Excretion Of 14C Research Articles

Studies on the Disposition of Finasteride. (I). Absorption, Distribution and Excretion of (14C)finasteride after Single Oral or Intravenous Administration in Rats.

The absorption, tissue distribution and excretion of [14C]finasteride were stu died in male and female rats after oral or intravenous administration. Plasma lev els of intact compound were also measured by HPLC after finasteride administration. 1. After oral administration, [14C]finasteride was rapidly absorbed and reached Cmax (1.23 and 1.38μg/ml) at 1 and 2 hr in male and female rats, respectively. The radioactivity disappeared biexponentially with the T1/2S of 1.4 and 20 hr in males and monoexponentially with the T1/2 of 2.2 hr in females. After in travenous administration, Cmax values of 2.54 and 2.20μg/ml were observed at 30 min and 1 hr in male and female rats, respectively. The presence of this peak was observed only in the case of radioactivity, suggesting the formation of a metabolite with a smaller volume of distribution than the parent drug. T1/2 were similar in both sexes (male, 1.3 hr: female, 1.8 hr). [14C]Finasteride was well absorbed (male, 81% and female, 100%). The non labeled finasteride study showed that oral bioavailability was similar in both sexes (male, 62% and female, 59%), whereas AUC was about 2 times larger in females and T1/2 was longer in females after oral administration. 2. Finasteride was absorbed mainly from the intestine. 3. After oral administration of [14C]finasteride, the maximum concentration in almost all tissues was reached within 1 hr, similar to the plasma peak time (0.5 hr). The radioactivity was especially highly distributed in stomach, liver, and adrenal gland. At 24 hr post dose, the levels in tissues were the same or higher than that of plasma, and then decreased and were lower than 11% of the maxi mum at 72 hr. Similar distribution was observed after intravenous administra tion. The ARG study also supported the above data. 4. [14C]Finasteride was excreted mainly into bile in both sexes, regardless of the route of administration. More than 94% of the radioactivity was excreted into bile during 48 hr, and approximately 30% of the administered radioactivity was reabsorbed due to entero-hepatic circulation.

Human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide

In order to determine the human in vivo percutaneous absorption of pyrethrin and piperonyl butoxide, a commercial formulation containing either [ 14C]pyrethrin (3.8 mCi/mmol) or [ 14C]piperonyl butoxide (3.4 mCi/mmol) was applied to the ventral forearm of six human volunteers. The formulation contained 0.3% pyrethrin and 3.0% piperonyl butoxide. Spreadability studies showed that concentrations of 5.5 μg pyrethrin/cm 2 and 75.8 μg piperonyl butoxide/cm 2 (used in this study) would be consistent with levels found in actual use. The forearms were thoroughly cleansed with soap and water 30 min after application (as recommended for actual use). Percutaneous absorption was determined by urinary cumulative excretion following dose application. With a 7-day urinary accumulation, 1.9 ± 1.2% (SD) of the dose of pyrethrin and 2.1 ± 0.6% of the dose of piperonyl butoxide applied was absorbed through the forearm skin. 1 hr after application blood samples contained no detectable radioactivity. The percutaneous absorption of pyrethrin and piperonyl butoxide from the scalp was calculated to be 7.5% of the applied dose for pyrethrin and 8.3% for piperonyl butoxide. The calculated half-life of 14C excretion was 50 hr for pyrethrin and 32 hr for piperonyl butoxide. The data should be of relevance to appropriate risk assessment in extrapolating animal data to humans.

Further studies on the involvement of selenium in peroxisome proliferation in rat liver: Comparison of effects with clofibric acid and perfluorooctanoic acid and the pharmacokinetics of [ 14C]clofibrate

