N-acetylpenicillamine potentiated excretion of methyl mercury in rat bile: influence of S-methylcysteine

N-acetylpenicillamine, 5 mmol/kg body weight increased biliary excretion of methyl mercury more than three fold. Upon simultaneous administration of the same dose of N-acetylpenicillamine and 2,5 mmol/kg body weight of S-methylcysteine biliary excretion of methyl mercury increased only 1.5 fold. In both cases biliary sulfhydryl concentration increased to the same extent, about 5 fold. Decreased biliary excretion of methyl mercury, as a result of liver depletion of reduced glutathione by cyclohexene oxide, could be restored by N-acetylpenicillamine. This restoration could be depressed by S-methylcysteine. The experiments undertaken indicate that N-acetylpenicillamine potentiated methyl mercury excretion occurs by a glutathione S-transferase dependent mechanism. Bile, collected after successive administration of methyl mercuric chloride, cyclohexene oxide, S-methylcysteine and N-acetylpenicillamine contained the methyl mercuric derivatives of N-acetylpenicillamine and glutathione together with other methyl mercury carrying components not present in control bile. Whether these components play any role in the mechanism of N-acetylpenicillamine potentiated methyl mercury excretion cannot be stated from the present investigation.     

Excretion of methyl mercury in rat bile: the effect of diethylmaleate, cyclohexene oxide and acrylamide

Diethylmaleate, cyclohexene oxide and acrylamide administered intraperitoneally to rats, have been shown markedly to inhibit biliary excretion of methyl mercury. Simultaneously the sulphhydryl and sulphide content of the bile decreases. These results probably reflect the conjugation of acrylamide, diethylmaleate and cyclohexene oxide to glutathione in the liver, thereby blocking the biliary excretion of methyl mercury. A high concentration of liver glutathione seems to be a prerequisite for the normal translocation of methyl mercury from liver to bile. These results indicate that methyl mercury is transported from liver to bile as a glutathione complex.     

7V-Acetylpenicillamine Potentiated Excretion of Methyl Mercury in Rat Bile: Influence of S-Methylcysteine

Abstract: N-acetylpenicillamine, 5 mmol/kg body weight increased biliary excretion of methyl mercury more than three fold. Upon simultaneous administration of the same dose of N-acetylpenicillamine and 2,5 mmol/kg body weight of S-methylcysteine biliary excretion of methyl mercury increased only 1.5 fold. In both cases biliary sulfhydryl concentration increased to the same extent, about 5 fold. Decreased biliary excretion of methyl mercury, as a result of liver depletion of reduced glutathione by cyclohexene oxide, could be restored by N-acetylpenicillamine. This restoration could be depressed by S-methylcysteine. The experiments undertaken indicate that N-acetylpenicillamine potentiated methyl mercury excretion occurs by a glutathione S-transferase dependent mechanism. Bile, collected after successive administration of methyl mercuric chloride, cyclohexene oxide, S-methylcysteine and N-acetylpenicillamine contained the methyl mercuric derivatives of N-acetylpenicillamine and glutathione together with other methyl mercury carrying components not present in control bile. Whether these components play any role in the mechanism of N-acetylpenicillamine potentiated methyl mercury excretion cannot be stated from the present investigation.     

The Effect of Selenium on the Biliary Excretion and Organ Distribution of Mercury in the Rat after Exposure to Methyl Mercuric Chloride

Abstract The influence of selenium compounds on the biliary excretion and the organ distribution of mercury after injection of methyl mercuric chloride (4 μmol/kg) have been tested. Selenite, seleno-di-N-acetylglycine and seleno-methionine strongly inhibited the biliary excretion of mercury. Selenite even in a molar dose of 1/40 of the methyl mercury dose inhibited the biliary excretion of mercury. The less toxic seleno-di-N-acetylglycine was needed in larger molar doses and did not act as rapidly as selenite. Biliary excreted methyl mercury is known to be partly reabsorbed in the gut. Subsequently a part of it is deposited in the kidneys since drainage of the bile lowered the kidney content of mercury. Rats given selenium compounds in combination with bile drainage showed further reduction of the kidney mercury content than bile duct drainage alone. Thus the demonstrated lowering effect of selenium compounds on the kidney mercury content cannot be completely explained by an inhibition of biliary excretion of mercury. The mercury concentration in the brain was increased by the selenium compounds; the effect being dependent of the selenium dose reaching a maximum at an equimolar selenite - to methyl mercury dose ratio. The mechanisms by which selenium influences the methyl mercury kinetics are discussed.     

