Effect of partial jejunectomy and colectomy on the disposition of hexachlorobenzene in rats treated or not treated with hexadecane

The disposition of hexachlorobenzene (HCB) was studied in partially jejunectomized (middle section) or colectomized (excision of cecum and proximal colon) rats after iv or ip dosage (1.5 to 2.0 mg/kg). Excision of about 50% of the jejunum had no effect on body weight, feed intake, volume of urine, weight of feces, or urinary and fecal excretion of HCB as demonstrated by a comparison of sham-operated and jejunectomized animals. Similarly colectomy did not affect body weight, feed intake, volume of urine, or urinary excretion of HCB. However, the wet weight of feces was significantly higher and the amount of HCB in feces significantly lower in colectomized than in sham-operated rats. Hexadecane increased fecal excretion of HCB about two- to threefold without affecting its urinary excretion. The effect of jejunectomy and colectomy was similar in hexadecane-treated animals to that seen in untreated rats. Concentration of HCB in adipose tissue was significantly higher in colectomized rats than in sham-operated controls. Data represent in vivo evidence that the major site of nonbiliary, intestinal excretion of HCB is the large intestine.     

Stimulation of nonbiliary, intestinal excretion of hexachlorobenzene in rhesus monkeys by mineral oil

Four rhesus monkeys were administered various doses of hexachlorobenzene (HCB) po, to achieve widely varying adipose tissue levels. One month later, each animal was provided with a bile duct bypass allowing for interruption of the enterohepatic circulation (EHC). Effects of mineral oil-supplemented diet and/or interruption of the EHC on urinary, biliary, and fecal excretion of HCB and its metabolites were quantified. Urinary excretion of HCB was not affected by mineral oil but was reduced 20 to 60% by interruption of the EHC. Similarly, biliary excretion of HCB was also reduced 25 to 60% by interruption of the EHC and was not altered by mineral oil. Fecal excretion was increased about fivefold by mineral oil, whereas interruption of the EHC had no effect on the amount of HCB in feces. Results demonstrate that interruption of the EHC reduced urinary and biliary excretion of HCB metabolites, whereas mineral oil specifically stimulated intestinal excretion of the parent compound.     

Distribution and elimination of 14C-hexachlorobenzene after single oral exposure in the male rat

The distribution and excretion of 14C-hexachlorobenzene (14C-HCB) after administration to rats of a single oral dose of 50 microCi 14C-HCB per kg body weight was studied by whole-body autoradiography and liquid scintillation counting. Radiolabelled HCB was distributed throughout the body in 2 hours. Peak levels were found at 4 hours in the liver and the brown fat and at 24 hours in the abdominal and subcutaneous fat. The highest concentrations were found in the adipose tissues, the bone marrow, the skin, the Harderian gland, the nasal mucosa, the praeputial gland, and the intestinal tract. After 90 days, substantial amounts were present only in the adipose tissue, the skin, the nasal mucosa, and the praeputial gland. Part of the radioactivity in the brown fat, the bone marrow, the praeputial gland, the adrenal gland, the liver, the blood, the kidney, the spleen, the lungs, the heart and the gastrointestinal contents was found not to be evaporable on sections heated to 50 degrees for 24 hrs and was considered to represent metabolites of HCB. Some radioactivity remained in the liver, the kidney, the heart and the intestinal contents after evaporation and extraction of the sections with polar and nonpolar solvents and was supposed to reflect metabolites of HCB associated to tissue macromolecules. Besides urine and faeces, the results indicated the following excretory pathways: Intestinal mucosa, sebacous glands, nasal mucosa and the praeputial and Harderian gland.     

Enhanced fecal elimination of stored hexachlorobenzene from rats and rhesus monkeys by hexadecane or mineral oil

The effect of various dietary treatments on the fecal excretion of [¹⁴C]-hexachlorobenzene (HCB) was studied in rats and rhesus monkeys. Cholestyramine and sesame oil failed to influence fecal excretion of HCB and/or metabolites. However, dietary administration of n-hexadecane (5%) increased fecal excretion of radioactivity 4–13-fold in rats and rhesus monkeys. Similarly, mineral oil in the diet (5%) of rhesus monkeys elicited a 6–9-fold increase in fecal excretion of HCB and/or metabolites. As a result of the mineral oil treatment, an enhanced depletion of HCB from blood and also of the stored HCB from adipose tissue was observed. The concentration of HCB in the blood declined in accordance with decreasing storage levels of HCB in adipose tissue. The major site of elimination of HCB and/or metabolites seemed to be the intestine; in particular, the cecum and the colon ascendens. Both hexadecane and mineral oil appeared to stimulate specifically this elimination pathway.     

