Comprehensive evaluation of canine renal papillary necrosis induced by nefiracetam, a neurotransmission enhancer.
The effects of nefiracetam, a neurotransmission enhancer, on renal biochemistry and morphology with toxicokinetic disposition were investigated in both in vivo and in vitro systems. In the in vivo studies with rats, dogs, and monkeys, only the dog exhibited renal papillary necrosis. Namely, when beagle dogs were orally administered with 300 mg/kg/day of nefiracetam over 11 weeks, decreased urinary osmotic pressure was noted from week 5, followed by increases in urine volume and urinary lactate dehydrogenase from week 8. The first morphological change was necrosis of ductal epithelia in the papilla in week 8. In toxicokinetics after 3 weeks of repeated oral administration to dogs, nefiracetam showed somewhat high concentrations in serum and the renal papilla as compared with rats and monkeys. As for metabolites, although metabolite-18 (M-18) concentration in the renal papilla of dogs was between that in rats and monkeys, the concentration ratios of M-18 in the papilla to cortex and papilla to medulla were remarkably high. In the in vitro studies, while nefiracetam itself showed no effects on the synthesis of prostaglandin E2 and 6-keto-prostaglandin F1alpha, a stable metabolite of prostaglandin I2, in canine renal papillary slices, only M-18 among the metabolites clearly decreased both prostaglandin syntheses. The basal prostaglandin synthesis in canine renal papillary slices was extremely low relative to those in rats and monkeys. Taken together, certain factors such as basal prostaglandin synthesis, M-18 penetration into the renal papilla leading to an intrarenal gradient, and inhibitory potential of M-18 on prostaglandin synthesis were considered to be crucial for the occurrence of renal papillary necrosis in dogs.
Tsuchiya
Yoshimi
Y
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co, Ltd, 16-13, Kita-kasai 1-chome, Edogawa-ku, Tokyo 134-8630, Japan. tsuchgtc@daiichipharm.co.jp
Takahashi
Yuji
Y
Jindo
Toshimasa
T
Furuhama
Kazuhisa
K
Suzuki
Kazuo T
KT
D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D007681:Kidney Papillary Necrosis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011760:Pyrrolidinones / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D018377:Neurotransmitter Agents; D011760:Pyrrolidinones; C058876:nefiracetam