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.