Tissue Levels Of Radioactivity Research Articles

The absorption and distribution of 14C-bacitracin in rainbow trout (Salmo gairdneri) after a single oral dose, as observed by whole body autoradiography.

This study was performed to investigate the absorption, distribution and elimination of orally given radiolabelled bacitracin methylene disalicylate (BMD) in rainbow trout kept in salt water. The level of radioactivity in skeletal muscle tissue remained low, but stable throughout the experiment, while radioactivity in bile and liver tissue increased for about 48 hr, before decreasing. There was a trapping of BMD and/or its metabolites in excretory kidney tissue, where the amount of radioactivity continued to increase when radioactive material was being removed from other tissues. The maximum concentration found in excretory kidney tissue was about 7 times as high as the maximum concentration found in the liver. Even though there is no appreciable absorption of BMD from the gastrointestinal tract in homoiotherms, we found the absorption in rainbow trout to be significant.

Effect of diet and route of administration on the DNA binding of aflatoxin B1 in the rat.

The effects of dietary Brussels sprouts and indole-3-carbinol (I3C) on xenobiotic-metabolizing enzyme activities and hepatic aflatoxin B1 (AFB1)-DNA binding were determined in rats. Animals were dosed intraperitoneally (i.p.) or intragastrically (i.g.) with [3H]AFB1 and killed 2 (i.p.) or 3 (i.g.) h later. Brussels sprouts caused a significant (P less than 0.01) 50-60% decrease in hepatic AFB1-DNA binding, and increased hepatic and intestinal glutathione S-transferase (GST) activities. Hepatic mono-oxygenase (AHH and ECD) activities were not altered in sprouts-fed rats, but greater than 2-fold increases in intestinal AHH and ECD activities were found. Although I3C increased intestinal AHH and ECD activities similarly to Brussels sprouts, I3C did not significantly decrease AFB1 binding, nor did it increase hepatic or intestinal GST activity. Route of administration did not alter the percentage inhibition of binding in comparison to control rats in either treatment group, suggesting that the small intestine may not play a significant role in the metabolism of AFB1. In a second experiment, rats were dosed either i.p. or i.g. with [3H]AFB1 and killed 2, 6, 12, 24 or 48 h later. Hepatic AFB1-DNA binding and tissue radioactivity levels were determined. Brussels sprouts once again significantly (P less than 0.001) decreased hepatic AFB1-DNA binding. Route of administration of the carcinogen did not affect DNA binding over time in sprouts-fed animals, confirming our previous results.

磁性体フェライト微粒子の静注によるマウスにおける生体内分布とその影響に関する研究

We undertook an experimental study on the tissue distribution of ferrite and its injurious effect on mice organs at various time points after intravenous administration. The tissue distribution of ferrite was observed by autoradiography. Furthermore, sample radioactivity counting was done for blood and main organs, such as the heart, lung, liver, kidney, and spleen. Further, biochemistry studies and light and transmission electron microscopic studies were carried out. 1) After intravenous administration of radioactive ferrite, the radioactivity was distributed in organs and tissues as follows. i. The autoradiograms showed increased uptake of radioactivity in the lungs and liver. The uptake of radioactivity in the lungs was the highest immediately after dose administration and declined with time thereafter. In the liver, on the other hand, there was increased uptake 1 hour after dose administration, without showing any appreciable decrease with time thereafter. ii. Tissue uptake of radioactivity as determined by the sample counting method was the highest in the lungs of all organs at 30 to 60% of total dose, and the liver ranked second at 14 to 35%. In other organs, tissue uptake of radioactivity was minimal, ranging from 0.1 to 1.4%. In time the tissue radioactivity levels were such that the lungs showed the highest increase immediately after dose administration, with a subsequent gradual decrease, while the liver showed a gradual increase with time. The accumulated uptake of radioactivity per gram of tissue was the highest in the lungs of all organs. The temporal change of tissue radioactivity levels was such that the spleen tended to show an increasing uptake with time. One week after dose administration, the spleen showed about the same uptake as the liver. 2) The injurious effects that radioactive ferrite exerted on organs and tissues after intravenous administration are as described below. i. Biochemistry studies indicated that the treated animals had slight hepatic function impairment at 1 and 3 months after dose administration. On the other hand, there was no remarkable change in their renal function. Serum levels of Fe showed little change throughout the study. ii. Examination under LM (light microscope) and TEM (transmission electron microscope) revealed ferrite deposition in the lungs throughout the study. In light micrographs, there was a slight degenerative change in the alveolar wall in the lungs at 1 day after dose administration, but it was recovered in 1 week. On the electron microscopic level, the tendency was similar to that of the lungs.(ABSTRACT TRUNCATED AT 400 WORDS)

