14-NM441 (20 mg/kg), the plasma concen tration of radioactivity reached a maximum at 0.7-3.3 h, and thereafte r decreased as observed after i.v. administration of C-14-NM394. An ef fect of food on the absorption of NM441 was found. No clear sex-relate d differences were observed in the plasma concentration profiles of ra ts. 3. The concentration of radioactivity in most tissues of rats reac hed a maximum within 1 h after oral administration of C-14-NM441 and t hereafter decreased along with the plasma concentration. At 0.5 h, the radioactivity concentrations were highest in the liver and kidney, mo derately high in the spleen, pancreas, lung and mandibular gland and e xtremely low in the cerebrum and cerebellum.4. The radioactivity in th e excreta collected over a 96-h period was 95-98 % of the oral dose (u rine, 22-32 %; feces, 64-75 %) in rats, dogs and monkeys. 35 % of the radioactivity administered was excreted in the bile of rats during a 4 8-h period after oral administration, and only a small portion of the biliary radioactivity was reabsorbed. 5. The proportion of C-14-NM394 that bound to serum proteins in vitro in rats, dogs, monkeys and human s was 41-59 % in a concentration range of 0.1-10 mu g/ml.