Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the distribution and biliary excretion of polychlorinated biphenyls in rats.

Plasma disappearance, biliary excretion, and tissue distribution of two polychlorinated biphenyls (PCBs), 2,5,2′,5′-[³H]tetrachlorobiphenyl (4-CB) and 2,4,5,2′,4′,5′-[³H]hexachlorobiphenyl (6-CB), was determined in rats 10 days after oral administration of a single 10 or 25 μg/kg dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Plasma disappearance of both PCBs was not altered by TCDD treatment, but biliary excretion was depressed. Associated with the depressed excretion was a reduction in bile flow and concentration of 4-CB- and 6-CB-derived ³H in bile. Treatment with TCDD resulted in less PCB being distributed to the skin and a greater percentage of the dose being accumulated in the liver. The content of PCB-derived ³H in skeletal muscle, adipose tissue, and urine was similar in control and TCDD-treated rats. Extraction of bile with hexane showed that the majority of biliary radioactivity was in the form of polar metabolites and that the proportion of parent PCB (hexane-extractable radioactivity) to polar metabolites was not altered by TCDD treatment. In rats given 4-CB and sacrificed 1 hr later, the majority of radioactivity in the liver was hexane extractable, and the smaller amount of hepatic radioactivity due to polar 4-CB metabolites was greater in the TCDD treatment group than in the control group. When biliary metabolites of 4-CB were administered, biliary excretion of the metabolites was depressed in TCDD-treated animals. Thus, TCDD treatment impairs the initial and main excretory pathway for PCB elimination in the rat—biliary excretion—and alters the distribution of PCBs to the skin and liver.     

Effects of biliary excretion on the disposition of felodipine and metabolites in the rat

1. After i.v. and intraduodenal administration of ³H-felodipine to rats, approx. 50% of the dose was excreted in bile in the first 6 h. Total urinary and biliary recoveries after both administration routes were similar.

2. Neither unchanged felodipine nor oxidized pyridine metabolite was detected in bile. Bile collection had no effect on the blood concentration-time profiles of either compound.

3. Bile collection decreased the area under the blood concentration-time curve (AUC) of total, unidentified felodipine metabolites by 30%, and their urinary recovery by 50%.

4. Of the total metabolites excreted in bile, 40% was calculated to be subject to enterohepatic recycling.

5. The dose-normalized AUC of both felodipine and pyridine metabolite were decreased after intraduodenal administration of drug, indicating pre-systemic elimination of drug, and possibly of the pyridine, in the gut. Route of administration had no effect on the AUC of total unidentified metabolites.     

Effects of biliary excretion on the disposition of felodipine and metabolites in the rat

1. After i.v. and intraduodenal administration of 3H-felodipine to rats, approx. 50% of the dose was excreted in bile in the first 6 h. Total urinary and biliary recoveries after both administration routes were similar. 2. Neither unchanged felodipine nor oxidized pyridine metabolite was detected in bile. Bile collection had no effect on the blood concentration-time profiles of either compound. 3. Bile collection decreased the area under the blood concentration-time curve (AUC) of total, unidentified felodipine metabolites by 30%, and their urinary recovery by 50%. 4. Of the total metabolites excreted in bile, 40% was calculated to be subject to enterohepatic recycling. 5. The dose-normalized AUC of both felodipine and pyridine metabolite were decreased after intraduodenal administration of drug, indicating pre-systemic elimination of drug, and possibly of the pyridine, in the gut. Route of administration had no effect on the AUC of total unidentified metabolites.     

Effects of butylated hydroxytoluene (BHT) on biliary excretion of xenobiotics and bile flow in rats

A significant enhancement in the biliary excretion of iv injected sulfobromophthalein (BSP), phenol- 3,6 -dibromphthalein disulfonate (DBSP), procaine amide ethobromide (PAEB) and ouabain was observed in rats maintained on diets containing 0.25% BHT for periods of 10 days. The enhanced biliary excretion of these drugs in BHT treated rats appears to be correlated with the increase in bile flow produced by BHT. The increased bile flow was due to an increase in canalicular bile production rather than a change in net ductular secretion or reabsorption of fluid since bile to plasma concentration ratios of erythritol were unchanged and no permeability change in the biliary tree was observed when mannitol was administered by retrograde intrabiliary injection. The increase in bile flow was not due to an enhanced excretion of bile salts into bile, because both the biliary bile acid concentration and total biliary excretion of bile acids were lower in BHT-treated rats than in control rats. It appears that the increase in bile flow produced by BHT is due to the osmotic choleresis related to the secretion of BHT and its metabolites into bile.     

