Alteration in the biliary and urinary excretion of acetaminophen metabolites by nephrotoxicants in rats.
It has been shown that ureter ligation increases the biliary excretion of acetaminophen (AA) conjugates, mainly as the sulfate in rats. This study was conducted to examine the effect of nephrotoxicants-that induce renal damage without liver injury on the biliary and urinary excretion of AA metabolites. Renal damage was produced in male S.D. rats, 1 day after dosing with 200 mg/kg p.o. of hexachloro-1,3-butadiene (HCBD), or 3 day after the dosage of 7.5 mg/kg iv of cisplatin (CIS). Renal damage without liver injury was confirmed by measuring serum enzymes, creatinine and BUN levels. AA and its metabolites were measured for 3 hr by HPLC in rats injected iv with 150 mg/kg of AA. The excreted amounts of AA-glucuronide (AA-G), AA-sulfate (AA-S) and AA-glutathione into bile were reduced to 57, 18 and 73% of control rats, respectively, by HCBD. HCBD pretreatment also altered the urinary excretion of AA-G, AA-S and AA-mercapturate to 75, 14 and 118% of controls. CIS drastically reduced the urinary excretion of AA metabolites, whereas this compound significantly enhanced the biliary excretion of AA-S. However, CIS did not cause an increase in the percentage of the dose excreted as AA-G in bile. Both HCBD and CIS caused marked elevations in the blood concentrations of AA-G and AA-S. These findings suggest that: 1) not all renal malfunction results in increased biliary excretion of AA metabolites to compensate for the lack of renal elimination, and 2) the selective reduction in biliary and urinary excretion of AA-S by HCBD appears to occur by mechanism(s) other than through alteration of AA and its metabolites.
Seo
K W
KW
Department of Toxicology, Korea Food and Drug Administration, Seoul, Korea.
Choung
S Y
SY
Park
K S
KS
Kim
H J
HJ
D000082:Acetaminophen / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D001219:Aspartate Aminotransferases / Q000097:blood; D001646:Bile / Q000737:chemistry / Q000378:metabolism*; D001806:Blood Urea Nitrogen; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D002070:Butadienes; D005659:Fungicides, Industrial; D000082:Acetaminophen; D003404:Creatinine; C001335:hexachlorobutadiene; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002945:Cisplatin