Biliary excretion of silver in the rat, rabbit, and dog.

The fecal elimination of silver is more important than urinary elimination. Within 4 days after iv administration of silver to the rat (0.1 mg/kg), 70% is excreted into the feces and less than 1% into the urine. The disappearance of ¹¹⁰Ag from the plasma and its excretion into the bile were measured for 2 hr after the iv administration of 0.01, 0.03, 0.1, and 0.3 mg/kg of silver to rats. The concentration of silver in the bile was 16–20 times higher than that of the plasma. With the two lower doses of silver used, the overall plasma-to-bile gradient was due almost equally to the plasma-to-liver gradient and the liver-to-bile gradient and with the two higher doses of silver the liver-to-bile gradient became more important. Marked species variation in the biliary excretion of silver was observed. Rabbits excreted silver at a rate about $\text{1}\text{10}$, and dogs excreted silver at a rate about $\text{1}\text{100}$ of that observed in the rat. These results suggest that while species variation exist, biliary excretion is an important route for the elimination of silver.     

Biliary excretion of arsenic in rats,rabbits, and dogs

The disappearance of ⁷⁴As from blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.01, 0.46, 1.0, 2.1, and 4.6 mg/kg of arsenic given as the trichloride. Arsenic disappearance from plasma was biphasic; the half-life during the late phase was greater than 2 hr. Even though the arsenic was injected iv, the concentration in the blood increased through the first 2 hr. Arsenic was rapidly excreted into the bile, reaching its highest rate of excretion 6 min after administration, after which it rapidly decreased. This rapid decrease in excretion is due to redistribution of arsenic from the liver to the blood. Arsenic enters bile against an apparent bile/plasma concentration gradient of 630, 8 min after 1 mg/kg of arsenic. At this time the liver/plasma gradient is 17 and the liver/bile gradient is 37. Twenty-five percent of the arsenic administered to bile duct-cannulated rats is excreted into the bile within 2 hr. However, less than 10% of the administered dose is excreted into the feces of intact rats over a 7-day period. In the rabbit and dog, arsenic is excreted into the bile at a much slower rate. These data demonstrate that arsenic is excreted into the bile, and this occurs against a large bile/plasma concentration gradient in rats, suggesting excretion by an active transport mechanism. However, the overall importance of bile as a route of elimination for arsenic is minimized due to enterohepatic circulation and species variations in its biliary excretion rate.     

Efficient biliary excretion of susalimod, probably via the bromosulphthalein carrier, studied in a chronic bile fistula model in dogs

Susalimod is a structural analogue of sulphasalazine, known to be extensively excreted in the bile in various animal species and for inducing bile duct hyperplasia after long-term treatment of the dog with doses exceeding 25 mg kg(-1). In this study local concentrations of susalimod in the bile duct were determined after oral administration in dogs. A chronic bile fistula experimental model was designed to affect the bile duct as little as possible. The dogs received repeated oral doses of 25-150 mg kg(-1) day(-1) for 5 days; these doses had been used in previous toxicology studies. Extremely high biliary concentrations of unchanged susalimod (20,000-43,000 microM) were measured. Biliary excretion approached saturation at the higher doses, resulting in super-proportional increases in peripheral plasma concentrations as the dose was increased. The maximal bile/plasma concentration ratio was 4300. The high biliary clearance was indicative of almost complete first-pass elimination at doses below saturation of the elimination process. Interaction studies with the biliary excretion marker bromosulphthalein (BSP) demonstrated that susalimod and BSP probably share the same carrier transport system in biliary excretion. The elimination of BSP from plasma was prolonged 20 times and the biliary excretion rate was markedly reduced when susalimod was co-administered with BSP. These results show that susalimod is highly enriched in the bile, in a saturable manner, after oral administration. The compound interacts with the biliary excretion of BSP, suggesting that it shares the same carrier-mediated transport system.     