Fate of hexachlorobenzene in C57BL/10 mice with iron overload

The distribution of radioactivity in male C57BL/10 mice dosed with [14C]hexachlorobenzene (HCB) was followed over 21 days and found to be high in adipose tissue and adrenals, moderate in thymus whereas liver was relatively poorly labelled. A predose of iron (500 mg/kg), which greatly promotes the porphyrogenic action of HCB in this strain, had only a small effect on the distribution of radioactivity in tissues and excreta. Iron induced excretion of urinary metabolites from HCB by C57BL/10 mice but not by the insensitive DBA/2 strain. However, there was no such difference in faecal metabolites, total metabolism was only slightly increased and there was no correlation between liver porphyrin levels and urinary excretion of metabolites by individual mice. At the end of 4 weeks exposure of iron-treated C57BL/10 mice to HCB urinary metabolites fell while porphyrin excretion continued to rise. Thus the considerable sensitisation of the C57BL/10 strain after iron overload to the induction of porphyria by HCB cannot be ascribed simply to enhancement of total metabolism but must be caused either by the formation of a specific undetected metabolite or induction of some other toxic process.     

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.     

Disposition and excretion of 2,3,4,7,8-pentachlorodibenzofuran in the rat

The disposition of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), a highly toxic environmental contaminant which accumulates in human tissues, was examined in the male Fischer rat after iv and oral exposure. Greater than 70% of an oral dose of 0.1, 0.5, or 1.0 mumol PeCDF/kg body wt was absorbed by the gastrointestinal system. After either oral or iv administration of 0.1 mumol/kg, the dibenzofuran was rapidly removed from the blood and accumulated in the liver and adipose tissue and to a lesser extent in the skin and muscle. Three days after administration, 70% of the iv dose of PeCDF was found in the liver, 7% in the fat, 1% in the skin, and 0.5% in the muscle. Route of exposure had little effect on tissue distribution. TLC analyses indicated that greater than 99% of the [14C]-PeCDF-derived radioactivity which had accumulated in the liver and adipose tissue was unmetabolized PeCDF which was eliminated very slowly (t1/2 = 193 and 69 days, respectively). The whole body half-life calculated from the daily fecal excretion rate was approximately 64 days. Excretion occurred primarily via the feces. No radioactivity was detected in expired air and less than 0.02% was detected in the urine. TLC analysis of fecal extracts indicated greater than 90% of the [14C]PeCDF-derived radioactivity in the feces was polar metabolites of the parent compound. Pretreatment with 500 micrograms PeCDF/kg body wt caused biliary excretion to nearly double. Treatment of bile with beta-glucuronidase or arylsulfatase had little effect on the chromatographic profile. Therefore, PeCDF was readily absorbed from the gastrointestinal tract, concentrated primarily in the liver, and was slowly eliminated from the body as polar metabolites. The long half-life and high body burden of PeCDF suggest that the toxicity of this chemical may be enhanced due to bioaccumulation upon chronic low-level exposure.     