Most effects of the peroxisome proliferator clofibrate on rat liver are marginal or absent in selenium (Se) deficiency. The purpose of the present study was to determine whether the uptake or distribution of clofibrate is altered by Se deficiency. Rats were fed a Se-adequate or -deficient diet for 10–11 weeks and then these same diets with 0.5% (w/w) clofibric acid (the direct acting hydrolysis product of clofibrate) or 0.02% (w/w) perfluorooctanoic acid (PFOA) for 10 days. Other groups of rats received radiolabeled clofibrate by intubation. Clofibric acid was as ineffective as clofibrate in producing effects (i.e. decreased body weight gain, increases in liver somatic index and protein content of the mitochondrial fraction, and increased activities of catalase and peroxisomal fatty acid beta-oxidation) in the liver of Se-deficient rats. Microsomal omega-hydroxylation was, howeer, equally induced in both dietary groups. In contrast to clofibric acid, the biological effects of PFOA were not affected by Se status. Furthermore, neither the tissue distribution (plasma, liver and kidney) nor the urinary excretion of 14C was affected by Se deficiency. These results demonstrate that the hydrolysis of clofibrate to clofibric acid is not impaired in the Se-deficient rat. In addition, the involvement of Se in the effects of peroxisome proliferators differs for different members of this structurally heterogenous group of compounds. It is concluded that the Se-deficient rat may provide valuable information concerning the biochemical mechanism(s) underlying peroxisome proliferation.

Pharmacokinetics of Cyfluthrin in Spodoptera littoralis (Boisd.). I. In vivo Distribution and Elimination of [ 14C]Cyfluthrin in Susceptible and Pyrethroid-Resistant Larvae

Pharmacokinetics of [ 14C]cyfluthrin were studied for a period of 32 hr following the topical application of 2.5 ng/larva (LD 20 for the susceptible strain) to fourth instar susceptible and pyrethroid-resistant S. littoralis larvae. Penetration rates were determined by rinsing the outer surface of the larvae with hexane. The amounts of 14C-radioactivity in the washed larvae, the feces, and the feeding medium were obtained by catalytic combustions. A compartmental model with curve-fitting was used in order to quantify the rates of penetration, distribution, and elimination of 14C-radioactivity for the 32 hr following treatment. Penetration of [ 14C]cyfluthrin showed identical biphasic kinetics in resistant and susceptible strains, with a rapid increase of the internal cyfluthrin concentration during the first 6 hr followed by a slow first-order loss of penetrated material from the insect body. Kinetics of 14C elimination by the larvae and of 14C recovery in the feces were different in resistant and susceptible larvae. Fitting to a three-compartment model showed that these differences result from changes in the relative capacities of the distributive phase (hemolymph) and the important regurgitation of gut contents in susceptible insects. However, the internal exposure to cyfluthrin was similar in both strains. Resistance did not therefore arise from pharmacokinetic mechanisms, but is more likely to result from modifications of the target sites for pyrethroids.

Fermentation and subsequent disposition of 14C-labelled plant cell wall material in the rat

A 14C-labelled plant cell wall preparation (14C-PCW) produced from spinach (Spinacia oleracea L.) cell culture exhibits uniform labelling of the major polysaccharide groups (%): pectins 53, hemicellulose 13, cellulose 21, starch 3. This 14C-PCW preparation has been used in rat studies as a marker for plant cell wall metabolism. Metabolism of the 14C-PCW occurred largely over the first 24 h. This was due to fermentation in the caecum. The pectic fraction of the plant cell walls was degraded completely in the rat gastrointestinal tract, but some [14C]cellulose was still detected after 24 h in the colon. Of the 14C, 22% was recovered in the host liver, adipose tissue and skin, 26% excreted as 14CO2 and up to 18% was excreted in the faeces. There was no urinary excretion of 14C. In vitro fermentation using a caecal inoculum showed reduced 14CO2 production, 12% compared with 26% in the intact rat. 14C-PCW is a useful marker to investigate the fate of plant cell wall materials in the gastrointestinal tract. These studies show both bacterial fermentation of the 14C-PCW and host metabolism of the 14C-labelled fermentation products.

Extrarenal clearance of oxalate increases with progression of renal failure in the rat.

