Renal toxicity of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate in the Wistar rat.
Celiptium (N2-methyl-9-hydroxy-ellipticinium) is an antitumoral agent used to treat bone metastases from breast carcinomas. This new drug appeared to be of great interest because of the absence of hepato- or myelotoxicity. Three different investigators recently mentioned cases of celiptium-induced renal failure. We therefore undertook a study of renal function and morphology in female Wistar rats. Two single i.v. doses (10 or 20 mg/kg) were administered and animals were sacrificed 4, 8, 15, 28 and 60 days after injection. One group of rats received multiple doses, 5 mg/kg/week for 8 weeks. No mortality was observed. With the 10 mg/kg single dose creatinine clearance (Ccr) and urinary enzymes did not change, and tubular lesions were rare. With the 20 mg/kg single dose CCr decreased on day 4 and returned to normal on day 28. Urinary enzyme excretion (AAP, NAG, gamma GT) increased. Renal lesions were diffuse with tubular necrosis, luminal dilation and later (day 28) interstitial cellular infiltration. These lesions persisted on day 60 and appeared to be irreversible. Ultrastructural studies showed numerous large fat droplets in proximal tubular cells. Glycerol concentrations in renal cortex homogenates were increased while phospholipids are slightly decreased. With 5 mg/kg every week (multiple doses) Ccr decreased and tubular lesions similar to the observed with the 20 mg/kg single dose were seen. Thus celiptium induced dose-dependent nephrotoxicity in rats with prolonged tubular alterations.(ABSTRACT TRUNCATED AT 250 WORDS)
Raguenez-Viotte
G
G
INSERM Unité 295-U.E.R. Médecine-Pharmacie, St. Etienne du Rouvray, France.
Dadoun
C
C
Buchet
P
P
Ducastelle
T
T
Fillastre
J P
JP
D000470:Alkaloids / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004611:Ellipticines / Q000633:toxicity*; D005260:Female; D005990:Glycerol / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D050356:Lipid Metabolism; D009929:Organ Size / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000470:Alkaloids; D000970:Antineoplastic Agents; D004611:Ellipticines; D010743:Phospholipids; C027767:elliptinium; D005990:Glycerol