Cholestatic effect of carmustine in rats.
A single i.p. dose of 20 mg/kg of carmustine [1,3-bis-(2-chloroethyl)-1-nitrosourea; BCNU] caused intrahepatic cholestasis in rats within 48 hr of administration. Cholestasis was characterized by a selective reduction of the bile salt independent fraction of bile flow. Increased plasma K+ and decreased plasma Na+ concentrations, consistent with this effect, were observed. Because bile: plasma osmolality and biliary bile salt concentrations were elevated, increased permeability to bile salts and other osmotically active solutes between bile and plasma is unlikely. Bile salt excretion was normal despite the reduced bile flow because biliary bile salt concentration was increased. In contrast, the treated rats were unable to concentrate bromosulfophthalein in bile before, during and after the onset of cholestasis. Because no reduction in hepatic perfusion was observed in vivo in BCNU-treated rats, reduced xenobiotic organic anion excretion may be a selective effect of the drug. The cholestatic effects of BCNU appear to be different from either alpha-naphthylisothiocyanate or estrogenic steroids.
Hoyt
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Department of Pharmacology and Toxicology, College of Pharmacy, Oregon State University, Corvallis.
Larson
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D000818:Animals; D001646:Bile / Q000187:drug effects; D002330:Carmustine / Q000494:pharmacology*; D002779:Cholestasis / Q000139:chemically induced*; D004573:Electrolytes / Q000378:metabolism; D004896:Erythritol / Q000493:pharmacokinetics; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D009994:Osmolar Concentration; D010539:Permeability; D051381:Rats; D011919:Rats, Inbred Strains; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D013448:Sulfobromophthalein / Q000493:pharmacokinetics
D004573:Electrolytes; D013448:Sulfobromophthalein; D000254:Sodium-Potassium-Exchanging ATPase; D004896:Erythritol; D002330:Carmustine