The effect of selenium on the biliary excretion and organ distribution of mercury in the rat after exposure to methyl mercuric chloride.

The influence of selenium compounds on the biliary excretion and the organ distribution of mercury after injection of methyl mercuric chloride (4 mumol/kg) have been tested. Selenite, seleno-di-N-acetylglycine and seleno-methionine strongly inhibited the biliary excretion of mercury. Selenite even in a molar dose of 1/40 of the methyl mercury dose inhibited the biliary excretion of mercury. The less toxic seleno-di-N-acetylglycine was needed in larger molar doses and did not act as rapidly as selenite. Biliary excreted methyl mercury is known to be partly reabsorbed in the gut. Subsequently a part of it is deposited in the kidneys since drainage of the bile lowered the kidney content of mercury. Rats given selenium compounds in combination with bile drainage showed further reduction of the kidney mercury content than bile duct drainage alone. Thus the demonstrated lowering effect of selenium compounds on the kidney mercury content cannot be completely explained by an inhibition of biliary excretion of mercury. The mercury concentration in the brain was increased by the selenium compounds; the effect being dependent of the selenium dose reaching a maximum at an equimolar selenite--to methyl mercury dose ratio. The mechanisms by which selenium influences the methyl mercury kinetics are discussed.     

Role of glutathione and hepatic glutathione S-transferase in the biliary excretion of methyl mercury, cadmium and zinc: a study with enzyme inducers and glutathione depletors

The effect of hepatic glutathione (GSH) depletion and enzyme induction on hepatic glutathione S-transferase (GST) activity, biliary excretion of GSH, methyl mercury, cadmium and zinc was studied in rats. The GSH depletors, methyl iodide and diethyl maleate, did not influence hepatic GST activity but, depending on the substrate used, benzo(a)pyrene, phenobarbital, pregnenolone-16 alpha-carbonitrile (PCN) and trans-stilbene oxide (TSO) increased it by 16-33, 44-89, 53-97 and 208-279%, respectively. GSH depletors decreased (-88%), benzo(a)pyrene and TSO did not affect, phenobarbital and PCN increased (+113 and +149%) the transport of GSH into bile. The biliary excretion of methyl mercury, cadmium and zinc was reduced by GSH depletors (-97, -74 and -93%), and enhanced by phenobarbital (+139, +280 and +220%) and PCN (+150, +121 and +160%). Treatment with benzo(a)pyrene and TSO did not affect the excretion of methyl mercury and zinc into bile, but decreased that of cadmium. These results do not provide evidence for the role of hepatic GST but strongly support the importance of biliary GSH excretion in the hepatobiliary transport of methyl mercury, cadmium and zinc. It is assumed that phenobarbital and PCN enhance the biliary excretion of these metals by increasing the transport of GSH, the carrier molecule, from liver to bile.     

Slow biliary elimination of methyl mercury in the marine elasmobranchs, Raja erinacea and Squalus acanthias

The present study examined the ability of two marine elasmobranchs (Raja erinacea, little skate, and Squalus acanthias, spiny dogfish shark) to excrete methyl mercury into bile, a major excretory route in mammals. 203Hg-labeled methyl mercury chloride was administered via the caudal vein, and bile collected through exteriorized cannulas in the free swimming fish. Skates and dogfish sharks excreted only a small fraction of the 203Hg into bile over a 3-day period: in the skate, the 3-day cumulative excretion (as a % of dose) was 0.44 +/- 0.10 (n = 4, +/- SD), 0.71 +/- 0.23 (n = 6), and 1.00 +/- 0.34(n = 4) for doses of 1, 5, and 20 mumol/kg, respectively, while the shark excreted only 0.15 +/- 0.15% (n = 8) at a dose of 5 mumol/kg. As in mammals, the availability of hepatic and biliary glutathione was a determinant of the biliary excretion of methyl mercury in these species: the administration of sulfobromophthalein, a compound known to inhibit both glutathione and methyl mercury excretion in rats, or of L-buthionine-S,R-sulfoximine, an inhibitor of glutathione biosynthesis, decreased the biliary excretion of both glutathione and mercury in the skate. The slow hepatic excretory process for methyl mercury in the skate and shark was attributed to an inordinately slow rate of bile formation: from 1 to 4 ml/kg X day. An inefficient biliary excretory process in fish may account in part for the long biological half-times for methyl mercury in marine species.     