Metabolic fate of the new .BETA.-adrenoceptor antagonist, bisoprolol, in animals (1): Absorption, distribution and excretion of 14C-bisoprolol in rats.

The absorption, distribution and excretion of bisoprolol were studied in rats after oral or intravenous administration of 14C-bisoprolol (1 mg/kg). 1. 14C-Bisoprolol was readily and almost completely absorbed from the gastrointestinal tract.2. Following oral administration, serum levels of radioactivity reached a maximum at 1 hr, and declined relatively rapidly with a half-life of 1.2 hr.3. Maximum levels of radioactivity in most tissues were reached within 1 hr after oral administration, and high levels of radioactivity were observed in the liver, kidney and lung. At 24 hr, slight radioactivity was found only in the excretory organs.4. Excretion of radioactivity was 70-80 % and 15-25 % of the dose in urine and feces, respectively, within 72 hr in either route of drug administration. No sex difference was observed in excretion of radioactivity.5. Biliary excretion of radioactivity was 22-26 % of the dose irrespective of dosage route, and partial reabsorption of biliary excreta occurred from the intestinal tract.6. The extent of in vitro binding of 14C-bisoprolol to plasma proteins of various animal species was 18-23 % in rats, rabbits and dogs, while that in human was about 40 %. The binding of bisoprolol to human plasma proteins was not affected by other co-administered drugs. In the in vivo experiment, the percent binding of 14C-bisoprolol and/or its radioactive metabolites to the rat plasma protein was about 17 % after the intravenous dose and about 8 % after the oral dose.7. Whole body autoradiograms obtained with pigmented rats demonstrated that specific binding of radioactivity to melanin containing tissues was noticed.

Metabolic fate of the new .BETA.-adrenoceptor antagonist, bisoprolol, in animals (2): Tissue accumulation after consecutive oral administration of 14C-bisoprolol in rats.

Accumulation characteristics of bisoprolol were studied in male rats after the consecutive oral administration (1 mg/kg/day) of 14C-bisoprolol for 14 days.1. After single oral administration of 14C-bisoprolol to fasted and non-fasted rats, no significant differences were observed in the Cmax, t1/2 and AUC (0-24 hr) values of blood radioactivity levels between two groups.2. During the consecutive oral administration, the blood radioactivity levels at 1 hr after each dosing reached the steady-state level following the second administered dose.3. The daily excretion of radioactivity in urine and feces was almost constant throughout the period of consecutive administration. The cumulative excretion of radioactivity in the urine and feces accounted for 72.3 % and 29.3 % of the total dose, respectively, within 72 hr after the final administration. The excretion pattern was similar to that achieved in the single-dosing group.4. At 1 hr after the consecutive oral administration (7 and 14 times), levels of radioactivity in the tissues tested were not significantly higher than those after single administration. At 24 hr after the final administration, radioactivity levels in most tissues decreased near the detection limit in either administration group.5. Thus, there was not any accumulation of the drug and its metabolites in the organs and tissues of rats following the consecutive oral administration of this drug.

