Biliary excretion of cadmium in the rat,rabbit, and dog

The fecal elimination of cadmium is more important than urinary elimination. Within 1 week after iv administration of cadmium to the rat (1 mg/kg), 17% is excreted into the feces and less than 0.5% into the urine. However, of the amount excreted into the feces in 1 week, 85% is excreted within 2 days. The disappearance of ¹⁰⁹Cd from the plasma and its excretion into bile were measured for 2 hr after the iv administration of 0.1, 0.3, 1.0, and 3.0 mg/kg of cadmium to rats. The bile/plasma concentration ratio of cadmium was highly dose dependent; at the lowest dose, it was 2.6, and, at the highest dose, it was 133. The bile/plasma ratio was greater than 1 because the concentration of cadmium in the liver was 100 to 700 times higher than in the plasma. However, the bile concentration of cadmium was equal to or much lower than that in the liver; at the lowest dose (0.1 mg/kg), the concentration of cadmium in the bile was less than 1% of that in the liver. The relationship of the dose of cadmium to its biliary excretion was also reflected in the percentage of cadmium excreted into the bile within 2 hr, which ranged from 0.23 to 9% as the dose was increased from 0.1 to 3 mg/kg. The biliary excretion of cadmium was increased approximately four times as the temperature of the rat was increased from 30 to 40°C. The effect of 4 days of pretreatment with phenobarbital, spironolactone, pregnenolone-16α-carbonitrile, or 3-methylcholanthrene on the biliary excretion of cadmium was measured; only phenobarbital significantly increased its excretion. Marked species variation in the biliary excretion was observed. Rabbits excreted cadmium at a rate of about $\text{1}\text{6th}$, and dogs excreted cadmium at a rate of about $\text{1}\text{300th}$ of that observed in the rat. These results suggest that, while biliary excretion is the main route for cadmium elimination, the rate at which it is excreted appears to be highly dependent on the time after administration, the dose, and the species employed. This rate is not as responsive to alteration in the temperature of the animal or to administration of microsomal enzyme inducers as is that of some other metals.     

Felbamate pharmacokinetics in the rat, rabbit, and dog.

Rats, rabbits, and dogs were given single iv or single and multiple oral doses of felbamate ranging from 1.6-1000 mg/kg. Absorption of oral drug was complete in all species. The mean Cmax increased with dose from 13.9 to 185.9 micrograms/ml in rats, from 19.1 to 161.9 micrograms/ml in rabbits, and from 12.6 to 168.4 micrograms/ml in dogs. The tmax also increased with dose from 1-8 hr in rats, 8-24 hr in rabbits, and 3-7 hr in dogs. The plasma elimination half-life for the drug increased with dose from 2-16.7 hr in rats, 7.2-17.8 hr in rabbits, and 4.1-4.5 hr in dogs. A proportional increase in Cmax with dose was observed in all species up to 300-400 mg/kg doses. A biexponential equation fitted the drug plasma concentration vs. time data well. For multiple oral doses of 50 mg/kg or less, projected and observed steady-state concentrations agreed well. Animals dosed with [14C]felbamate eliminated most of the radioactivity in urine (58-87.7%), less in feces (7-23.7%), with considerable amounts in the bile. In rats, radioactivity was readily distributed into tissues and crossed the placenta and blood-brain barrier, but no accumulation in any tissue was observed. The volume of distribution was 131, 54, and 72% of body weight for rats, rabbits, and dogs, respectively. Binding of drug to rat, rabbit, and dog plasma proteins ranged from 22.4-35.9%. The overall plasma clearance of the drug for rats, rabbits, and dogs was 327, 52, and 108 ml.h-1.kg-1, respectively. Renal clearance of unchanged drug accounted for an estimated 20-35% and hepatic clearance due to metabolism for 65-80% of the overall clearance.     

Felbamate metabolism in the rat, rabbit, and dog.