The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats.

We investigated whether lack of the canalicular multispecific organic anion transporter in transport-deficient (TR-) rats would result in plasma and urinary accumulation of troglitazone or its major metabolites and whether any accumulation would be associated with increased levels of bilirubin or bile acids. Administration of a single oral dose of troglitazone (200 mg/kg) to TR- rats resulted in 2- and 50-fold increases in plasma levels and 30- and 500-fold increases in urinary amounts of troglitazone sulfate and troglitazone glucuronide, respectively, compared with normal rats. No changes were found in the plasma concentrations and urinary amounts of troglitazone or troglitazone-quinone. Accumulation of troglitazone metabolites in plasma was accompanied by a 2-fold increase in the serum level of conjugated bilirubin in TR- rats, whereas no changes were observed in normal animals. Bile acids were detected in the urine of both TR- and normal rats, with an average 3-fold greater level found in the urine of TR- animals. Biliary metabolic profiles revealed a delay in the secretion of troglitazone sulfate and troglitazone glucuronide in TR- rats over the first 2- and 4-h periods, respectively. These results demonstrate the role of multidrug resistant associated protein-2 in biliary secretion of troglitazone glucuronide and troglitazone sulfate and suggest the presence of compensatory mechanisms responsible for transport of troglitazone metabolites and bilirubin-glucuronide at the basolateral and canalicular sites of hepatocytes.     

Effects of organic anions and vinblastine on biliary excretion of erythromycin in rats.

Since little is known about the mechanism of biliary excretion of cationic drugs, biliary excretion of erythromycin was studied in rats. Infusion of sulfobromophthalein and taurocholate significantly decreased biliary erythromycin excretion, whereas infusion of dibromosulfophthalein, cefpiramide, ursodeoxycholate-3-O-glucuronide and taurolithocholate-3-sulfate had no effect on biliary excretion of erythromycin. Vinblastine significantly inhibited biliary erythromycin excretion. Phenothiazine treatment significantly increased biliary erythromycin excretion. However, erythromycin infusion did not affect biliary vinblastine excretion. These findings indicate a multiplicity of biliary excretory pathways for organic cations; at least one additonal pathway may exist for organic cations apart from P-glycoprotein.     

Profile of disposition,tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C _max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC_0?t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t _1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96–99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.     

Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats.

Cosalane and dihydrocosalane are potent inhibitors of HIV replication with a broad range of activity. The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration. Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles. Dose dependence of cosalane was studied over a dose range of 1.0 to 10 mg/kg. The extent of enterohepatic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexponential disposition with very long half-lives of 749 +/- 216 and 1016 +/- 407 min, along with very large volumes of distribution 23.1 +/- 4.4 and 24.4 +/- 2. 5 liter/kg, respectively. Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability. The biliary and renal excretions of cosalane were found to be negligible with no detectable metabolites either in urine or bile. After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound. Also, cosalane was sequestered significantly in liver with quantifiable levels in all tissues tested, even 48 h after the dose was administered. Therefore it was concluded that the poor oral bioavailability of cosalane may be due to its poor enterocytic transport coupled with sequestration in liver parenchymal cell membrane layers.     

Intestinal distribution, absorption and secretion of dimethylamine and its biliary and urinary excretion in rats