Oxalic acid is an end product of metabolism, and no significant degradation of oxalate occurs in mammals. The sole route of oxalate excretion is believed to be via the kidney. The extrarenal clearance of oxalate in control rats (N = 16) and in 5/6 nephrectomized rats (N = 25) with renal insufficiency was investigated. [14C]oxalic acid, approximately 2 microCi/day, was infused sc by a mini osmotic pump over 4 days. Excretion of 14C was measured in urine, in feces, and in expired CO2. The 14C content of kidney, heart, liver, muscle and bone was also determined at the time the animals were killed. Plasma oxalate was determined by an enzymatic method and by an isotopic dilution procedure. Creatinine clearance in the controls was 1.82 +/- 0.1 mL/min (mean +/- SE) compared with 0.31 +/- 0.04 mL/min (P < 0.0005) in the nephrectomized rats. Plasma oxalate was 5.6 +/- 0.6 mumol/L in controls and 27.0 +/- 3.9 (mean +/- SE; N = 24) in nephrectomized animals (P < 0.0005). The total 14C recovered in urine, feces, and CO2 combined was similar in both groups. The 14C excreted in the feces over the 4-day period was 27.8 +/- 1.5% (of the 14C recovered) in rats with renal failure and 6.5 +/- 0.5% in controls (P < 0.0005). Percent fecal 14C excretion in nephrectomized rats was inversely correlated with creatinine clearance (r = 0.80; P < 0.0001) and directly correlated with plasma oxalate (r = 0.66; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of pyridoxine in rats fed various levels of casein

[ 14C] pyridoxine (PN) was orally administered to male rats and lactating dams fed an 8%, 20%, or 50% casein diet. There was no effect of the level of dietary protein on plasma pyridoxal 5′-phosphate (PLP) concentration. Analysis of fecal radioactivity indicated no dietary effect on the intestinal absorption of [ 14C]PN. There was greater retention of 14C in the liver when male and lactating rats were fed increased amounts of protein. Increased dietary protein resulted in reduced levels of 14C in the brain of the male rats. There was no dietary effect on the urinary excretion of total 14C or [ 14C]4-pyridoxic acid. Increasing the level of dietary protein resulted in increased retention of 14C in the liver of the lactating dams, however, the concentration of 14C and the 14C:protein ratio in milk was not affected. Although not significant, the level of 14C in the liver of the suckling pups was two or three times greater when dams were fed 8% protein than when dams were fed 20% or 50% protein. These results demonstrate that altered tissue distribution of vitamin B-6 occurs with varied protein intake without influencing the metabolic utilization and urinary excretion of vitamin B-6 or plasma PLP concentration, the primary assessment parameter for vitamin B-6 status. Furthermore, increased intake of protein by the lactating rat does not influence the concentration vitamin B-6 or the vitamin B-6:protein ratio in milk.

Influence of glucocorticoid on the metabolism of aldosterone in the isolated perfused rat liver and kidney

The effect of glucocorticoid deficiency and excess on the extraadrenal metabolism of D-[4- 14C] aldosterone (at 4 nM) was studied by radioimmunoassay and by high-performance liquid chromatography in the isolated perfused liver and kidney of adult Wistar rats. Bilateral adrenalectomy was performed 3 weeks before experiments. In nonadrenalectomized rats, 0.3 mg/kg/day dexamethasone was continuously infused subcutaneously for 1 week before experiments. Adrenalectomy did not affect hepatic or renal metabolism of aldosterone. Dexamethasone treatment did not change the renal handling of aldosterone. However, the hepatic clearance of aldosterone was 19% lower (P < 0.05) in livers of dexamethasone treated rats than in livers of normal rats. After 5 minutes, perfusate [4- 14C] aldosterone metabolites were lower in livers of dexamethasone-treated than in livers of normal rats (P < 0.05). Similar perfusate levels were then obtained. Radiometabolite peaks with similar relative retention times were found in the hepatic perfusate of all groups. However, the ratio between circulating polar metabolites of aldosterone and the metabolites less polar than tetrahydroaldosterone, after 5 and 15 minutes, was highest in livers of dexamethasone-treated rats. Biliary elimination of 14C was similar in all groups. Significant amounts of conjugated tetrahydroaldosterone were only excreted in the bile of dexamethasone-treated rats. In conclusion, glucocorticoid excess reduced the hepatic clearance of aldosterone and changed the pattern of the hepatic metabolites of aldosterone both in circulation and in bile.

The effect of co-administration of parbendazole on the disposition of oxfendazole in sheep.