Disposition of the Aldose Reductase Inhibitor AL01576 in Rats

The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4mg/kg intravenous bolus and oral doses of [14C] AL01576 were administered and levels of radioactivity in blood, excreta, and various tissues were determined over a 168-h period. The decline of radioactivity in blood was quite similar for the two routes of administration, with an apparent half-life of ~30 h. At 120 to 144 h, a second, slower elimination phase began that was not fully characterized in the 168-h duration of the study. The HPLC analysis of plasma samples revealed intact AL01576 as the only compound in plasma. The mean plasma parent and radioactivity concentrations are in agreement; suggesting the absence of or an insignificant amount of metabolite in the plasma. The urinary and fecal excretion rate data showed a kinetic pattern similar to that of blood radioactivity. Fecal excretion was the primary route of elimination following both intravenous and oral dosing, accounting for 59% of the administered intravenous dose and 61% of the oral dose. Urinary excretion accounted for 32% of the intravenous dose and 29% of the oral dose. Negligible amounts of radioactivity were recovered as expired 14CO2. Experiments with bile-duct cannulated rats confirmed that the major route of elimination of the drug is biliary excretion. The pattern of distribution of [14C] AL01576 in tissues was quite similar following the two routes of administration. Tissue radioactivity concentration peaked at 4 h (the first sampling time) following both routes of administration in all tissues except the Gl tract. The highest radioactivity concentrations at 4 and 24 h were in the Gl tract, kidney, adrenals, and liver. At 168 h, the highest concentrations of radioactivity were found in the testes, kidneys, lungs, and adrenals, although the recovery from these four tissues combined represented <0.5% of the administered dose. After intravenous dosing, the recovery of radioactivity in the selected tissues (blood, liver, kidney, lung, brain, heart, spleen, testes, muscle, eyes, adrenals, skin, fat, and Gl tract) measured was 82, 75, 13, and 4% of the administered dose at 4, 24, 72, and 168 h, respectively. Overall, the data suggest that AL01576 is readily absorbed when administered orally, is distributed throughout the body tissues, is excreted predominantly by the feces through biliary excretion, and has a low systemic clearance and a long biologic half-life.

Studies on biological fate of 14C-trazodone hydrochloride in rats.

Absorption, distribution and excretion of trazodone hydrochloride, a new antidepressant, after single and repeated oral administration in rats were studied using 14C-labelled drug (14C-trazodone hydrochloride). After single dose (4 mg/kg), the concentration of radioactivity in blood increased rapidly in male and female rats, suggesting rapid absorption of this drug. Similarly, tissue levels of radioactivity were immediately increased after the administration and declined thereafter without delay, which was consistent with the results of wholebody autoradiography. Urinary and fecal excretion during 96 hours was 38.6 and 60.1 % of total ingested radioactivity, respectively. At least 72.9 % of radioactivity excreted in bile was shown to be reabsorbed, which suggested significant contribution of enterohepatic circulation to time course of blood concentration. Concentration of radioactivity in the milk of lactating rats was slightly higher than that in the blood. Plasma protein binding of 14C-tradozone was shown to be constant within the concentration range studied in both in vitro and in vivo, although a large difference in fraction bound (88.7-89.9 % and 33.1-41.5 % for in vitro and in vivo, respectively) was found. After repeated oral dose (4 mg/kg/day), values of Cmax, AUC and T1/2 in blood concentration and tissue levels of radioactivity tended to increase with increasing administration period. However, values of tissue-to-plasma concentration ratio and the minimum blood concentration after each administration had reached the steady-state after 14 th administration. Ratio of radioactivities excreted into urine and feces was not so much changed by multiple dosing.

Studies on the metabolic fate of S-3460. (II). Absorption, distribution and excretion after repeated subcutaneous administration to rats.

The absorption, distribution and excretion of S-3460 in male rats were studied following 7- or 28-day period of daily subcutaneous administration of 3H-S-3460 or 14C-S-3460 at 0.5 mg/kg. 1. The concentrations of radioactivity in plasma and blood 24 hr after daily administration rose with increasing of dosing times, and its concentration after the 28 th dose was 4.3 and 17 times higher than that after a single dose, respectively. Thus, it seems that the accumulation in plasma is low while that in blood is significantly high. Tissue concentration of radioactivity also rose and reached plateau levels by the 28 th dose in most tissues except for the blood, kidney and spleen. 2. The concentrations of radioactivity in the plasma, blood and most tissues after repeated administration of 3H-S-3460 were slightly higher than those after a single dose, but the disappearances were significantly slow. In some tissues, the levels after 3H-S-3460 administration differed from those after 14C-S-3460 administration. This may have been due to detachment of 3H from the 1, 2 position of 3H-S-3460. Tissue levels of radioactivity in female rats were lower than those in male rats and transfer of radioactivity with blood cell was also low. 3. Excretion of radioactivity into the urine and feces was almost constant during repeated administration and that after the 7 th or 28 th dose was similar to that after a single dose. Most of the radioactivity was excreted via the feces in both male and female rats.