In the gastro-intestinal tract of male Wistar rats fed a commercial diet containing 23.6 ppm dimethylamine (DMA), the concentration of DMA was highest (11.2 +/- 2.1 ppm) in the stomach and declined towards the lower regions. In contrast, the highest DMA concentration (6.6 +/- 2.5 ppm) was observed in the upper small intestine in rats fed a diet containing only 1.0 ppm DMA. DMA was absorbed in the intestines, and the disappearance curves were monoexponential. The t1/2 values for DMA in the ligated stomach, upper and lower small intestine, caecum and large intestine were 198, 8.3, 11.6, 31.5 and 11.0 min, respectively. The DMA concentration in the blood had increased to 3.0 +/- 1.0 ppm (from a pre-injection level of 0.28 +/- 0.06 ppm) 5 min after the injection of 250 micrograms DMA into the ligated upper small intestine. The disappearance curve for DMA in the blood was monoexponential and the t1/2 for the initial 15 min was 12.5 min when 250 micrograms DMA was injected into a femoral vein. The peak concentrations of DMA in the intestine and bile, respectively, were 15.6 +/- 12.6 ppm (at 15 min) and 3.7 +/- 1.9 ppm (at 30 min after the iv injection of DMA). In this 30-min period, urinary DMA increased from 17.3 +/- 9.4 to 139 +/- 23 ppm. These results show that, following ingestion, DMA is absorbed from the intestine into the blood, from which it disappears rapidly, the major part being excreted in the urine while a small proportion is excreted in the bile or secreted into the intestine, where it may be reabsorbed.     

Effects of phalloidin on the biliary excretion of cholephilic compounds in rats

Phalloidin is known to cause cholestasis by preventing microfilament depolymerization. In addition, phalloidin is reported to inhibit the vesicular targeting of canalicular transporters. The aim of the present study was to examine the effect of phalloidin on the biliary excretion of substrates typical for various canalicular transporters in rats. Phalloidin decreased the biliary excretion of tracer amounts of taurocholate, leukotriene C(4), pravastatin, and vinblastine. Increases in bile flow and biliary bile acid excretion caused by taurocholate infusion were completely inhibited by phalloidin. These data indicate that, in addition to multidrug resistance protein 2 and P glycoprotein, the vesicular targeting of the bile salt export pump, a major canalicular bile acid transporter, is also impaired by phalloidin. The decrease of biliary excretion of glutathione may also relate to the increase in the bile acid independent canalicular bile flow in phalloidin-treated rats.     

Tissue distribution, urinary, fecal and biliary excretion of 14C bendazac L-lysine salt in rats

The distribution of bendazac in the plasma and some rat tissues was studied after single oral administration of 14C bendazac L-lysine salt. The drug is distributed in varying amounts in the liver, kidneys, spleen, muscle, plasma and lens. In these tissues, the drug kinetics is similar, except for the lens where elimination of the drug is slower. More than 80% of the radioactivity administered is excreted through the urine and feces. Fecal excretion is due to the high biliary excretion.     

Absorption, distribution, metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rats.

The metabolism of 14C-MCPA (4-chloro-2-methylphenoxyacetic acid) in male and female rats was compared to that of 14C- MCPA dimethylamine salt (MCPA.DMA) or 14C-MCPA ethylhexyl ester (MCPA-EHE) in adsorption, distribution, metabolism and excretion studies. Compounds were administered by the oral route. The studies demonstrated the bioequivalence of the various forms of MCPA, established the extent of metabolism and metabolite identity. Following single or multiple oral administration of 5 mg/kg 14C-MCPA quantitative recovery of radioactivity, predominantly in urine, was obtained within 168 h. Rats dosed at 100 mg/kg showed similar absorption kinetics but apparent saturation of urinary excretion led to a prolonged elimination phase. MCPA was not extensively metabolised but the oxidation product HMCPA (4-chloro-2-hydroxymethylphenoxyacetic acid) was found at low levels, together with the glycine conjugate. These metabolites were more prominent shortly after dosing, suggesting that MCPA is not retained in the liver and that these metabolites may be excreted faster than MCPA itself. MCPA.DMA and MCPA-EHE were very rapidly converted into MCPA and toxicokinetics and metabolism were indistinguishable from parent compound.     

Effects of phenobarbital steady state levels on antipyrine clearance and distribution in the rat

A group of 15 rats received two intravenous bolus doses of antipyrine (15 mg/kg) separated by a 57 hour infusion (with bolus dose) of phenobarbital. Phenobarbital bolus doses and infusion rates were based on a preliminary pharmacokinetic study (7 rats) and were varied to achieve a broad range of steady state levels. Antipyrine and phenobarbital blood levels were measured by high pressure liquid chromatography. Antipyrine kinetics obeyed first order monoexponential decay, and the parameters (clearance, volume, half-life) were determined. Antipyrine clearance increased in all animals during phenobarbital infusions with a per cent increase ranging between 54.6 and 269 per cent. However, no significant correlation was found between the per cent increase in antipyrine clearance and phenobarbital concentration (r = 0.19). The volume of distribution of antipyrine increased in 14 of 15 animals with increases ranging between 7.7 and 45.8 per cent.     