Two major and one minor metabolite of felbamate (FBM) as well as unchanged drug were isolated and identified by electron impact and chemical ionization mass spectrometry from rat and dog urine after dosing with [14C]FBM. The metabolites were 2-(4-hydroxyphenyl)-1,3-propanediol dicarbamate (p-OHF), 2-hydroxy-2-phenyl-1,3-propanediol dicarbamate, and 2-phenyl-1,3-propanediol monocarbamate. The metabolites and FBM were excreted mainly in urine, where their sum accounted to 81-94% of the radioactivity in hydrolyzed rat urine samples, 71-82% in rabbit urine samples, and 69-83% in dog urine samples. The amount of metabolites in the conjugated form was estimated to be 20-35% in rat, 20-30% in rabbit, and 10-20% in dog urine. The major biliary metabolite in all three species was p-OHF, whereas the amount of FBM was small. Metabolites found in dog feces were the same as those in the urine.     

Oxymorphone metabolism and urinary excretion in human, rat, guinea pig, rabbit, and dog

Oxymorphone was extensively metabolized by human, rat, dog, and guinea pig and to a lesser extent by rabbit. The most abundant metabolite in urine for all species was conjugated oxymorphone (12.7-81.7% administered dose) followed by 6 beta- and 6 alpha-carbinols produced by 6-keto reduction of oxymorphone. 6 beta-Oxymorphol (0.2-3.1%) was found in the urine of all species, whereas 6 alpha-oxymorphol (0.1-2.8%) was found only in human, rabbit, and guinea pig. Small amounts of free oxymorphone (less than or equal to 10%) were excreted by all species except rabbit, which excreted 31.7%. Overall recoveries of oxymorphone and metabolites from urine ranged from 15-96%, of which greater than 80% was excreted in the first 24 hr by all species except dog. Only 35% was excreted by dog during the first day. Stereoselectivity of 6-keto- reduction was observed for all species with the 6 beta-carbinol metabolite being most abundant in the urine of all but guinea pig. Considerable individual variability occurred in the excretion of free and conjugated oxymorphone by six human subjects following oral dosing. Species trends in the metabolism of 6-keto-opioids are discussed.     

Fluorocarbons and general metabolism in the rat, rabbit, and dog.

The metabolic effects of fluorocarbon inhalation were studied in the rat, rabbit, and dog. The fluorocarbons, monofluorotrichloromethane (FC 11) and difluorodichloromethane (FC 12) were inhaled either alone in air or combined in a $\text{50}\text{50}$ or $\text{10}\text{90}$ mixture. In single exposure experiments the only metabolic reactions were produced by FC 11 at 5%, giving a slight hyperglycemia with hyperlactacidemia. In prolonged exposure experiments (inhalation 2 hr/day for 15 days) only FC 11 at 5% produced slight metabolic modifications, these modifications being quickly reversed after inhalation ceased.     

Biliary excretion and enterohepatic circulation of paracetamol in the rat

1. Within 8?h after i.v. administration of paracetamol (100?mg/kg) to rats, 28.7% was excreted into bile; 1.2% dose as unchanged drug, 14.3% as the glucuronide, 8.2% as the sulphate, 4.7% as the glutathione conjugate, 0.32% as the mercapturate.

2. Rats with cannulated bile-ducts excreted 62.8% dose in the urine in 8?h compared with 83.5% in sham-operated rats. Metabolites in urine were paracetamol sulphate (63.2%), the glucuronide (12.1%), unchanged paracetamol (7%), and the mercapturate (1.2%).

3. Bile containing paracetamol and its conjugates was infused into the duodenum and within 8?h 45.3% was excreted (5.6% in bile and 39.7% in urine).

4. In rats not subjected to surgery, 91.3% dose (100?mg/kg, i.v.) was excreted in urine in 24?h. However, in rats treated twice with activated charcoal or cholestyramine (2 × 1?g/kg orally), urine excretion was decreased to 72.8 and 59.3% dose, respectively.

5. These results indicate the enterohepatic circulation of paracetamol and its metabolites in the rat.     

Biliary excretion and enterohepatic circulation of pregnanolone in the rat

Studies were made of the metabolism and biliary excretion of pregnanolone, a metabolite of progesterone exhibiting a variety of pharmacologie activities, in rats bearing venous and biliary catheters. Pregnanolone glucuronide appeared rapidly and in large amounts in the bile, with a concentration gradient in the order of 400 relative to serum. The relative concentration of various metabolites in the bile remained constant over a 5-day period. An enterohepatic cycle was established by finding peaks in the serum concentration of pregnanolone after intragastric administration of bile collected from pregnanolone-pretreated rats, containing pregnanolone and pregnanolone glucuronide. It appeared that hydroxylation of pregnanolone at C6 and 17 and reduction of C20 occurred during its passage through the intestine.     