Excretion of Methyl Mercury in Rat Bile: The Effect of Thioctic Acid,Thionalide, Hexadecyl- and Octadecylmercaptoacetate

Abstract: Thioctic acid markedly increases the sulfhydryl and sulphide content of bile. This probably reflects the reduction of thioctic acid in the liver, followed by biliary excretion of a reduced derivative. The total biliary excretion of methyl mercury was not increased. Thionalide markedly inhibits biliary excretion of methyl mercury. Simultaneously, the sulfhydryl and sulphide content of bile decreases. This is probably caused by the conjugation of thionalide to glutathione in the liver, thereby blocking the biliary excretion of methyl mercury. Hexadecylmercaptoacetate increases the biliary content of methyl mercury moderately after a temporary decrease, whereas biliary sulfhydryl and sulphide concentrations were unchanged. Octadecylmercaptoacetate does not change the biliary content of methyl mercury, sulfhydryl and sulphides significantly. Smaller parts of hexadecylmercaptoacetate, octadecylmercaptoacetate and thionalide seemed to be excreted as such in bile. These results indicate that methyl mercury cannot be transported from liver to bile as complexed to the sulphides thioctic acid, thionalide, hexa- and octadecylmercaptoacetate.     

N-acetylpenicillamine potentiation of biliary excretion of methyl mercury: influence of glutathione depletors

The effect of 1-chloro-2,4-dinitrobenzene (DNB), sulfobromophtalein (BSP) and cyclohexene oxide (cho) on N-acetylpenicillamine (NAPA) potentiated biliary excretion of methyl mercury in rats pretreated with cho for liver glutathione (GSH) depletion, has been tested. DNB, BSP and cho depressed NAPA potentiation of methyl mercury excretion in bile, while simultaneously biliary sulfhydryl concentration increased, due mainly to a relatively large proportion of unchanged NAPA, being excreted in bile. The fact that relatively large amounts of unchanged NAPA are excreted in bile, without affecting mercury excretion, indicates that NAPA per se cannot carry methyl mercury from liver to bile. In addition to unchanged NAPA, bile collected after administration of NAPA and DNB or BSP contained relatively large amounts of GSH conjugates of DNB or BSP, respectively, together with smaller amounts of GSH and another methyl mercury carrying component. The data are interpreted as suggesting that NAPA potentiation of methyl mercury excretion in bile can be due to an increased availability of GSH. However, it cannot be excluded that methyl mercury carrying components other than GSH and NAPA appearing in bile upon NAPA administration could play a role in NAPA potentiation of methyl mercury excretion in bile.     

The influence of some thiols on biliary excretion of methyl mercury

N-Acetylpenicillamine and thiola increased biliary excretion of methyl mercury and sulfhydryl right after administration. Cysteine increased excretion of methyl mercury in bile after a temporary decrease following administration. During the interval of decreased mercury excretion biliary excretion of cysteine passed through a maximum. This indicates the existence of a common factor of the excretory systems for cysteine and methyl mercury and illustrates that cysteine cannot carry methyl mercury from liver to bile. Relatively large proportions of unchanged thiola and N-acetylpenicillamine were excreted in bile. Bile collected after administration of one of these compounds, in addition to thiola or N-acetylpenicillamine, contained other methyl mercury carrying components not present in control bile. From the experiments undertaken it cannot be stated whether these components play any role in the increased excretion of methyl mercury in bile caused by thiola and N-acetylpenicillamine. The mechanisms of increased biliary excretion of methyl mercury following administration of N-acetylpenicillamine, thiola and cysteine are discussed.     

Disposition of the aromatic amine, benzidine, in the rat: characterization of mutagenic urinary and biliary metabolites

