Effects of clofibrate and indocyanine green on the hepatobiliary disposition of acetaminophen and its metabolites in male CD-1 mice

Abstract

1. The effects of clofibrate (CFB) and indocyanine green (ICG) on the biliary excretion of acetaminophen (APAP) and its metabolites were investigated. 2. Male CD-1 mice were pretreated with 500 mg CFB/kg, i.p. for 10 days. Controls received corn oil vehicle only. After overnight fasting, common bile duct-cannulated mice were challenged with a non-toxic dose of APAP (1 mmol/kg, i.v.). 3. CFB pretreatment did not affect bile flow rate, nor did it affect the cumulative biliary excretion of APAP and its conjugated metabolites. 4. Additional CFB or corn oil pretreated mice were given 30 mumol indocyanine green (ICG)/kg, i.v., immediately before APAP dosing. ICG is a non-metabolizable organic anion that is completely excreted into the bile through a canalicular transport process for organic anions. 5. ICG significantly decreased the bile flow rate and biliary concentration of APAP-glutathione, APAP-glucuronide and APAP-mercapturate within the first hour after dosing without affecting the biliary concentration of APAP. 6. The results indicate that CFB pretreatment does not affect the total amount of APAP and its metabolites excreted in bile. They also suggest that the biliary excretion of several conjugated metabolites of APAP share the same excretory pathway with the organic anion ICG.

HEPATOBILIARY EXCRETION OF ACETAMINOPHEN GLUTATHIONE CONJUGATE AND ITS DERIVATIVES IN TRANSPORT-DEFICIENT (TR-) HYPERBILIRUBINEMIC RATS

“…Recently, Brouwer and coworkers (Xiong et al, 2000) reported that the biliary excretion of APAP-GLU and, to a lesser extent, APAP-SUL, was impaired in isolated perfused livers from TR Ϫ rats, which indicates the involvement of Mrp2 in the hepatobiliary transport of these two metabolites. Their results are in agreement with our observations that the biliary concentration of APAP-GLU, but not that of APAP-SUL, is significantly decreased by coadministration of the organic anion ICG (Chen et al, 2000). Their studies, however, did not examine the biliary disposition of APAP-GSH and its hydrolytic derivatives, which are reflective of APAP oxidation by cytochrome P450.…”

“…With the recent identification and characterization of several apical and basolateral transporters (Muller and Jansen, 1997), it is now clear that the hepatic levels of some transport systems can be modulated by prototypical microsomal inducers such as pregnenolone 16␣-carbonitrile (Salphati and Benet, 1998), dexamethasone (Courtois et al, 1999), and phenobarbital (Ogawa et al, 2000). Therefore, these types of APAP disposition studies should be interpreted with respect to both xenobiotic inducibility of hepatic transporters and molecular mechanisms for the hepatic excretion of APAP and its metabolites.We recently showed that the biliary concentration of APAP-GSH, APAP-NAC, and APAP-GLU, but not that of APAP itself, APAP-SUL or APAP-CG/CYS, was significantly decreased by coadministration of the nonmetabolizable organic anion indocyanine green (ICG) in male CD-1 mice (Chen et al, 2000). These findings suggest that several APAP conjugates share hepatobiliary transport systems with ICG.…”

“…We recently showed that the biliary concentration of APAP-GSH, APAP-NAC, and APAP-GLU, but not that of APAP itself, APAP-SUL or APAP-CG/CYS, was significantly decreased by coadministration of the nonmetabolizable organic anion indocyanine green (ICG) in male CD-1 mice (Chen et al, 2000). These findings suggest that several APAP conjugates share hepatobiliary transport systems with ICG.…”

“…A reduction in the biliary concentration of APAP-GLU, APAP-GSH, and APAP-NAC produced by coadministration of ICG (Chen et al, 2000) suggests that these APAP metabolites and the model organic anion may be excreted in bile through common transport systems. Since the biliary excretion of ICG is partially impaired in Mrp2-deficient EHBR and TR Ϫ rats (Jansen et al, 1993;Johnson and Klaassen, 2002), it is possible that Mrp2 mediates, at least in part, the biliary excretion of conjugated metabolites of APAP.…”

“…APAP-GSH is the major constituent of APAP metabolites in bile of mice and its biliary concentration was decreased the most by ICG treatment (Chen et al, 2000). The main objective of the present study was to further investigate the involvement of Mrp2 in the biliary excretion of APAP-GSH and its thiol-containing derivatives using bile duct-cannulated TR Ϫ and normal Wistar rats.…”