Biliary excretion and enterohepatic circulation of paracetamol in the rat

Within 8 h after i.v. administration of paracetamol (100 mg/kg) to rats, 28.7% was excreted into bile; 1.2% dose as unchanged drug, 14.3% as the glucuronide, 8.2% as the sulphate, 4.7% as the glutathione conjugate, 0.32% as the mercapturate. Rats with cannulated bile-ducts excreted 62.8% dose in the urine in 8 h compared with 83.5% in sham-operated rats. Metabolites in urine were paracetamol sulphate (63.2%), the glucuronide (12.1%), unchanged paracetamol (7%), and the mercapturate (1.2%). Bile containing paracetamol and its conjugates was infused into the duodenum and within 8 h 45.3% was excreted (5.6% in bile and 39.7% in urine). In rats not subjected to surgery, 91.3% dose (100 mg/kg, i.v.) was excreted in urine in 24 h. However, in rats treated twice with activated charcoal or cholestyramine (2 X 1 g/kg orally), urine excretion was decreased to 72.8 and 59.3% dose, respectively. These results indicate the enterohepatic circulation of paracetamol and its metabolites in the rat.     

Metabolism of isotretinoin. Biliary excretion of isotretinoin glucuronide in the rat

The biliary metabolites of isotretinoin were examined after iv administration of 4-20-mg/kg doses to vitamin A-normal bile duct-cannulated rats. Analysis of bile by reverse phase high performance liquid chromatography showed that injection of isotretinoin is followed by a rapid excretion of metabolites in bile. Isotretinoin glucuronide was identified as the major metabolite in bile. A specific high performance liquid chromatography method based on the assay of generated isotretinoin in beta-glucuronidase-treated bile was developed for the determination of isotretinoin glucuronide in bile samples. The excretion rate of isotretinoin glucuronide increased rapidly to reach a maximum 55 min after dosing and then declined exponentially. After 330 min of collection, biliary excretion of isotretinoin glucuronide was almost complete, and the metabolite accounted for 34.8-37.9% of the dose. These results indicate that conjugation with glucuronic acid represents a major pathway for the metabolism of pharmacological doses of isotretinoin. The maximum excretion rate of isotretinoin glucuronide in bile increased in a linear manner with the dose of isotretinoin, and no delay was observed after the larger doses. These data suggest that glucuronidation and biliary excretion are not saturated at high pharmacological doses of isotretinoin.     

Species differences in blood profiles, metabolism and excretion of 14C-propofol after intravenous dosing to rat, dog and rabbit.

1. Bolus i.v. doses of 14C-propofol (7-10 mg/kg) to rat, dog and rabbit, or an infusion dose (0.47 mg/kg per min for 6 h) to dog were eliminated primarily in urine (60-95% dose); faecal elimination (13-31%) occurred for rat and dog, but was minimal (less than 2%) for rabbit. 2. After bolus administration, blood 14C concentrations were maximal (8-30 micrograms equiv./ml) at 2-15 min; these declined rapidly during the 0-2 h period and thereafter more slowly. Propofol concentrations were maximal (4-16 micrograms/ml) at 2 min and the profiles were best fitted by a tri-exponential (rat and dog) or bi-exponential (rabbit) equation. Duration of sleep ranged from 5 to 8 min. 3. Infusion of 14C-propofol in dog gave a blood 14C concentration of 117 micrograms equiv./ml at the end of the 6 h infusion period; this declined at a similar rate to that after the bolus dose. Propofol concentration on termination of infusion was 13 micrograms/ml; thereafter, propofol concentrations declined less rapidly than after the bolus dose. Waking occurred about 44 min post-infusion. 4. Propofol was cleared by conjugation of the parent molecule or its quinol metabolite; hydroxylation of an isopropyl group also occurred in rat and rabbit. Biliary excretion leading to enterohepatic recirculation, and in turn increased sulphate conjugation, occurred in rat and dog, but not rabbit, resulting in a marked interspecies variation in drug clearance and metabolite profiles.     

Acute and subchronic toxicity of mirex in the rat, dog, and rabbit.