Uptake of low density lipoproteins by rat tissues. Special emphasis on the luteinized ovary.

The aim of this study was to determine how luteal cells of the hormone-primed (luteinized) ovary process low density lipoproteins (LDL). Ovary uptake of perfused 125I-LDL was assessed by tissue levels of radioactivity; the distribution of LDL protein in cells was assessed on autoradiograms of the fixed tissue; and the level of stimulation of steroidogenesis, as well as degradation of LDL protein, was assessed on effluent perfusion samples. Human LDL ligand used in these studies was rigorously defined biochemically and physiologically. Homologous (rat) LDL was used as a special ligand control. Other tissue controls included the use of perfused or in vivo-infused luteinized ovaries from animals pretreated to reduce circulating lipoprotein levels, perfused ovaries from a second hormone-primed model, perfused liver from estrogen-treated rats, and isolated and cultured cells from the same ovarian tissues used in the perfusion experiments. The results show that perfused LDL promptly stimulates steroidogenesis. However, the labeled protein moiety of the LDL is not interiorized by the luteal cells, nor is there evidence of LDL protein degradation in the effluent samples. In contrast, internalization of the ligand occurs when luteal cells are incubated with the ligand in vitro. We have observed also that uptake of the 125I-LDL by the ovary can be displaced equally well by excess unlabeled LDL or HDL3. Overall, these experiments suggest that in the intact luteinized ovary, LDL binds to the same sites on the cell surface where HDL "binds," and that LDL cholesterol must be obtained by these steroid hormone-producing cells by a mechanism that does not require internalization of the intact lipoprotein particle.

Tissue Distribution and Excretion of Copper-67 Intraperitoneally Administered to Rats Fed Fructose or Starch

It has been suggested that impaired gut absorption of copper is the cause of the exacerbated copper deficiency signs in rats fed fructose when compared to rats fed starch. The present study was designed to examine how rats fed fructose or starch diets, either copper-deficient or supplemented, distributed and excreted 67Cu when the isotope was administered i.p. Intraperitoneal administration was chosen in an effort to circumvent primary gut absorption as a factor in the metabolism of 67Cu. After 7 wk of dietary treatment, rats received an i.p. injection of 67Cu and were placed in metabolic cages for 4 d. Regardless of dietary carbohydrate, copper-deficient rats retained similar levels of radioactivity in various tissues and excreted similar amounts of 67Cu in feces and urine. This similarity in copper metabolism in copper-deficient rats fed either fructose or starch when the gut was circumvented for isotope administration suggests that the gut could be responsible, at least in part, for the exacerbated signs associated with the copper deficiency in rats fed fructose. The possibility is discussed that alterations in metabolism may increase the requirement for copper when fructose is the main dietary carbohydrate.

In vivo imaging of intracranial human glioma xenografts comparing specific with nonspecific radiolabeled monoclonal antibodies.

Current diagnostic and therapeutic modalities for malignant human gliomas are largely nonspecific. The development of monoclonal antibodies (MA's) with their high degree of specificity may allow precise tumor imaging and selective administration of therapeutic agents. However, the ability of these antibodies to specifically localize tumor tissue in vivo remains speculative. This study compares the localization and imaging properties of two MA's: a specific human glioma-associated extracellular matrix glycoprotein MA, 81C6, and a nonspecific control MA, 45.6, against a human glioma cell line, D-54 MG, intracranially inoculated into athymic rats. Forty-one animals received MA's labeled with iodine-131 (131I) or 125I and underwent imaging with a gamma camera. The images were independently evaluated and compared to tissue radioactivity levels. Radiolabeled antiglioma MA 81C6 specifically localized in intracranial xenografts. The percent of injected dose per gram of tissue for tumor was 1.707 +/- 0.405/gm for 81C6 and 0.118 +/- 0.056/gm for 45.6. All other organs had equivalent levels of specific and nonspecific MA's. For brain, these were 0.004 +/- 0.002/gm and 0.005 +/- 0.005/gm, respectively, and for the other organs, the range was from 0.053 to 0.284/gm. Statistically, 45.6 achieved levels in tumor that were significantly higher than normal brain (p less than 0.05) but significantly less than that achieved with 81C6 (p less than 0.005). With 81C6, the degree of localization was high enough to allow imaging of intracranial tumors at sizes as small as 20 mg. Intracranial tumors were imaged with 45.6 only when they achieved sizes greater than 300 mg. In this imaging study, radiolabeled 81C6, a specific antiglioma MA, proved to be significantly better for imaging small and intermediate-sized tumors than the control MA's. Large tumors were visualized by both MA's, although higher quality scans were obtained earlier and more frequently with specific MA's than with nonspecific immunoglobulin G. These data suggest that specific MA's have a role to play in both the diagnosis and treatment of primary intracranial human tumors.