The effect of intraruminal administration of parbendazole (PBZ) on the flow rate of bile and the pharmacokinetic behaviour of oxfendazole (OFZ) was examined in sheep. PBZ given at 18, 9 and 4.5 mg/kg resulted in a dose-related reduction in bile flow rate which was also inversely related to changing concentration of PBZ and its metabolites in plasma. Co-administration of 4.5 mg PBZ/kg with 5.0 mg [14C]-OFZ/kg resulted in increased concentrations of fenbendazole (FBZ), OFZ and fenbendazole sulphone (FBZ-SO2) in plasma, although total 14C levels remained unchanged compared with that observed when OFZ alone was administered. The presence of PBZ also reduced biliary secretion of 14C by 22% and altered the relative proportions of OFZ metabolites in bile during the 72-h experimental period. The ratio of 4'-hydroxy-OFZ (OH-OFZ) to 4'-hydroxy-FBZ (OH-FBZ) changed from 7:1 in the absence of PBZ to approximately 1:1 in the presence of PBZ. There was no change in urinary or faecal 14C excretion. The PBZ-induced effects were temporary since the pharmacokinetic behaviour of OFZ given alone two weeks before was similar to that given two weeks after PBZ co-administration. It is suggested that the presence of PBZ temporarily slowed hepatic metabolism and biliary secretion of OFZ metabolites but concomitantly increased extra-biliary transfer of OFZ and/or its metabolites from plasma into the gastrointestinal tract. Elevated exposure of parasites in the gut wall to plasma-derived drug, coupled with higher concentrations of anthelmintically active OH-FBZ secreted in bile, could contribute to the previously reported increased efficacy of OFZ when co-administered with PBZ.

Body distribution of fully biodegradable [ 14C]-poly(lactic acid) nanoparticles coated with albumin after parenteral administration to rats

Fully biodegradable polylactic acid (PLA) nanoparticles (90–250 nm) coated with human serum albumin (HSA) were prepared by high-pressure emulsification and solvent evaporation, using the protein as surfactant. A new analytical tool was developed, based on Mie's law and size exclusion chromatography, to establish that, after evaporation of the solvent, the protein saturates the surface of the nanoparticles, masking the PLA core. According to this technique, no HSA is encapsulated in the polymer matrix. A radiolabelled [ 14C]-PLA 50 was synthesized to follow the fate of this new drug carrier after i.v. administration to rats. The time necessary to clear the albumin-coated nanoparticles from the plasma was significantly longer than for the uncoated ones but not extended enough to target cells other than mononuclear phagocytes. As deduced from whole-body autoradiography and quantitative distribution experiments, the 14Cl-abelled polymer is rapidly captured by liver, bone marrow, lymph nodes, spleen and peritoneal macrophages. Nanoparticle degradation was addressed following 14C excretion. The elimination of the 14C was quick on the first day (30% of the administered dose) but then slowed down. In fact, if the metabolism of the PLA proceeds to lactic acid which is rapidly converted into CO 2 via the Krebs cycle (80% of the total excretion was fulfilled by the lungs), anabolism from the lactic acid may also have taken place leading to long-lasting radioactive remnants, by incorporation of 14C into endogenous compounds.

Pharmacokinetic Studies of 6-amidino-2-naphthyl 4-((4,5-dihydro-1H-imidazol-2-yl)amino) benzoate dimethanesulfonate (FUT-187). (1). Absorption, Distribution and Excretion after a Single Oral Administration to Rats.

6-Amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate (FUT-187), a novel protease inhibitor, is an ester of 4-[(4, 5-dihydro-1H-imidazol-2-yl)amino]benzoic acid (IABA) and 6-amidino-2-naphthol (AN). Absorption, distribution and excretion of FUT-187 were investigated in rats after single oral (1. 10. 30 and 100mg/kg) or intravenous (1 mg/kg) administration of [14C-IABA] FUT-187 or [14C-AN] FUT-187. 1. Blood levels of radioactivity (14C) after oral administration were higher in case of [14C-AN] FUT-187 administration, however, after intravenous administration, higher blood levels were observed in case of [14C-IABA] FUT-187. It was suggested, from the viewpoint of the different profiles of blood levels of 14C, that FUT-187 was easily hydrolized to its constituents by calboxvl-esterases. 2. Tissue distribution pattern of 14C was similar to the blood levels profiles. High levels of 14C were observed in the liver and kidney after oral administration of both forms of labeled FUT-187, but there was no evidence of accumulation of 14C in any tissues. 3. In general, urinary excretion of 14C after oral administration was higher in case of[14C-AN] FUT-187 administration, but the excretion ratio was not proportional to administered dose.4. The levels of 14C in the milk and fetuses were lower than those in the meternal blood.5. Binding of 14C to human, dog or rat serum albumins was about 10.2 ?? 35.2%.