Distribution, excretion, and metabolism of butylbenzyl phthalate in the rat

The disposition of butylbenzyl phthalate (BBP), a widely used plasticizer, was evaluated after oral and iv administration to rats. Male Fischer-344 rats were dosed with [14C]BBP at 2, 20, 200, or 2000 mg/kg po or 20 mg/kg iv to determine the effects of dose on rates and routes of excretion. In 24 h, 61-74% of the dose was excreted in the urine and 13-19% in the feces at 2-200 mg/kg. At the 2000-mg/kg dose, 16% of the 14C was excreted in the urine and 57% in the feces. Urinary 14C was composed of monophthalate derivatives (MP: 10-42% of the dose) and glucuronides of these monophthalate derivatives (2-21% of the dose). At 4 h after iv administration of BBP (20 mg/kg), 53-58% of the dose was excreted in the bile of anesthetized rats. No parent compound was found in the bile, but monobutyl phthalate-glucuronide and monobenzyl phthalate-glucuronide (26% and 13% of the dose, respectively) and trace amounts of free monoesters (2% of the dose) and unidentified metabolites (14% of the dose) were present. Although BBP is an asymmetric diester with the potential of forming equal amounts of monobutyl phthalate (MBuP) and monobenzyl phthalate (MBeP), larger quantities of MBuP were formed (MBuP = 44% versus MBeP = 16% of the dose). The half-lives of BBP, MP, and total 14C in blood (20 mg/kg, iv) were 10 min, 5.9 h, and 6.3 h, respectively. This study indicates that BBP is rapidly metabolized and that the major route of excretion of metabolites is biliary. These metabolites are reabsorbed and ultimately eliminated in the urine.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

Prevention of chlorphentermine-induced pulmonary phospholipidosis in rats by phenobarbital

It has been shown previously that the induction of pulmonary phospholipidosis in rats by chlorphentermine (CP) is essentially prevented by the concurrent administration of phenobarbital (PB). This study was conducted to investigate the mechanism(s) responsible for this protection. Male Long-Evans hooded rats received either 14C-CP (30 mg/kg, ip) or both PB (30 mg/kg, po) and the 14C-CP daily for up to 1 week. Associated with the PB-induced prevention of phospholipid accumulation in the lungs was an 84% reduction in CP content in the tissue. Excretion in urine and feces was 55 and 6%, respectively, of the administered 14C for the CP group, and 66 and 11%, respectively, for the CP + PB group. Increased urinary excretion was not due to enhanced glomerular filtration or urine output. With each group, nearly 80% of the 14C was extracted into ether from alkalinized urine and co-chromatographed on TLC with pure CP. The difference in nonextractable 14C (presumably polar metabolites of CP) between the two groups is small and cannot account for the difference in total 14C excreted in the urine. All of the fecal 14C was CP. These experiments rule out an increase in CP metabolism as the primary basis for the CP-induced enhancement in 14C excretion. PB appears to actually protect against CP-induced pulmonary phospholipidosis rather than reversing it. This occurs by an enhancement in excretion of CP, thereby preventing it from reaching levels in the lungs which lead to PL accumulation.     

Disposition of (5H-dibenzo [a,d]cyclohepten-5-ylidene)acetic acid in laboratory animals

The disposition of (5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (Wy-41,770), an anti-inflammatory agent, was investigated in rats, mice, rhesus monkeys, and dogs following single 12.5-mg/kg doses of 14C-labeled or unlabeled drug and in rodents receiving single 225-mg/kg doses of 14C-Wy-41,770. The drug was rapidly and well absorbed in all four animal species. Following an iv dose, plasma elimination half-lives of Wy-41,770 in monkeys and dogs were, respectively, 5.0 +/- 1.8 and 0.24 +/- 0.01 hr. Total body clearances (CL) of 1.8 +/- 0.2 ml/min/kg in monkeys and 7.7 +/- 1.1 ml/min/kg in dogs are low, indicating that, after an ig dose, little Wy-41,770 would be eliminated on first passage through the liver. The steady state volumes of distribution of 0.37 +/- 0.1 and 0.14 +/- 0.01 liters/kg, respectively, in monkeys and dogs are low, indicating limited extravascular distribution of Wy-41,770. Plasma half-lives of Wy-41,770 in rats and mice were, respectively, 10.8 and 8.4 hr. The longer half-life in rats compared to other animals is due to the extensive enterohepatic recycling of the drug in rats. The extensive cycling of the drug in rats may explain why ileocecal inflammation occurred in this species but not in mice and dogs following prolonged oral administration of high doses of Wy-41,770. Following a 12.5 mg/kg, ig dose, the rates of urinary excretion of radioactivity in monkeys, mice, and rats were, respectively, 73.4 +/- 10.7, 52.6 and 15.2% of the dose, whereas the fecal excretion was 9.1 +/- 3.7% in monkeys and 74.7% in rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of arsenic-, platinum-, and gold-containing drugs on the disposition of exogenous selenium in rats.

