Pharmacokinetics, hepatic biotransformation and biliary and urinary excretion of bromosulfophthalein (BSP) in an experimental liver disease mimicking biliary cirrhosis

Abstract

We studied the hepatic handling of bromosulfophthalein in healthy rabbits with hepatic coccidiosis 28 days after an experimental infection with sporulated oocysts of Eimeria stiedai, an experimental model of liver disease histopathologically resembling primary biliary cirrhosis in man. A pharmacokinetic study of the results was performed following a multicompartmental model with 7 transfer constants to describe the physiological disposition of the dye. The study showed that the plasma disappearance, distribution volume (Vi), hepatic biotransformation and the biliary and urinary elimination of conjugated (BSPc) and unconjugated (BSPu) bromosulfophthalein were markedly altered. Whereas Vi and urinary excretion of the dye were significantly increased, the hepatic clearance, biotransformation and biliary excretion of BSPc and BSPu were drastically reduced in infected rabbits. Satisfactory agreement was obtained between the experimental and estimated data, particularly those relating to biotransformation clearance and biliary and urinary excretion of the dye. These results demonstrate that severe liver disease in rabbits with histopathological liver alterations resembling several hepatic dysfunctions in man markedly reduce hepatic uptake, metabolism and biliary excretion of a xenobiotic such as BSP.

Acid-base disturbances in the rabbit during experimental hepatic parasitosis

“…It has been reported that lactic acidosis generally occurs in the presence of severe hepatic damage and in conjunction with other metabolic alterations in the liver cells (Kaehny 1983;Oster and Pérez 1986); our morphological observations and plasma biochemistry data show severe hepatocellular damage, and other studies have demonstrated equally important metabolic and functional alterations in the liver during hepatic coccidiosis (Esteller et al 1990;Hoening et al 1974;Jiménez et al 1991a, b;Smetana 1933). Thus, it is probable that hepatic uptake and/or disposal of lactate is reduced, since some authors have suggested that the fall in systemic pH could inhibit lactate uptake by the liver (Saez et al 1985) and, among other causes of lactic acidosis, an inhibition of gluconeogenesis from lactate has also been proposed (Iles et al 1977).…”

“…The plasma bilirubin concentration and the specific activities of γ-GT, AST, ALT, and LDH were significantly higher in the IR group in relation to the controls. Hepatomegaly, hyperbilirubinemia, and changes in plasma levels of several enzymes have previously been reported by other authors during hepatic coccidiosis in the rabbit (Barriga and Arnoni 1981;Esteller et al 1990;Gómez-Bautista et al 1985. Figure 1 shows the blood values of pH, bicarbonate concentrations, and pO 2 and pCO 2 determined in healthy rabbits and in infected rabbits after 28 days of experimental infection.…”

“…Since acidosis is far less prevalent than alkalosis (13% versus 71%) in chronic liver disease in humans, with morphological and physiopathological changes being similar to those observed in rabbits with hepatic coccidiosis (Esteller et al 1990;Kreisberg 1980;Oster and Pérez 1986;Picchiotti et al 1994;Rosmini and Simoni 1979;Smetana 1933), this alteration of the acid-base homeostasis in this model differs noticeably from that clinically established as a general pattern in the terminal phases of such diseases.…”

“…Among other alterations, the following are outstanding: hepatomegaly, hypertrophy and hyperplasia of the bile ducts, periportal fibrosis, alteration and disorganization of the hepatic parenchyma, as well as portal hypertension, hypercholeresis, and ascites; hyperbilirubinemia, hypoproteinemia, elevation in transaminase levels, and other signs arising from hepatocellular dysfunction are also common abnormalities (Barriga and Arnoni 1981;Esteller et al 1990;Gómez-Bautista et al 1985Hein and Lammler 1978;Martine and Yvore 1974). In humans, alterations similar to those appearing in hepatic coccidiosis are observed in chronic liver diseases such as cirrhosis, congenital hepatic fibrosis, sclerosing cholangitis, and primary biliary cirrhosis, among others (García-Tsao 1995; Greenwel et al 1994;Jaskiewicz and Hall 1995;Kirsch et al 1995).…”

“…We have previously observed that in healthy rabbits a close relationship exists between plasma and biliary lactate levels (Jiménez et al 1986) and that during hepatic coccidiosis the biliary secretion of HCO 3 -and the hepatobiliary transport of several endogenous and exogenous organic anions are profoundly altered (Esteller et al 1990;Jiménez et al 1991a, b).…”