Effects of halogenated dibenzo-p-dioxins on plasma disappearance and biliary excretion of ouabain in rats

A single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7-tribromodibenzo-p-dioxin (2,3,7-TBDD), 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (1,2,3,7,8,9-HCDD), 1,2,4,6,7,9-hexachlorodibenzo-p-dioxin (1,2,4,6,7,9-HCDD), or 1,3,6,8-tetrachlorodibenzo-p-dioxin (1,3,6,8-TCDD) was given to male rats (25 micrograms/kg, p.o.) and plasma concentration and biliary excretion of ouabain assessed 10 days later. Treatment of TCDD, 2,3,7-TBDD and to a lesser extent 1,2,3,7,8,9-HCDD increased the plasma concentration of ouabain and decreased its excretion into ouabain. TCDD, 2,3,7-TBDD and to a lesser extent, 1,2,3,7,8,9-HCDD decreased the bile flow. Liver wet weight was increased in TCDD and 2,3,7-TBDD treated rats. The magnitude of depression in ouabain excretion by those compounds was closely related to the reported relative binding affinity of the compound to liver cytosol and their induction potency of aryl hydrocarbon hydroxylase activity.     

Tissue distribution, disposition, and metabolism of cyclosporine in rats

Tissue distribution, disposition, and metabolism of 3H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak 3H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. 3H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of dithiocarbamates on cadmium distribution and excretion in chronically exposed rats

One month after termination of a 3-mo exposure of rats to cadmium (Cd in drinking water at a concentration of 50 mg/l), the effects of dithiocarbamate analogs on the excretion and distribution of the cadmium were determined. Sodium salts of three dithiocarbamates [sodium bis(hydroxyethyl) dithiocarbamate, DEDTC; sodium N-methyl-D-glucamine dithiocarbamate, MGDTC; and sodium 4-carboxamidopiperidine dithiocarbamate, INADTC] were given to rats ip 2 times at 2.46 mmol/kg. In the following administration of the first injection of DEDTC, cadmium excretion via the urine amounted to 15.8 micrograms and via bile amounted to 124.4 micrograms Cd. Following administration of MGDTC, the urinary and biliary excretions of cadmium were 14.5 and 47 micrograms, respectively, while in the case of INADTC the corresponding values were 23.6 and 7.9 micrograms cadmium. In control animals the urinary and biliary excretion per 12 h reached 0.09 and 0.12 micrograms Cd. Gel permeation chromatography (GPC) analysis of bile revealed differences in the distribution of Cd in the elution fractions after the first injections of the individual dithiocarbamates. For all three dithiocarbamates, significant decreases of the concentrations of cadmium in the liver and kidney were found. DEDTC (but neither of the other compounds) increased the concentration of cadmium in the brain from control levels of 49 +/- 5 ppb to 105 +/- 16 ppb.     

Absorption, distribution and excretion of a new thienodiazepine derivative (Y-7131) in rats and mice.

The synthesis of radioactive 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine (Y-7131), a new psychotropic agent, is descirbed. The labelled compound was rapidly and completely absorbed following oral administration to rats and mice. The blood levels of radioactivity reached maximum at 0.5 h in rats, and 1 h in mice, respectively, and then declined rapidly with biological half-lives of about 1.5 h in both animals, although the level was higher in mice than in rats. Approximately 45% of the radioactivity in the serum was bound to the serum protein at 1 h after oral administration. The dosed radioactivity was almost completely excreted within 3 days. In rats, more radioactivity was excreted in feces than in urine, while the reverse was noted in mice. An extensive biliary excretion of radioactivity was evidenced in rats after oral dosing. The highest concentrations of radioactivity were found in the liver, kidney, and adrenals, while relatively low levels in the brain of rats. The distribution patterns of radioactivity in mice were similar to those in rats except for the serum and liver. No remarkable accumulation of radioactivity in rat tissues was observed by repeated oral doses of the labelled compound for periods up to 21 days. The metabolic pathways of Y-7131 were qualitatively similar in rats and mice, and one of them was demonstrated to be the hydroxylation at alpha-position in the ethyl side chain.