Having found that the electrophilic model compound sulfobromophthalein markedly altered the fate of exogenous selenium in the body by reacting in vivo with nucleophilic selenium metabolites, the effects of metal-containing drugs with expected selenium reactivity were tested on biliary, urinary, and pulmonary excretion. Tissue distribution of selenium in selenite-injected rats was also examined. Coadministration with [(75)Se]selenite (10 micromol/kg, iv) of the trypanosomicid arsenicals (100 micromol/kg, iv) trimelarsan (TMA) or melarsoprol (MAP), the antitumor cisplatin (25 micromol/kg, iv), or the antirheumatic gold sodium thiomalate (25 or 50 micromol/kg, iv) significantly altered the disposition of (75)Se, whereas carboplatin (100 micromol/kg, iv) did not produce such an effect. The most dramatic alterations included the approximately 20-fold increase in the biliary excretion rate of selenium in response to TMA and MAP, the almost complete cessation of the exhalation of selenium as dimethyl selenide after administration of the arsenic- and gold-containing drugs, and the manifold accumulation of selenium in the blood plasma following gold injection. Direct chemical reaction of the drugs with nucleophilic selenite metabolites in the body may underlie these alterations. The tight coordination in time and extent observed between the biliary excretion of arsenic and selenium in rats receiving either of the arsenicals and selenite supports this hypothesis. However, attempts to detect selenium-containing biliary metabolites of TMA and MAP have failed, possibly owing to their instability. In summary, the arsenic-, platinum- and gold-containing drugs significantly influence the fate of exogenous selenium, whereby they may adversely affect the availability of this essential element for synthesis of selenoenzymes. Furthermore, the capability of TMA and MAP to enhance the biliary and total excretion of selenium renders these drugs significant candidates for antidotes in selenium intoxication.     

Excretion and metabolism of intramuscularly administered [14C]-haloperidol decanoate in rats

Urinary, fecal and biliary excretion, together with enterohepatic circulation, of radioactivity were studied after intravenous (50 mg eq/kg) and intramuscular (5 and 50 mg eq/kg) administration of [14C]-haloperidol decanoate in rats. The composition of urinary and biliary metabolites was also examined. The rate of excretion after intravenous administration lowered rapidly with the half-life of about 1.5 days and about 95% of dose was excreted in excreta within 10 days. Shortly after intramuscular administration, the rate of excretion lowered rapidly but then more gradually later (half-lives after administration of 5 and 50 mg eq/kg were 16.4 and 11.2 days, respectively). About 90% of dose was excreted within 42 days after intramuscular administration. About 1.6% of dose/day was excreted in the bile during 15-17 days after intramuscular administration, of which about 30% was reabsorbed within 24 h (enterohepatic circulation). The major urinary metabolite was p-fluorophenylaceturic acid and the biliary metabolite, glucuronide and sulfate of haloperidol. No unchanged decanoate was detected in the excreta.     

Effects of aloe, aloesin, or propolis on the pharmacokinetics of benzo[a]pyrene and 3-OH-benzo[a]pyrene in rats

This study was conducted to examine the effects of aloe and aloesin on the weight gain and blood chemistry as well as the pharmacokinetics of benzo[a]pyrene (BaP) and 3-OH-BaP in rats. The rats treated with multiple doses of aloe and aloesin (100 mg/kg every 12 h for 14-19 d) did not show any significant changes in the weight gain and blood biochemical parameters. In addition, the effects of oral treatment with aloe, aloesin, and propolis on the absorption and pharmacokinetics of benzo[a]pyrene (BaP) and its metabolite, 3-OH-BaP, were studied in rats. The treatment with a single oral dose (200 mg/kg) of aloe, aloesin, and propolis did not alter the concentration-time profiles of BaP and 3-OH-BaP after iv and oral administration of BaP. At higher oral doses (500 mg/kg), the biliary excretion of BaP and the urinary excretion of 3-OH-BaP were significantly increased, but the urinary excretion of BaP and the fecal excretion of 3-OH-BaP remained unaltered. Whether high doses of aloe increase the overall elimination of BaP deserves further investigation.     