The mutagenic and carcinogenic aromatic amine, benzidine (BZ), underwent extensive biotransformation in the rat. Three days after po (5.0 mg/kg) or iv (2.5 mg/kg administration of [14C]BZ, 90% of the radiolabel had been excreted in the urine (25%) and feces (65%); 7% was recovered in the animal. As the dose was increased from 0.5 to 50 mg/kg, the percentage of the dose excreted in urine increased twofold. In distribution studies, a major portion of the iv dose accumulated in the intestinal tract due to the excretion of 71% of the administered radiolabel in bile. The liver, which is a primary target organ of BZ carcinogenicity in rats, contained a higher concentration of radiolabel than other tissues studied. A minimum of 17 urinary and/or biliary metabolites were separated by HPLC. The major metabolites were N-acetyl-BZ(ABZ), N,N'-diacetyl-BZ(DABZ), BZ-N-glucuronide, ABZ-glucuronide, N-OH-DABZ glucuronide, 3-OH-DABZ glucuronide, and a glutathione conjugate of DABZ (3-GSH-DABZ). At low doses (0.5 to 5 mg/kg), 3-OH-DABZ glucuronide, 3-GSH-DABZ, and DABZ were the major urinary or biliary metabolites. However, at higher doses (50 mg/kg), N-OH-DABZ glucuronide, which was a minor metabolite at low doses, became a major urinary and biliary metabolite. Several urinary and biliary metabolites displayed significant mutagenicity in the Salmonella typhimurium (strain TA98)-liver S9-beta-glucuronidase assay. However, N-OH-DABZ glucuronide exhibited a mutagenic potency 10X greater than the other urinary metabolites. Results of these studies demonstrate that BZ is rapidly metabolized via N-acetylation, N-hydroxylation, and aromatic hydroxylation to a variety of mutagenic metabolites which are excreted in urine or bile primarily as glucuronide and/or glutathione conjugates. The most potent mutagen studied was also a major urinary and biliary metabolite.     

The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity

Following po administration of a nephrotoxic dose (200 mg/kg) of hexachloro-1:3-butadiene (HCBD) to male rats, the principal route of excretion was biliary, 17-20% of the dose being eliminated on each of the first 2 days. Fecal excretion over this period was less than 5% of the dose per day, suggesting enterohepatic recirculation of biliary metabolites. Urinary excretion was small, not exceeding 3.5% of the dose during any 24-hr period. The major biliary metabolite was a direct conjugate between glutathione and HCBD itself. The cysteinylglycine conjugate of HCBD has also been found in bile. Evidence was obtained to show that biliary metabolites of HCBD are reabsorbed and excreted via the kidneys. The glutathione conjugate, its mercapturic acid derivative, and bile containing HCBD metabolites were all nephrotoxic when dosed orally to rats. In common with HCBD, these metabolites caused localized damage to the kidney with minimal effects in the liver. Rats fitted with a biliary cannula were completely protected from kidney damage when dosed with HCBD, demonstrating that hepatic metabolites were solely responsible for the nephrotoxicity of this compound. It is proposed that the hepatic glutathione conjugate of HCBD was degraded to its equivalent cysteine conjugate which was cleaved by the renal cytosolic enzyme beta-lyase to give a toxic thiol which caused localized kidney damage. A urinary sulphenic acid metabolite of HCBD has been identified which is consistent with this hypothesis. The mode of activation of HCBD conjugates in the kidney is believed to be analogous to that proposed for S-(1,2-dichlorovinyl)-L-cysteine.     

Unequal disposition of enantiomers of the organic cation oxyphenonium in the rat isolated perfused liver

This paper describes the results of pharmacokinetic experiments in the rat isolated perfused liver with enantiomers of oxyphenonium. The study was performed with the [14C]methyl labelled compounds. In this preparation both metabolism and biliary excretion were significantly different for the (+)- and the (-)-isomer. Hepatic uptake rate was similar, but total biliary excretion (including metabolites) of the (-)-isomer was only 55% compared with the excretion of the (+)-isomer. In line with these data, after 2 h only 30% of the dose of the (+)-isomer and over 50% of the dose of the (-)-isomer was still found in the liver, predominantly in the form of metabolites. The metabolic profile was investigated using ion pair TLC. At least two metabolites were detected in bile for both enantiomers. However, unchanged (-)-oxyphenonium persisted for longer in bile, indicating either a more rapid canalicular transport of the (+)-isomer and/or a more rapid metabolism of (+)-oxyphenonium to cholephilic metabolites.     

Effect of lipoic acid on biliary excretion of glutathione and metals.