The absorption, distribution, metabolism and elimination of bevirimat in rats

Bevirimat is the first drug in the class of maturation inhibitors, which treat HIV infection by disrupting the activity of HIV protease enzyme with a mechanism of action distinct from that of conventional protease inhibitors. The absorption, distribution, metabolism and elimination characteristics of single intravenous (25 mg/kg) and oral (25 mg/kg and 600 mg/kg) doses of 14C-bevirimat were studied in male Sprague Dawley and Long Evans rats. Pharmacokinetic and mass-balance studies revealed that bevirimat was cleared rapidly (within 12-24 h) after dosing, although plasma radioactivity was quantifiable up to 168 h. Radioactive metabolites of bevirimat were responsible for approximately 60-80% of plasma radioactivity. Systemically available bevirimat was predominantly (97%) excreted via bile in the faeces, with 相似文献   

The effects of spironolactone on the biliary excretion of mercury,cadmium, zinc,and cerium in rats

The effect of spironolactone (Sp) pretreatment on the biliary excretion of intravenously injected heavy metals (mercury, cadmium, zinc and cerium) was investigated in rats, using five metal compounds (four inorganic metals in chloride form, and methyl mercuric chloride). The oral administration of Sp ($\text{5 mg}\text{100 g}$) 1–3 hr before the bile excretion study increased the biliary recovery of mercury more than ten times over a period of 4 hr in rats injected with mercuric chloride, but did not increase the biliary excretion of the other three metals (Cd, Zn and Ce). Multiple-dose pretreatment (2 doses a day for 3 days) also increased the biliary excretion of mercury but much less than in the acutely treated rats. Cadmium excretion was significantly decreased by multiple dose pretreatment. Sequential nuclear imagings after intravenous injection of ¹⁹⁷HgCl₂, demonstrated clear differences in the tissue distribution of mercury between control and Sp-treated rats.     

The effect of altered hepatic function on the toxicity, plasma disappearance and biliary excretion of diethylstilbestrol

The present investigation was prompted by the observation that the toxicity of diethylstilbestrol (DES) was about 140 times greater in bile duct-ligated (BDL) rats than in control rats when dimethylsulfoxide was the vehicle (24-hr LD50: 0.75 vs 100 mg/kg, respectively). The DES was also more toxic (about 70 times) in the BDL rats when ethyl alcohol was the solvent (0.47 vs 34 mg/kg), and was 5 times more toxic in the BDL rats when administered in propylene glycol (100 vs 530 mg/kg). Since it appeared that altered hepatic function markedly alters the acute toxicity of DES, the plasma disappearance and biliary excretion of DES (0.118 mg/kg, iv) were measured in control rats and in rats with altered hepatic function (produced by surgical removal of two-thirds of the liver, ip injection of 1 ml CCl₄/kg, or bile duct ligation). All three procedures of altering hepatic function decreased the plasma disappearance of DES. In the BDL rats, the total plasma concentration of DES did not decrease over the 2-hr period, suggesting that even when the biliary route of excretion is blocked, other routes are not efficent for the excretion of DES. During the furst 15 min after DES administration, the biliary excretory rate of DES was 2.1 μg/min/kg in control rats and 1.2 μg/min/kg in the rats that had a $\text{2}\text{3}$ hepatectomy or CCl₄. Therefore, impaired hepatic function increased the plasma concentration and toxicity of DES as it decreased its conjugation and biliary excretion.     

Effects of chronic methadone treatment on bile flow and on metabolism and excretion of 3H-methadone. Experiments with isolated perfused rat livers

Methadone, administered subcutaneously to rats once daily for 12 days, nearly doubled the bile flow rate in isolated perfused livers. The increase in bile flow was accompanied by an increase in the biliary excretion rate of metabolites of ³H-methadone, which was added to the perfusion system at a dose of 1 mg/kg body weight. To determine whether an alteration of the rate of methadone metabolism accounted for this effect, Phenol-3,6-dibromphthalein disulfonate (DBSP), an analogue of BSP which is excreted unchanged in the bile, was added (80 mg/kg) to the perfusion system. It was also excreted at an enhanced rate by the livers of the methadone pretreated rats. Neither the plasma disappearance rate of methadone or DBSP nor the pattern of biotransformation of methadone was significantly affected by the methadone pretreatment. It is concluded that chronic methadone treatment of rats stimulates bile flow via an unknown mechanism, resulting in increased biliary excretion of methadone metabolites and possibly of other compounds which undergo elimination in the bile.     