Sex differences in the metabolism and excretion of nilvadipine, a new dihydropyridine calcium antagonist, in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1 mg/kg of the 14C-labelled compound. 2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48 h were 84.1% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces. 3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with 14C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats. 4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24 h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Disposition of 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) in rats with decreasing adipose tissue mass. II. Effects of restricting food intake before and after 6-CB administration

Excretion and tissue distribution of the virtually unmetabolizable lipophilic model 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) was studied in rats with decreasing adipose tissue mass imposed by various food intake manipulations. Single doses of 6-CB (0.6 mg/kg iv) were administered to adult male rats. Excretion was followed daily and tissue distribution was determined after 7 weeks. Gradual disappearance of adipose tissue was induced by restricting food intake to 25% of ad libitum consumption. In a first series of experiments, 6-CB was administered simultaneously with the start of food restriction. The fecal excretion rate of 6-CB increased, reached a maximum in the second week, and then leveled off. After 7 weeks, some 50% of the dose was excreted and 26% was located in the skin. Amounts in muscle, liver, lung, kidney, brain, gastrointestinal contents, and residual adipose tissue were between 2.5 and 0.1% of the administered dose. In a second series of experiments, 6-CB was administered 2 weeks after the commencement of food restriction, i.e. when adipose tissue reserves had already largely disappeared. Fecal excretion rate was maximal at the outset and gradually decreased. Cumulative excretion and distribution values for skin and other tissues were not significantly different from the values determined in the above series after 7 weeks. The results, which are discussed in the context of previously published data, demonstrate the profound difference in the pharmacokinetics of 6-CB, depending on whether adipose tissue mass is increasing (as in the ad libitum fed adult rat) or decreasing.     

Pharmacokinetics of morphine and its surrogates. III: Morphine and morphine 3-monoglucuronide pharmacokinetics in the dog as a function of dose.

The pharmacokinetics of morphine and its derived metabolite, morphine 3-monoglucuronide, were studied in normal and bile-cannulated dogs. High doses (7.2-7.7 mg/kg iv) caused renal and biliary shutdowns and time lags in urinary drug and metabolite excretion and in biliary secretion of the hepatically formed conjugate. Intermediate doses (0.41-0.47 mg/kg iv) inhibited urine flow but not renal clearance. Low doses (0.019-0.07 mg/kg iv) had no apparent effect. Dose-related effects on the total, metabolic, and biliary clearances imply saturable enzymes and/or dose-inhibited hepatic flows, accounting for the major elimination half-lives of 83 +/- 8 and 37 +/- 13 min at the high and low doses, respectively. The slow terminal phase in plasma morphine and metabolite elimination and urinary accumulation is due apparently to the enterohepatic metabolite recirculation after biliary excretion, gastrointestinal hydrolysis, and hepatic first-pass reconjugation. Bile-cannulated dogs showed no fecal drug and no slow terminal plasma and urine elimination phases. Intravenous morphine 3-monoglucuronide was eliminated only renally and showed neither biliary excretion nor prolonged hepatically formed glucuronide elimination. Hepatic morphine clearances at normal therapeutic doses parallel hepatic blood flow and explain the lack of oral morphine bioavailability by anticipating complete first-pass liver metabolism. Renal morphine and morphine conjugate clearances were 85 (+/- 9 SEM) and 41 (+/- 4 SEM) ml/min, respectively, indicating glomerular filtration for the latter and glomerular filtration plus tubular secretion for the former. Urinary morphine and morphine conjugate excretion accounted for approximately to 83% of the dose. Biliary secretion accounted for 11-14% of the dose. Morphine showed dose-independent plasma protein binding of 36 (+/- 1 SEM) % and a red cell-plasma water partition coefficient of 1.11 +/- 0.04 SD. New equations were developed to model the discontinuous morphine and morphine metabolite pharmacokinetics.     