Several metals are excreted in bile as glutathione complexes, and their biliary excretion is facilitated by increased hepatobiliary transport of glutathione. The present study analyzed the effect of lipoic acid (LA; thioctic acid; 37.5-300 mumol/kg, iv), an endogenous disulfide which can be reduced in vivo to a dithiol, on the hepatobiliary disposition of glutathione-related thiols and the biliary excretion of metals (10 mumol/kg, iv) in rats. Administration of LA enhanced the biliary excretion of reduced glutathione in a dose-dependent fashion. Despite increasing glutathione output, LA (150 mumol/kg, iv) did not increase, but rather decreased, the biliary excretion of methylmercury, cadmium, zinc, and copper, which are transported into bile in a glutathione-dependent manner, as indicated by a marked reduction in their biliary excretion after diethyl maleate-induced glutathione depletion. In contrast, biliary excretion of inorganic mercury, which is minimally affected by glutathione depletion, was dramatically enhanced (12- to 37-fold) by LA administration. Following injection of LA, the concentrations of endogenous disulfides in arterial blood plasma (e.g., cystine, glutathione disulfide, cysteine-glutathione, protein-cysteine, and protein-glutathione mixed disulfides) were considerably diminished, while the levels of endogenous thiols (e.g., glutathione and cysteine) were increased. This finding indicates that LA, probably after enzymatic conversion to dihydrolipoic acid, can reduce endogenous disulfides to thiols. It appears that LA induces the transport of glutathione into bile by the temporary formation of dihydrolipoic acid-glutathione mixed disulfide, which after being translocated into bile is cleaved to LA and reduced glutathione. Because the glutathione molecule thus transported into bile cannot complex metals at the thiol group, this might be the mechanism for the observed failure of the LA-induced increase in biliary excretion of glutathione to enhance the hepatobiliary transport of metals that are transported into bile as glutathione complexes (i.e., methylmercury, cadmium, zinc, and copper). The observations also raise the possibility that endogenous dihydrolipoic acid, by forming a stable complex with mercuric ion, may play the role of a carrier molecule in the hepatobiliary transport of inorganic mercury.     

Studies on the fate of the glutathione and cysteine conjugates of acetaminophen in mice

Studies were conducted in mice to examine the origin and fate of the amino acid-containing conjugates of acetaminophen (APAP). Collection of bile containing [14C]APAP metabolites (mainly the glutathione conjugate) in common duct-cannulated mice given a 250 mg/kg oral dose of the drug reduced by greater than 70% the urinary excretion of the cysteine and mercapturic acid conjugates of APAP. This confirmed previous reports which indicated that these urinary metabolites originated from the glutathione conjugate excreted in bile. The urinary excretion of cysteine and mercapturic acid conjugates was not altered, however, by ligation of the common bile duct in mice given APAP. Thus, biliary excretion of the glutathione conjugate is not obligatory for the appearance of cysteine and mercapturic acid conjugates in urine. Intravenous administration of purified glutathione conjugate to mice having a bile-duct cannula indicated that this conjugate did not appear in bile but appeared in urine primarily in the form of the cysteine conjugate. An identical pattern of excretion was observed after an iv dose of the purified cysteine conjugate of APAP to bile duct-cannulated mice. These results indicated that, if the glutathione conjugate leaves the liver via the blood, it is rapidly converted to the cysteine conjugate which is eliminated in urine. This conversion takes place at multiple sites in the body and evidence is presented to implicate both intestine and kidney in the process. The appearance of a small amount of glutathione conjugate in urine (16%) after an iv dose of the cysteine conjugate indicates that formation of the glutathione of APAP can occur by a route that does not involve direct conjugation of reactive metabolites of the drug with glutathione.     

Impairment of sulfobromophthalein biliary excretion and inhibition of glutathione S-transferase activity induced by perhexiline maleate in rats

The effect of the antianginal agent perhexiline maleate (160 mg/kg i.g., daily for 4 days) on the biliary excretion of sulfobromophthalein (BSP) and BSP-glutathione and the hepatic activity of glutathione S-transferases was investigated in Wistar rats. Perhexiline maleate caused a significant reduction in the maximal biliary excretion of BSP (-28%). The decrease corresponded to a lowered excretion of the conjugated dye whereas the excretion of the parent compound did not change significantly. Administration of the drug caused no effect on the maximal biliary excretion of infused BSP-glutathione. Liver glutathione concentrations were similar in control and treated rats. Perhexiline maleate significantly reduced liver glutathione S-transferase activities toward BSP (-25%), 3,4-dichloronitrobenzene (DCNB) (-21%) and 1-chloro-3,4-dinitrobenzene (DNCB) (-27%). Kinetic studies of the enzyme in liver cytosol showed that perhexiline maleate induced an uncompetitive inhibition for the BSP substrate with a reduced Vmax and Km. The results indicate that the reduction in glutathione S-transferase activity plays an important role as a factor determining the impairment in the hepatobiliary transport of BSP caused by perhexiline maleate.     