Deposition of ultrafine aggregate particles in exercising rats

The effect of exercise on particle deposition in rats was investigated. Twenty male rats were trained to run on a treadmill and were exposed to gallium-67 oxide (67Ga2O3) particles (0.1 micron activity median diffusion diameter) for 30 min while running at 30 m min-1. Twenty resting controls were exposed in the same system while confined in wire mesh cages. Ten exercising and 10 resting rats were killed 2 h and 12 days after exposure. Tissue radioactivity levels of 67Ga2O3 were measured and normalized for differences in exposure concentration and body weight. Significantly (P less than 0.05) more 67Ga was deposited in the nasal passages (20 vs 5 nCi) and in the trachea and mainstem bronchi (0.05 vs 0.03 nCi) of exercising rats than in resting rats. There were no significant differences between the exercising and resting rats in amounts of 67Ga in the lung lobes at 2 h after exposure. Using assumed minute volumes, exercising rats had a significantly (P less than 0.05) lower lung deposition efficiency, expressed as percentage of estimated inhaled material, than did resting rats (3 vs 10%). The results suggest that exercising rats inhale more ultrafine particles, but deposit a smaller fraction of them in their lungs. The result is a similar lung burden of 0.1 micron particles in resting and exercising animals.

Effect of phenobarbital and polychlorinated biphenyls on the toxicity and disposition of 1,2,4,5-tetrachlorobenzene in the rat

Control and phenobarbital (PB) or polychlorinated biphenyl (PCB) pretreated rats were given single oral doses of 14C-1,2,4,5-tetrachlorobenzene (TCB) at 30 or 300 mg/kg b.w. Urine and feces were collected daily for the determination of 14C-content. Five animals per group were killed 2 days after dosing and another five animals were killed 7 days later for the determination of hepatic microsomal enzyme activities, histological changes and 14C-content in the major organs and tissues. Pretreatment with PCB or PB did not alter the effects of TCB biochemically or histologically. Both PB and PCB increased the rate of TCB excretion and decreased the levels of radioactivity in most tissues examined at 7 days after dosing. It was concluded that, at the dose ranges studied, pretreatment with PB or PCB did not significantly alter the toxic effects produced by TCB.

The bioaccumulation and biotransformation of cis, trans‐cypermethrin in the rat

AbstractThe disposition of the pyrethroid insecticide cypermethrin, (RS)‐a‐cyano‐3‐phenoxybenzyl (1RS)‐cis, trans‐3‐(2,2‐dichlorovinly)‐2, 2‐dimethylcyclopropane‐carboxylate, has been studied in male and female rats following a single toxic oral dose (200mg kg−1) of two radiolabelled forms ([14C‐benzyl] and [14C‐cyclopropyl]) of the insecticide. The bioaccumulation and elimination of 14C‐benzyl‐labelled cypermethrin, following repeated administration at a sub‐toxic dose (2mg kg−1), has also been studied in male and female rats. Although, at the toxic dose, radioactivity from the two radiolabelled forms was rapidly eliminated in urine and faeces, the increased excretion in the faeces, over that for low doses, was evidence that absorption was incomplete. The major pathways of metabolism involved cleavage of the ester bond, with subsequent hydroxylation and glucuronidation of the cyclopropyl acid moieties, together with hydroxylation and sulphation of the 3‐phenoxybenzyl moiety. The absence of sex‐ or dose‐dependent changes was reflected by the constant proportions of these metabolites found in the urine. Constant levels of radioactivity in tissues were achieved rapidly, generally within the first week of repeated administration. Elimination was rapid on the cessation of dosing, although less rapid from the fat and skin. The material in the fat was mainly the cis‐isomers of cypermethrin, which were eliminated with a mean half‐life of 18.2 days, compared with 3.4 days for the trans‐isomers.

