Pharmacokinetics of prulifloxacin. 2nd communication: 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 ((+/-)-6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-car boxylic acid, CAS 123447-62-1, NM441) is a prodrug of a new quinolone carboxylic acid antibacterial agent, NM394 (CAS 112984-60-8). The pharmacokinetics of radioactivity after repeated oral administration of 14C-NM441, the effects of NM441 on hepatic drug-metabolizing enzyme activities after repeated oral administration of NM441, and the transfer of radioactivity into the fetus and milk after a single oral administration of 14C-NM441 were investigated in rats. 1. The plasma concentration of radioactivity 6 h after each oral dose of 14C-NM441 (20 mg/kg) to male rats once a day for 21 days was almost constant. There was no marked difference 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 administration did not differ from the corresponding values after a single administration. The concentration of radioactivity 8 h after each dose had reached a plateau in most tissues by the 14th administration. After the 21st dose, the radioactivity concentration in most tissues decreased along with the plasma concentration, whereas a slower elimination was observed in the skin and bone. 2. Repeated oral administration of 20 or 200 mg/kg of NM441 to male rats did not affect hepatic drug-metabolizing enzyme activities. 3. In pregnant rats, the maximum concentration of radioactivity in the fetus was lower than that in the maternal plasma. Furthermore, the total amount of radioactivity in the fetus was only 0.01% of the dose at 0.5 h. 4. In lactating rats, the concentration of radioactivity in the milk was substantially higher than in the plasma. 5. In conclusion, repeated administration of NM441 did not alter its pharmacokinetics, and no evidence was found that it accumulated in the body. Furthermore, there was little placental transfer. These characteristics add to the suitability of NM441 as an effective prodrug of NM394.
Okuyama
Y
Y
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Momota
K
K
Morino
A
A
D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001345:Autoradiography; D001711:Biotransformation; D004148:Dioxolanes / Q000493:pharmacokinetics* / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D005260:Female; D024841:Fluoroquinolones; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D008892:Milk / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011247:Pregnancy; D015363:Quinolones / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000890:Anti-Infective Agents; D004148:Dioxolanes; D024841:Fluoroquinolones; D010879:Piperazines; D015363:Quinolones; C074191:prulifloxacin