Metabolic Fact of a New 5-HT3 Receptor Antagonist, Y-25130. (I). Plasma concentration, Distribution, Metabolism and Excretion of 14C-Y-25130 after Intravenous Administration to Rats.

The plasma concentration, distribution, metabolism and excretion of 14C-Y-25130 were investigated in rats after intravenous administration. 1. Plasma levels of radioactivity (14C) decreased multiexponentially at the dose levels of 0.4, 1, 2, 10mg/kg, and the terminal half-lives (t1/2z) were 8.4 -9.5 hours. No dose or sex differences in t1/2z were observed. The areas under the plasma level-time curve were approximately proportional to the dose. Tissue levels of 14C were high in the liver, lung, kidney, pituitary gland, submaxillary gland, pancreas, stomach, adrenal, bone marrow, thyroid and spleen. Radioactivity rapidly disappeared from all tissues and was not detected in carcasses 96 hours after administration, suggesting no accumulation of 14C. 2. Binding rates of 14C to plasma proteins were 42.8-44.6% during 0.25-2 hours after administration. 3. Four days after administration to male rats at a dose of 1 mg/kg, urinary and fecal excretion of 14C were 45.5% and 52.9% of administered dose, respectively. At this dose, urinary excretion was much higher in female rats than in male rats. The excretion in male rats increased significantly at the highest dose level. Unchanged drug was found mainly in urine, while the unchanged drug, M1 and M3 were present in feces. The amount of unchanged drug in urine was much higher in female rats than in male rats. This amount increased at the highest dose level in male rats. 4. Fourty eight hours after administration to bile-duct cannulated male rats, 42.0% of the dose was excreted in bile and 12.8% in feces. This result indicates that another direct excretion route to the gastrointestinal tract exist besides the bile. About 13% of 14C excreted in bile was reabsorbed from the intestines by the enterohepatic circulation.

Comparative metabolism of the cysteine and homocysteine conjugates of propachlor by in situ perfused kidneys of rats.

1. 14C-Cysteinyl- and homocysteinylpropachlor were metabolized to their respective mercapturic acids by rat kidneys in situ. First-pass elimination of 14C in urine was 47.5% for the cysteine conjugate and 36% for the homocysteine conjugate. 2. About half of the perfused 14C-labelled material isolated from urine from kidneys perfused with homocysteinylpropachlor was unchanged homocysteinylpropachlor and about half was the corresponding mercapturic acid. However, only the corresponding mercapturic acid and the S-oxide of this mercapturic acid (31.4% and 1.7% of the dose) were found in urine from kidneys perfused with cysteinylpropachlor, indicating that rat kidneys more efficiently acetylated the natural substrate, the cysteine conjugate.

Disposition of Parathion in Neonatal and Young Pigs

Pharmacokinetics, metabolism (in vivo and in vitro), elimination and tissue distribution of 14C-parathion was studied after intravenous administration of 0.5 mg/kg to newborn, 1 week and 8 weeks old piglets. Body clearance increased from 7 ml/min./kg in newborn to 35 and 121 ml/min./kg in 1 and 8 weeks old piglets, respectively. Urinary excretion during the first 3 hr rose from 18 to 48 and 82% of the dose in newborn, 1 and 8 week old piglets. The main metabolite of parathion was p-nitrophenyl-glucuronide making up 85% of the urinary 14C excretion. About 6% was excreted as p-nitrophenyl-sulfate and only 1% as free (non-conjugated) p-nitrophenol. Unchanged parathion or paraoxon was not detectable in urine from any of the age groups. The in vitro experiments showed that biotransformation of parathion took place only when cofactors for oxidative reactions were present, indicating that oxidation is the first and necessary metabolic step and that hydrolysis does not contribute significantly to the elimination of parathion. The highest concentration of 14C 3 hr after administration was found in kidney and liver. In newborn piglets the 14C-concentration in tissues was higher than or equal to the plasma concentration. The 14C tissue/plasma ratio decreased with age for all tissues except kidney. Parathion was present in high concentrations in plasma, liver and kidney from newborn piglets, whereas the level just exceeded the detection limit in the 8 week old ones. Paraoxon was clearly detectable in plasma and liver from newborn piglets, while only traces were found in the older groups.