The acute and subchronic (13 weeks) toxicity of orally administered mirex was studied in mongrel dogs, beagle dogs, and rats. Percutaneous toxicity was evaluated in rabbits. The acute oral LD50 in male mongrel dogs was found to be > 1000 mg/kg. Beagles of both sexes fed 4 and 20 ppm of mirex for 13 weeks exhibited no toxic effects. Two animals receiving 100 ppm died during the test period. Also observed at this dosage level were a reduced rate of weight gain, abnormal blood chemistry values, increased liver/body weight ratios, and decreased spleen/body weight ratios. No histopathologic changes were attributed to mirex. Male and female rats received diets containing 0, 5, 20, 80, 320, and 1280 ppm. No significant adverse effects were observed at levels of 5, 20, and 80 ppm. The following were observed at 320 and 1280 ppm; depressed growth, decreased hemoglobin concentrations, elevated white cell counts, enlarged livers showing histopathological changes, and deaths in the 1280-ppm groups. Rabbits exposed percutaneously to 3.33 or 6.67 g of mirex bait/kg, 6–7 hr each day, 5 days a week, for 9 weeks, exhibited no evidence of mirex intoxication.     

Studies on the biliary excretion mechanisms of drugs. II. Biliary excretion of thiamphenicol, chloramphenicol and their glucuronides in the rat

Thiamphenicol (TP) or chloramphenicol (CP) administered intravenously (14 μmoles) to rats with ligated renal pedicles is rapidly excreted in bile mostly as the glucuronide (about 23 and 75 per cent in 7 hr respectively). Increasing the dose of either drug does not result in an increased excretion of glucuronide, indicating that the excretion process is saturable. TP glucuronide (TPG) or CP glucuronide (CPG) administered intravenously to rats with ligated renal pedicles is rapidly excreted into bile in high concentration as unchanged glucuronide. The maximal excretion rate of TPG or CPG (about 14.0 and 18.0 gmmoles/10 min respectively) when each glucuronide (100 μmoles) was administered is much higher than that (about 5.1 and 8.5 gmmoles/10 min respectively) when each aglycone (200 μmoles) was administered. The results suggest that the transport maxima (Tms) for the biliary excretion of TP and CP are due to a saturation of the conjugating process. CPG used in this study is isolated by a new method.     

Metabolic fate of the new cardiotonic denopamine in animals. 1st communication: absorption, distribution and excretion in the rat, rabbit and dog

Absorption, distribution and excretion of (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol (denopamine, TA-064) a new positive inotropic agent, were studied after oral and intravenous administration of 3H- or 14C-denopamine (5 mg/kg) to different animal species. After oral administration to rats, rabbits and dogs, the time to attain the peak and the maximum concentration of the plasma levels of radioactivity were about 15 min, 4 micrograms eq./ml in rats, 15-45 min, 8 micrograms eq./ml in rabbits and 2-4 h, 2 micrograms eq./ml in dogs, respectively. The plasma denopamine levels in dogs reached the peak (0.34 microgram/ml) at 0.5-3 h after administration, and thereafter gradually decreased with half-lives of 1.6-3.1 h. Following oral administration to rats, the amounts remaining of the parent compound in the digestive tract at 0.5 and 3 h after administration were about 27 and 2% of the dose administered, respectively. This indicated that the compound was rapidly and almost completely absorbed from the intestinal tract. When 3H-denopamine was orally administered to rats, cumulative excretion of radioactivity in the urine and feces within 24 h were about 60 and 32% of the dose, respectively. Almost 100% of the dose were recovered from the urine and feces within 120 h. About 50% of the dose administered were excreted in the bile within 24 h. The occurrence of enterohepatic circulation was indicated in rats. Distribution of radioactivity was investigated in rats by means of whole body autoradiography and the tracer technique.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the biliary excretion mechanism of drugs. I. Biliary excretion of azo dyes in the rat

The mechanism of biliary excretion of the azo dyes, Azorubin S (AS), Amaranth (AM) and New Coccine (NC), in rats was investigated. It was observed that these azo dyes have an apparent transport maximum (Tm) for their biliary excretion. Further, the biliary excretion of these dyes was markedly depressed by phenolphthalein glucuronide (PPG) and probenecid, which are considered to be actively excreted into bile. The results, therefore, suggest that the biliary excretion of these dyes in rats involves an active transport process.