PHARMACOKINETICS OF PRULIFLOXACIN .2. PHARMACOKINETICS AND EFFECT ON HEPATIC DRUG-METABOLIZING ENZYME-ACTIVITIES AFTER REPEATED ADMINISTRATION AND TRANSFER INTO FETUS AND MILK AFTER A SINGLE ADMINISTRATION IN RATS

Prulifloxacin -oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid, CAS 123447-62-1, NM441) is a prodrug of a new quinolone carboxylic ac id antibacterial agent, NM394 (GAS 112984-60-8). The pharmacokinetics of radioactivity after repeated oral administration of C-14-NM441, the effects of NM441 on hepatic drug-metabolizing enzyme activities after repeated oral administration of NM441, and the transfer of radioactiv ity into the fetus and milk after a single oral administration of C-14 -NM441 were investigated in rats. 1. The plasma concentration of radio activity 6 h after each oral dose of C-14-NM441 (20 mg/kg) to male rat s once a day for 21 days was almost constant. There was no marked diff erence in the plasma concentration-time curves for radioactivity after the single, 7th, 14th or 21st administration. The averaged cumulative urinary and fecal excretion of radioactivity during repeated administ ration did not differ from the corresponding values after a single adm inistration. The concentration of radioactivity 8 h after each dose ha d reached a plateau in most tissues by the 14th administration. After the 21st dose, the radioactivity concentration in most tissues decreas ed along with the plasma concentration, whereas a slower elimination w as observed in the skin and bone. 2. Repeated oral administration of 2 0 or 200 mg/kg of NM441 to male rats did not affect hepatic drug-metab olizing enzyme activities. 3. In pregnant rats, the maximum concentrat ion of radioactivity in the fetus was lower than that in the maternal plasma. Furthermore, the total amount of radioactivity in the fetus wa s only 0.01 % of the dose at 0.5 h. 4. In lactating rats, the concentr ation of radioactivity in the milk was substantially higher than in th e plasma. 5. In conclusion, repeated administration of NM441 did not a lter its pharmacokinetics, and no evidence was found that it accumulat ed in the body. Furthermore, there was little placental transfer. Thes e characteristics add to the suitability of NM441 as an effective prod rug of NM394.