Transport of [ 14C]coenzyme Q 10 from the liver to other tissues after intravenous administration to guinea pigs

After intravenous injection of [ 14C]coenzyme Q 10 into guinea pigs, the blood level of radioactivity declined rapidly within 30 min. However, radioactivity in the blood subsequently increased, reached a peak at 8 h after the injection and thereafter decreased slowly. Since the liver uptake of radioactivity at 30 min after the injection was 87.8% of the dose and the increase of blood level was also seen in guinea pigs with bile duct fistula, it was concluded that the radioactivity taken up by the liver was redistributed to the blood and then transferred to other tissues. Tissue radioactivity levels were highest in the liver and spleen at 30 min after the injection and decreased thereafter. The levels in the blood and kidney peaked at 8 h, while those in the heart and brain peaked at 24 h and subsequently decreased. In contrast, the level in the adrenal gland was still increasing at 168 h after the injection; it rose sharply from 30 min, and at 24 h was higher that the level in any other tissue. Electrophoretic analysis showed that the radioactivity in serum at 8 h after the injection was associated with lipoproteins. It was confirmed by thin layer radiochromatography that the radioactivities in serum and liver at various times were due to coenzyme Q 10 hydroquinone.

Autoradiographic studies on the distribution of 14C-labeled timiperone, a new butyrophenone antipsychotic, in the rat and monkey

The distribution of 14C-timiperone, a butyrophenone antipsychotic, was studied in rat and monkey by means of autoradiography. Tissue levels of radioactivity in the rat at 2h after a single oral administration of 0.5mg of the drug per kg were high in the order of the gastrointestinal contents, liver, urinary bladder, salivary gland, thyroid, pituitary, adrenal, harderian gland, kidney, lung, heart, testis, skeletal muscle and brain. In the rat brain, higher concentrations of radioactivity were detected in the striatum, nucleus accumbens and frontal cortex in which cerebral dopamine receptors were localized, as compared with other brain regions. The tissue levels of radioactivity persisted up to 10h after dosing. Repeated oral administration did not affect the distribution pattern of radioactivity. In the monkey which received a single oral dose of 1mg per kg, tissue levels of radioactivity at 2h after the administration were high in the order of the gastrointestinal contents, gall-bladder, liver, kidney, thyroid, pituitary, salivary gland, lung, heart, eye, blood, bone marrow, skeletal muscle and brain. In the monkey brain, radioactivity was localized in the brain regions including the caudate nucleus, putamen and cortex. The monkey uveal tract had a similar concentration of radioactivity to the blood. Thus, it was confirmed that 14C-timiperone could be transferred to the cerebral dopaminergic systems associated closely with the exhibition of antipsychotic activity of major tranquilizer.

The metabolic disposition of 14C-labelled Ponceau 4R in the rat, mouse and guinea-pig

The absorption, metabolism and excretion of 14C-labelled Ponceau 4R has been studied in the rat, mouse and guinea-pig. Following administration of a single oral dose of 0·5 or 50 mg/kg body weight substantially all of the dose was excreted in the urine and faeces within 72 hr, with the majority being accounted for in the faeces. In all three species, naphthionic acid was the major urinary metabolite, whereas in the faeces naphthionic acid, 7-hydroxy-8-aminonaphthalene-1,3-disulphonic acid and unchanged dye were found. Pretreating male rats with unlabelled Ponceau 4R in the diet (50 mg/kg/day) for 28 days prior to dosing with the 14C-labelled colouring had no effect on the route of excretion or the time taken to eliminate the majority of the label. Following a single dose of 14C-labelled colouring to previously untreated rats, mice and guinea-pigs or to rats pretreated as above, no marked accumulation of radioactivity in any tissue was found, although tissue levels of radioactivity at 72 hr after dosing were higher in the pretreated rats than in those that were not pretreated. Pregnant rats eliminated a single oral dose of 14C-Iabelled colouring at a similar rate to non-pregnant females; however, some retention of radioactivity in the foetuses was found. In studies of absorption from isolated loops of small intestine containing 50, 500 or 5000 ppm Ponceau 4R, no significant absorption was detected in rats, but some absorption was seen in mice at the lowest concentration, and in the guinea-pig at the two higher concentrations.