The excretion and characterization of intravenously administered olestra

Although sucrose octaoleate that is consumed is neither digested or absorbed, following intravenous injection it is found mainly in the liver. Olestra is a mixture of the hexa-, hepta-, and octaesters of sucrose. To follow the metabolic fate of intravenously administered [14C]sucrose-labeled olestra, we measured its urinary elimination, and the rate of excretion of 14C in the feces, and characterized the 14C-labeled material that appeared in bile. The fecal excretion for days 4-14 after dosing was found to be first order with the half-life of the injected olestra being 5.0 +/- 0.5 days. The 14C recovered in the bile was soluble in chloroform. Two-dimensional thin-layer chromatography autoradiograms of the biliary lipid showed the pattern of the biliary 14C to be essentially the same as that of the dosed olestra. Biliary excretion and subsequent fecal egestion of essentially unhydrolyzed sucrose esters is the principal route for the removal of intravenously administered olestra. Only traces of 14C were found in the urine.

Influence of 2,2'‐dichlorobiphenyl and 2,4,6‐trichlorophenol on development of rainbow trout eggs and larvae

Eggs of rainbow trout (salmo gairdneri) were exposed to 10 μg/l of 2,2'‐dichlorobiphenyl (DCB) or 200 μg/l of 2,4,6‐trichlorophenol (TCP) immediately after fertilisation in a static system using 14C‐labelled substances. After three days of exposure DCB‐concentration in fish eggs reached equilibrium with the concentration in water with a bioaccumulation factor of 609–648. The TCP‐concentration in fish eggs increased steadily during the exposure period. Nine (TCP) or thirteen (DCB) days after reaching the eye stage depuration was started and continued until 74 days after fertilisation. Elimination of 14C was fit to first order kinetic equations using least squared regression analysis. No negative effects of both chemicals on fertilisation of fish eggs could be observed. Hatching was decreased in eggs exposed to TCP (38%) compared to DCP (84%) or controls (77%). Eggs kept in TCP exhibited a high incidence of deformations (73 %). For DCB and controls the deformation rates were 21% and 12%, respectively.

Disposition of perfluorodecanoic acid in male and female rats

The elimination, tissue distribution, and metabolism of [1- 14C]PFDA were examined in male and female rats for 28 days after a single ip dose (9.4 μmol/kg, 5 mg/kg). A sex difference in the fecal elimination of perfluorodecanoic acid (PFDA) was observed with 51 and 24% of the administered 14C being recovered in the feces of male and female rats, respectively, by 28 days post-treatment. The cumulative excretion of PFDA-derived 14C in the urine in 28 days was less than 5% of the administered dose in both sexes. The sex-related difference in the rate of fecal elimination resulted in the observed difference in whole body elimination t 1 2 of PFDA in males ( t 1 2 = 23 days ) and females ( t 1 2 = 45 days ). The liver contained the highest concentration of PFDA-derived 14C in both males and females, followed by the plasma and kidneys. The heart, fat pads, testes, and gastrocnemius muscle of males, and the ovaries of females contained much lower concentrations of PFDA. The reason for the high percentage of the ip dose of [1- 14C]PFDA in the liver (53% males and 41% females, 2 hr post-treatment) was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that approximately 25% of the [ 14C]PFDA in the perfusate was extracted by the liver in a single pass. The basis for the sex difference in fecal elimination of PFDA does not appear to be due to a sex difference in biliary excretion. In a 6-hr period, male and female rats with kidneys ligated ȩliminated essentially the same percentage dose of [ 14C]PFDA into bile. We had hypothesized that the persistence of PFDA in rats was due to formation of a PFDA-containing lipid (i.e., a [ 14C]PFDA-containing mono-, di-, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid). However, no evidence that PFDA is conjugated to form persistent hybrid lipids was obtained, nor were polar metabolites of PFDA detected in urine or bile. In addition, daily urinary excretion of fluoride in male and female rats before and after PFDA treatment was similar, suggesting that the parent compound is not defluorinated. Thus, the disposition of PFDA in male and female rats is characterized by an apparent lack of biotransformation.