Influence of experimental renal impairment in the pharmacokinetics of cefoxitin after intravenous administration to rabbits

The pharmacokinetics of cefoxitin have been studied in rabbit with normal renal function or with varying degress of renal impairment caused experimentally by uranyl nitrate, after i.v. administration of a single dose of 40 mg/kg. The plasma concentrations of cefoxitin 12 min after administration were 40 μg/ml in rabbits with normal renal function, and reached 36 μg/ml at 6 h in the case of terminal renal impairment. With respect to the pharmacokinetic parameters established in rabbits with normal renal function: K₁₂, K₂₁ K_e are decreased while there is an increase in t_{$\text{1}\text{2}$}α, t_{$\text{1}\text{2}$}β, V_c, V_p and (AUC)₀^∞ in rabbits with induced renal impairment. Linear relationships have been established between log K_e and serum creatinine. The dose percentage excreted through the kidney in normal rabbits was 85–90%. Biliary excretion of cefoxitin was increased in parallel to the increase in the degree of renal impairment, there being a linear relationship between the dose percentage excreted of the antibiotic and serum creatinine. The values of K_B fell from 1.62 h^?1 to 0.84 h^?1, indicating that the duration of the biliary excretion process of cefoxitin is longer in the case of severe renal impairment.     

The fate of 2,4-dichlorophenoxyacetic acid (2,4-D) following oral administration to man

The pharmacokinetic profile of 2,4-D is defined in man. Five male human volunteers ingested a single dose of 5 mg/kg 2,4-D without detectable clinical effects. Concentration of 2,4-D were determined in plasma in 3 of 5 subjects and in urine in all subjects at intervals after ingestion. The elimination of 2,4-D from plasma in all subjects occurred by an apparent first-order rate process with an average half-life ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$) of 11.6 h. All subjects excreted 2,4-D in the urine with an average $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of 17.7 h. Excretion occurred mainly as 2,4-D (82.3%) with smaller amounts excreted as a 2,4-D conjugate (12.8%). Essentially all of the 2,4-D was absorbed from the gastrointestinal tract in man. Clearance of 2,4-D from the plasma and excretion from the body are first-order rate processes. There was no evidence that 2,4-D would accumulate following repeated administration.     

Pharmacokinetics and Biliary Excretion of Mitoxantrone in Rats

The objective of this investigation was to compare the observed biliary clearance (CL_b) and % of dose excreted in the bile (PD_b) of mitoxantrone with the predicted values obtained from quantitative structure pharmacokinetic relationship (QSPKR) models. Blood and bile samples were collected from bile duct cannulated rats after an intravenous bolus dose of 0.5 or 2 mg/kg mitoxantrone, and the concentrations were measured by HPLC. Mitoxantrone plasma concentrations exhibited a tri‐exponential profile with systemic clearance of 118 ± 6.8 mL/min/kg. After dosing, 6.08 ± 2.32% and 5.69 ± 0.59% of the dose were excreted into bile in unchanged form after a 3‐h collection. CL_b was 7.20 ± 4.54 and 7.46 ± 0.62 mL/min/kg after the two doses. With the co‐administration of 10 mg/kg GF‐120918, a P‐glycoprotein and BCRP inhibitor, PD_b was reduced to 0.69 ± 0.07%, suggesting that BCRP or P‐glycoprotein may play an important role in the biliary elimination of mitoxantrone. Using QSPKR models developed for the biliary excretion of cations/neutral compounds in rats, CL_b and PD_b of mitoxantrone were predicted as 5.18 mL/min/kg and 7.21%, respectively, suggesting that the models could be used to predict the biliary excretion of mitoxantrone. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2502–2510, 2010     

Effects of blockage of urine and/or bile flow on diflunisal conjugation and disposition in rats

1. The effects of surgical blockage of either or both of the urinary and biliary excretion routes on the elimination of diflunisal (DF) and its conjugates were investigated in pentobarbitone-anaesthetized rats given DF at 10mg/kg i.v.

2. In control animals the acyl glucuronide and phenolic glucuronide conjugates were excreted predominantly in bile, whereas the sulphate conjugate was eliminated almost exclusively in urine.

3. Bilateral ureter ligation had little effect on DF elimination, except for accumulation of the sulphate conjugate in plasma. Compensatory biliary excretion did not occur.

4. Total plasma clearance of DF decreased from 1.01 to 0.68 ml/min per kg following bile duct ligation. Plasma concentrations and urinary excretion of the glucuronides were elevated.

5. In rats with blockage of both urinary and biliary excretion routes, total plasma clearance of DF decreased to 0.59 ml/min per kg. Both the sulphate and phenolic glucuronide conjugates accumulated in plasma, whereas the acyl glucuronide peaked at 30 min and then declined in parallel with DF. The latter result indicates systemic instability of DF acyl glucuronide with hydrolytic regeneration of DF as the likely major consequence.     

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.     

Dose-dependent biliary and renal excretion of paracetamol in the rat.