Distribution of radioactivity and anthracycline-fluorescence in tissues of mice one hour after [14C]-labeled AD 32 administration. Evidence for tissue aglycone formation.

Levels of radioactivity and total anthracycline fluorescence in tissues of A/JAX mice were compared 1 h after IV administration of unlabeled or [14C]-labeled AD 32 (50 mg/kg). Highest levels of both fluorescence and radioactivity were found in the small intestine (including contents) and liver, a result consistent with the known hepatobiliary excretion of AD 32 and metabolites. Significant accumulations of radioactivity and fluorescence were found in kidney, spleen, large intestine (including contents), lung, and heart. Lesser levels were found in muscle and fat. Little radioactivity and fluorescence were found in brain. Liquid chromatographic analysis of extracts of small intestine and liver homogenates showed N-trifluoroacetyladriamycin (AD 41) as the major fluorescent species, and also revealed N-trifluoroacetyladriamycinol (AD 92) and occasional low levels of AD 32. In addition, there was a major peak of nonfluorescent radioactive material and two fluorescent nonradioactive signals (unknowns 1 and 2), indicative of cleavage of the radiolabel from the chromophore.

Excretion balance, metabolic fate, and tissue residues of N-phenyl-N'-1,2,5,-thiadiazol-3-ylurea (photothidiazuron) in rats.

Photothidiazuron-14C, a major photoconversion product of thidiazuron defoliant on cotton leaves, was rapidly absorbed and eliminated following oral administration to rats. By 96 hr posttreatment, 90.7% of the administered dose was accounted for in the urine (75.5%) and feces (15.2%). Between 5.0 and 10% of the radioactive material in the urine partitioned into ethyl acetate. In addition to photothidiazuron and several unknowns, the following metabolites were present: 4-hydroxyphenylphotothidiazuron, phenylurea, and 4-hydroxyphenylurea. There was also some evidence for the presence of 4-hydroxyacetanilide. The major portion of the radioactivity (>90%) remained in the urine after extraction with ethyl acetate. Cleavage data withbeta-glucuronidase and aryl sulfatase indicated that at least 12.1% and 6.3%, respectively, of the urinary radioactive materials were conjugated with glucuronic and sulfuric acids. Compounds included 4-hydroxyphenylurea, 4-hydroxyphenylphotothidiazuron, and several unknowns. Fractionation of the feces indicated that about 10% of the radioactive material was organosoluble, about 20% was water soluble and about 70% was unextractable from the fecal residue. Tissue levels of radioactivity were low and in the ppb range.

Pharmacokinetics of the Anti-Inflammatory Tiaprofenic Acid in Humans, Mice, Rats, Rabbits, and Dogs

The pharmacokinetics of tiaprofenic acid were studied in rats, dogs, mice, and rabbits using the 14C-labeled compound and in humans using the radioinert compound. Its absorption was partially gastric but mainly intestinal and was total in all species. Its apparent volume of distribution was small; it was bound markedly to albumin, and its plasma clearance was high in all species. Absence of retention was confirmed in rats by the very low tissue radioactivity levels 24 hr after oral dosing. In humans, identical maximum plasma concentrations and elimination rates were recorded after the first and 40th dose during a 2-week treatment with 200 mg three times daily. During this period, constant residual levels were recorded before the first dose of the day. These results indicate that, for a dose in the therapeutic range, a steady state was reached as early as the end of the 1st day of treatment and that tiaprofenic acid did not inhibit or induce its own biotransformation. Urinary excretion accounted for one-half of the dose in rats and from 0.6 to 0.9 in humans, dogs, mice, and rabbits. Two metabolites were formed, one resulting from the reduction of the ketone group to an alcohol and the other from oxidation generating a phenol in the benzene ring in the paro-position to the ketone group. These two metabolites were common to all species, but the latter was present in minute amounts only in dogs. Tiaprofenic acid was conjugated as an amide in dogs and as an acylglu- curonide in the other species. In rats, phenobarbital induced the oxidative, but not the reductive, pathway.