Effect of sodium salicylate on the fate of warfarin in the rat

Salicylate (88.9 mg/kg, po) decreased the blood level of radioactivity emanating from [¹⁴C]warfarin (1 mg/kg, iv and po) during the 24 hr following drug administration, reduced the area under the blood radioactivity vs time curve, and shortened the half-life for elimination of radioactivity from the blood. During the first 6 hr after drug administration, salicylate increased the biliary excretion of radioactivity, which resulted in enhanced fecal excretion of warfarin and its metabolites. Salicylate administration initially increased and later decreased the amount of radioactivity in the liver, and increased the proportion of warfarin metabolites to unchanged warfarin in this organ. It did not affect the proportion of unchanged warfarin to metabolites in the blood, bile and urine, or the total amount of radioactivity excreted during 48 hr in the urine and feces. In vitro, salicylate decreased the binding of [¹⁴C]warfarin to rat serum proteins in a linear manner. It is concluded that, in the rat, salicylate competes with warfarin for serum protein binding sites, thereby facilitating its uptake by the liver. Second, through a combination of its choleretic action and effect on membrane transport, salicylate enhances the biliary excretion of warfarin and its metabolites, thus accounting for the decreased concentration in the blood and lowered antiboagulant action.     

Long-term pharmacokinetics of 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) in rats with constant adipose tissue mass

Long-term (280 days) pharmacokinetics of 2,2',4,4',5,5'-hexachlorobiphenyl (6-CB) was studied in rats with constant adipose tissue mass. This was achieved by feeding the animals 50% of their mean ad libitum food intake. 6-CB was administered as a single iv injection of 0.6 mg/kg. Tissues and excreta were analyzed at various time points from 4 to 280 days. After the redistribution phase, all tissue concentrations declined with terminal half-lives of 431-478 days, and concentration in adipose tissue was 1000 times higher than in blood. The corresponding ratios were: for skin 40, lung 30, liver 25, brain 10, and muscle 10. From day 4 on only adipose tissue, skin, and muscle contained significant amounts of 6-CB. Between 2 and 4 weeks adipose tissue and skin reached a maximum corresponding to 68 and 15% of the dose, respectively. After 280 days these values declined to 38 and 7% of the dose. Fecal excretion during this period was 43% of the dose with a terminal half-life of 478 days. Polar metabolites (1.5% of dose) were detectable in urine only. Extrapolation of fecal excretion kinetics yields a total excretion value of 99% of the dose at infinite time. Thus, in the rat with constant adipose tissue mass, 6-CB shows first order kinetics with reversible storage and total excretion. This is in sharp contrast with the situation of increasing adipose tissue, i.e. ad libitum feeding, which is characterized by irreversible storage in adipose tissue and limited excretion.     

Age-related changes in disposition and metabolism of benzene in male C57BL/6N mice.

Benzene disposition and metabolism were examined as a function of age in male C57BL/6N mice aged 3 and 18 months. Mice received a single oral dose of either 10 or 200 mg/kg 14C-benzene (approximately 25 microCi/kg). Excretion of 14C-derived benzene radioactivity (RA) was monitored in urine, feces, and as exhaled 14CO2 from 0 to 72 hr, and as exhaled unmetabolized benzene from 0 to 6 hr. At 10 mg/kg 14C-benzene, urinary elimination was the major route of excretion in both 3- and 18-month mice. Urinary excretion of 14C-derived benzene RA was significantly decreased in 18- vs. 3-month mice at 4, 6, 24, and 48 hr, while fecal excretion was significantly increased at 72 hr. Elimination of 14C-benzene as 14CO2 and unmetabolized 14C-benzene was also increased in 18- vs. 3-month mice at this dose. Hydroquinone glucuronide (HQG), phenylsulfate (PS), and muconic acid (MUC) were the major urinary metabolites at 10 mg/kg 14C-benzene in both 3- and 18-month mice, representing approximately 40, 28, and 15% of an administered dose of 14C-benzene. Smaller amounts of phenyl glucuronide (4.0%), pre-phenyl mercapturic acid (1.2%), and catechol glucuronide (0.5%) were also detected. No significant differences were found with age in the percentage of an administered dose of benzene excreted as the various metabolites at 10 mg/kg. At 200 mg/kg 14C-benzene, the total percentage of 14C-derived benzene RA eliminated in urine within 72 hr was not significantly different with age, but elimination at early time points (4, 6, and 8 hr) was significantly decreased in 18- vs. 3-month mice.(ABSTRACT TRUNCATED AT 250 WORDS)