In rats, the biliary and renal excretion of paracetamol changed in a dose-dependent manner. After an oral nonhepatotoxic dose of 200 mg/kg paractamol, the drug excreted in the bile amonted to only 5.5% within 24 h, whereas 72% of the dose were excreted into the urine. Following an oral hepatoxic dose (1,000 mg/kg), the biliary excretion of thotal paracetamol was enhanced to 13.5% whereas the renal elimination was reduced to 51% of the dose. After a nontoxic intravenous treatment with paracetamol (25-100-400 mg/kg), both the excretion of paracetamol conjugates into the bile and the elimination of free paracetamol into the urine were augmented in a dose-dependent manner. Hepatic damage due to carbon tetrachloride pretreatment (0.5 ml/kg i.p. 24 h before 100 mg/kg paracetamol i.v.) diminished both the bile flow and the biliary excretion of paracetamol conjugates, whereas the renal elimination was not affected.     

Biliary excretion of lead in rats rabbits,and dogs

The disappearance of ²¹⁰Pb from the blood and plasma of rats and its excretion into bile was measured for 2 hr after the iv administration of 0.1, 0.3, 1.0, 3.0, or 10 mg/kg of inorganic lead. The maximal rate of excretion of lead into the bile was approximately 1.0 μg/min/kg after the 3 higher doses. The concentration of lead in the bile was found to be 40–100 times that in the plasma for the 3 lower doses. This was due largely to the higher concentration of lead in the liver than in the plasma (10- to 35-fold higher) and partially to the higher concentration in the bile than in the liver (3- to 4-fold higher). Essentially none of the lead in the bile, plasma, and liver was dialyzable. Lead exhibited a 5-fold greater affinity for liver than bile and a 3-fold greater affinity for liver than plasma. The mitochondrial fraction contained the highest concentration of lead. Changing the rectal temperature of rats altered the biliary excretion of lead markedly; when the temperature was increased from 30 to 40°C, the biliary excretion of lead increased 20-fold. Marked species differences in the biliary excretion of lead were observed. Rabbits excreted lead into the bile at a rate less than one-half, and dogs excreted lead at a rate less than one-fiftieth, that observed in the rat. The results indicate that lead is excreted into the bile of rats against an apparent concentration gradient and that an apparent transport maximum exists. This suggests that the liver may have an active transport mechanism for the excretion of metals.     

Elimination of Thioethers Following Administration of Naphthalene and Diethylmaleate to the Rhesus Monkey

ABSTRACT

As a measure of glutathione (GSH) conjugation, urinary, fecal and biliary excretion of thioethers and hepatic GSH content were measured in rhesus monkeys following administration of single doses of naphthalene and diethylmaleate (DEM). Naphthalene had little or no effect on hepatic GSH content and the excretion of thioethers into urine, feces or bile of rhesus monkeys which is similar to that observed in chimpanzees and humans and is in contrast to results obtained from rats. Apparently, conjugation of naphthalene and/or its metabolites with GSH does not play a major role in the metabolism of naphthalene in primates, whereas it is one of the major pathways in rodents. Rhesus monkeys, like chimpanzees, excreted about 13% of the various doses of DEM (30, 75 and 200 mg/kg) as thioethers into urine which is half of that excreted by rats. Six hrs after administration of 200 mg/kg DEM, the hepatic GSH content was decreased by 90% in the rhesus monkey. During the first day after this dose (200 mg/kg), the increase in the excretion of thioethers into bile corresponded to about 15% of the dose of DEM administered. Since fecal excretion of thioethers corresponded to only 1% of the dose and urinary excretion represented 12% of the dose, it appears that biliary thioethers of DEM are reabsorbed from the intestine and then excreted into urine. It appears that the rhesus monkey as well as the chimpanzee is, whereas the rat is not, a good animal model to study GSH-related conjugation reactions with predictive value for man.     

Biliary excretion of nicotinamide riboside. A possible role in the regulation of hepatic pyridine nucleotide dynamics