Excretion of Zinc in Rat Bile – A Role of Glutathione

Abstract: Fractionation of the bile from rats injected with ⁶⁵ZnCl₂ (5 μmol/kg) showed that zinc was mainly bound to low molecular weight compounds eluted corresponding to the zinc-glutathione complexes. Diethylmaleate (3.9 mmol/kg), cyclohexene oxide (4.9 mmol/kg) and acrylamide (3.5 mmol/kg) administered intraperitoneally to rats caused a rapid decrease in the endogenous excretion of both zinc and reduced glutathione into bile. This depression probably reflects the conjugation of the aforementioned substances to glutathione in the liver cells. These results indicate that zinc is transferred from liver to bile by glutathione dependent process and most likely as zinc-glutathione complexes.     

Disposition of metals in rats: a comparative study of fecal, urinary, and biliary excretion and tissue distribution of eighteen metals

Fecal (0-4 days), urinary (0-4 days), and biliary (0-2 hr) excretion and tissue distribution of 18 metals were examined in rats after iv administration. Total (fecal + urinary) excretion was relatively rapid (over 50% of dose in 4 days) for cobalt, silver, and manganese; was between 50 and 20% for copper, thallium, bismuth, lead, cesium, gold, zinc, mercury, selenium, and chromium; and was below 20% for arsenic, cadmium, iron methyl mercury, and tin. Feces was the predominant route of excretion for silver, manganese, copper, thallium, lead, zinc, cadmium, iron, and methyl mercury whereas urine was the predominant route of excretion for cobalt, cesium, gold, selenium, and chromium; while both excretion routes were equally important for bismuth, mercury, arsenic, and tin. Biliary excretion seems to be an important determinant for the fecal excretion of silver, arsenic, manganese, copper, selenium, cadmium, lead, bismuth, cobalt, and methyl mercury. Between 45 (silver) and 0.8% (methyl mercury) of the dosages administered of these metals was excreted into bile in 2 hr, and they exhibited high bile/plasma concentration ratios. The biliary excretion of copper, selenium, lead, and chromium did not increase proportionally with dosage, suggesting that the hepatobiliary transport of these metals is saturable. The fraction of dosage excreted into bile was independent of the dosage for silver, arsenic, manganese, bismuth, methyl mercury, mercury, gold, cesium, thallium, and tin, but markedly increased with increase in dosage of cadmium, cobalt, zinc, and iron. The latter phenomenon is probably due to saturation of hepatic (cadmium, zinc) or extrahepatic (iron) metal-binding sites. Comparison of biliary and fecal excretion rates indicates that arsenic and selenium undergo intestinal reabsorption, whereas thallium and zinc enter the feces also by non-biliary routes. Most of the metals reached the highest concentration in liver and kidney. However, there was no direct relationship between the distribution of metals to these excretory organs and their primary route of excretion.     

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

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.     

Biliary excretion of mercury compounds.

The disappearance of ²⁰³Hg from the plasma of rats and its excretion into bile was quantitated for 2 hr after the iv administration of 0.03, 0.1, 0.3, 1.0, and 3.0 mg Hg/kg as ²⁰³mercuric chloride. The concentration of ²⁰³Hg in the bile was usually about 0.66 that in the plasma. The concentration of ²⁰³Hg in the liver was 1.8–3.4 times higher than that in the plasma, and the bile concentration was about three times lower than that in the plasma. Methyl mercuric chloride was given to rats at dosages of 0.1, 0.3, 1.0, and 3.0 mg Hg/kg, iv. The concentration of ²⁰³Hg in bile averaged about nine times higher than that in the plasma, the liver concentration was about 25-fold higher than that in the plasma and the bile concentration about 0.33 that in the liver. Thus the radioactivity associated with either mercuric chloride or methyl mercury were not highly concentrated in bile as are some other heavy metals. Over a 2-hr period, regardless of the dose or the form of Hg administered, less than 0.5% of the dose was excreted into the bile. The effect of 4 days pretreatment with phenobarbital, spironolactone, pregnenolone-16-carbonitrile (PCN), and 3-methylcholanthrene on the biliary excretion of mercuric chloride and methyl mercury was also measured. PCN was the most effective, doubling the amount of ²⁰³Hg excreted into the bile.