Excretion and distribution of nitrite-treated or untreated 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid in rats

The excretion and distribution of 14C were studied in rats given by oral intubation 14C-labelled (−)-(1 S,3 S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid and its stereoisomer, (−)-(1 R,3 S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCAs), compounds that are known to become mutagenic on reaction with nitrite. For comparison, another group of rats was given by oral intubation products of the in vitro treatment of [ 14C]MTCAs with nitrite. When rats were given the untreated [ 14C]MTCAs, most of the 14C was excreted in the faeces within 24 hr and was noted only in the intestine on autoradiograms of rats killed 30 min and 6 hr after dosing. In contrast, when rats were given the nitrite-treated [ 14C]MTCAs, 14C was mainly excreted in the urine within 24 hr and was noted not only in the intestine but also in the liver and kidney on autoradiogram. These results suggest that the majority of MTCAs pass rapidly through the gastro-intestinal tract, while the bulk of the reaction products of MTCAs with nitrite are absorbed from the gastro-intestinal tract and excreted in the urine.

The metabolism of 4-aminobiphenyl in rat. I. Reaction ofN-hydroxy-4-aminobiphenyl with rat bloodin vivo

1. 3H-4-Aminobiphenyl (ABP, 5 mg) given i.p. to rat had elimination half-lives of 15.6, 17 and 17 h, respectively, for urinary, faecal and total 3H elimination. 14C-ABP administered orally to rats at 100 mg/kg gave elimination half-lives of 31, 36.7 and 34 h, respectively, for urinary, faecal and total 14C elimination. 2. Semi-log plots of percentage dose remaining in the body versus time indicated that: (i) 82% of 3H activity was excreted in 36 h with a half-life of 14.4 h and 18% with a half-life of 46.2 h, and (ii) 77% of 14C activity was excreted in 48 h with a half-life of 15 h and 23% with a half-life of 180 h. 3. After i.p. injection of 10 mg/kg 14C-ABP to rats, ferrihaemoglobin (HbFe3+) concn increased to 60% in 2 h, accompanied by accumulation of 14C activity in erythrocytes, indicating that the active metabolite, N-hydroxy-4-aminobiphenyl (N-hydroxy-ABP) had oxidized haemoglobin-Fe2+ (HbFe2+) and was bound to the erythrocyte. 4. ABP given i.p. to rats at 0.24 mmol/kg rapidly appeared in blood, disappeared with a half-life of 30 min, and blood concn plateaued at 30 nmol/ml. The concn of 4-acetyl-aminobiphenyl (AABP) plateaued at 17 nmol/ml after 15 min, indicating a dynamic equilibrium between N-acetylation of ABP and N-deacetylation of AABP. The concn of 4'-hydroxy-4-acetylaminobiphenyl (4'-hydroxy-AABP) increased slowly at 1.65 nmol/h. 5. AABP given i.p. to rats at 0.88 mmol/kg slowly appeared in the blood, accompanied by the appearance of ABP and 4'-hydroxy-AABP and formation of HbFe3+. After 4 h the concn of AABP and ABP was 27-35 mmol/ml, indicating a dynamic equilibrium between N-deacetylation of AABP and acetylation of ABP. Neither N-hydroxy-ABP nor N-hydroxy-4-acetylaminobiphenyl (N-hydroxy-AABP) were found.

Effect of Processing on Fate of Dietary [14C]Taurine in Cats

The objective of this study was to determine the fate of a pulse-labeled oral dose of uniformly labeled [14C]taurine in cats fed four separate diets. The diets were a heat-processed commercial diet, the same diet frozen-preserved and two purified diets containing 0 or 1325 mg taurine/kg. The commercial formulations contained 1070 mg taurine/kg dry matter (by analysis). The excretion of 14C in CO2, urine and feces was monitored. Significant quantities of 14CO2 were produced, with greater amounts excreted by cats fed the heat-processed commercial diet (9.4% of initial dose) than by those fed the frozen-preserved diet (0.09%), indicating extensive taurine degradation by the intestinal microflora. Purified diet groups were intermediate between the two commercial diet groups. Carbon-14 excreted in urine peaked at 24 h and was highest for cats fed the frozen-preserved commercial diet or 1325 mg taurine/kg purified diet. Carbon-14 excreted in feces was highest for cats fed the two commercial diet formulations, with peak amounts at 48-72 h. Because the frozen-preserved commercial diet had previously been shown to maintain plasma taurine concentration, whereas the heat-processed diet did not, these results indicate that processing affects the digestive and/or absorptive process in a manner that increases the catabolism of taurine by gastrointestinal microorganisms.