Female rats fed approximately 5 mg/day/kg of body wt of nicotinic acid-¹⁴C excreted 10 per cent of the daily ingested label in bile and 57 per cent in urine. Approximately two-thirds of the label in bile was present as nicotinamide riboside. Chemical analysis of nicotinamide riboside indicates that about 7 μmoles/day/kg of body wt are excreted into bile. Chemical and radiochemical analyses both indicate that biliary nicotinamide riboside excretion may account for a major fraction of the hepatic pyridine nucleotide turnover. Nicotinamide riboside was not detected in urine, while 1-methylnicotinamide was present in urine but not in bile. Of the daily dietary intake, 6.7 per cent was excreted in bile as nicotinamide riboside while 19.6 per cent was excreted in urine as 1-methylnicotinamide. After intra peritoneal administration of 150 mg/kg of nicotinic acid or 500 mg/kg of nicotinamide, the hepatic NAD⁺ content increases 2 to 4-fold, accompanied by a marked increase in the turnover of this newly formed NAD⁺. The biliary excretion of nicotinamide riboside increases up to ten times the normal rate during this period of increased hepatic NAD⁺ turnover. The nicotinamide riboside excretion appears to be related to the elevation of NAD⁺ and is independent of whether nicotinic acid or nicotinamide is used as the precursor. Comparison of the biliary nicotinamide riboside excretion with published values for the urinary excretion of NAD⁺ metabolites during a similar hepatic NAD⁺ increase indicates that the biliary route may be a major pathway for the elimination of hepatic NAD⁺ metabolites. 1-Methylnicotinamide was not found in bile unless very large intravenous doses were given to animals with ligated renal pedicles. The possible role of the biliary system in pyridine nucleotide dynamics and the possible relation of biliary nicotinamide riboside excretion to the secretion of other organic cations into bile are discussed.     

Influence of Indocyanine Green on Plasma Disappearance and Biliary Excretion of a Synthetic Thrombin Inhibitor of the 3-Amidinophenyl-alanine Piperazide-type in Rats

Purpose. The pharmacokinetics of a number of synthetic peptidomimetic thrombin inhibitors is determined by extensive hepatic elimination. The objective was to further characterize the disposition in vivo of Pefa 1023, a novel 3-amidinophenylalanine piperazide-type thrombin inhibitor, by influencing the hepatic handling with indocyanine green (ICG), which is actively taken up by the liver. Methods. Pefa 1023 was administered intravenously to bile duct-cannulated rats, either alone or in combination with ICG. The concentrations of Pefa 1023 in blood plasma and bile were measured by a bioassay (thrombin clotting time), concentrations of indocyanine green were measured spectrophotometrically. Results. ICG (10 mg/kg i.v. 15 min prior to or simultaneously with Pefa 1023) markedly influenced the plasma level and biliary excretion rate of the thrombin inhibitor Pefa 1023 given in a dose of 1 mg/kg i.v. The plasma level was more than twice that of the control, the maximum biliary excretion rate about one third and the fraction of dose excreted in bile about two thirds. Conclusions. The anionic dye ICG is able to interfere with the hepatic handling of a cationic, amidinophenylalanine piperazide-type thrombin inhibitor with the consequence of reduced hepatic clearance leading to higher plasma levels and lower biliary excretion of the latter.     

Effect of N-benzyl-D-glucamine dithiocarbamate on distribution and excretion of cadmium in rats

The effect of sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) on the distribution and excretion of cadmium in rats exposed to cadmium and the chemical form and intestinal reabsorption of cadmium compound excreted in the bile were studied. Rats were injected intraperitoneally with 109CdCl2 (1 mg Cd and 10 microCi 109Cd/kg) and 24 h later, they were injected with NBG-DTC (400 or 1200 mumol/kg). The biliary excretion of cadmium was remarkably increased by intraperitoneally injection of NBG-DTC, while there was only a small increase in urinary excretion of cadmium. Such an enhancement effect of NBG-DTC on the biliary excretion of cadmium was much larger at the high dose (1200 mumol/kg) of NBG-DTC. The treatment with NBG-DTC significantly decreased the cadmium content in the liver at the dose of 1200 mumol/kg and did not result in the undesirable redistribution of cadmium to the tissues, such as brain, testes, heart and lung. In addition, it was found that the cadmium compound excreted in the bile was mainly characterized as cadmium-NBG-DTC and which was not reabsorbed from the intestinal tracts.     

Disposition and excretion of cefoperazone in rabbits

The pharmacokinetics of cefoperazone were studied after i.v. administration of a single 30 mg/kg dose in a total of 40 New Zealand rabbits. Determination of the plasma levels of the drug revealed a slow elimination half-life of 0.48 h. The disappearance half-life of cefoperazone in interstitial tissue fluid shows a mean value of 1.9 h, being statistically higher than the value found for the half-life of the slow phase of elimination from the systemic circulation. 12 h after i.v. administration, 32.1% of the drug was seen to be excreted by the kidney and a further 15.2% in bile. The urinary excretion constant had a mean value of 0.29 h-1, whereas that of biliary excretion was 0.12 h-1.     

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.