Metabolic fate of the new anti-ulcer drug enprostil in animals. 3rd communication: tissue accumulation after consecutive oral administration of [3H]-enprostil in rats

Accumulation characteristics of radioactivity in organs and tissues were investigated after oral administration of [3H]-enprostil ((+/-)-11a,15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorp r osta-4,5,13(t)- trienoic acid methyl ester, TA-84135) to male rats once a day (20 micrograms/kg/d) for 1, 7 or 14 days. [3H]-Enprostil was found to be partially metabolized in vivo to volatile tritium (3H2O). The ratios of volatile tritium to total radioactivity in plasma increased with repeated administration of [3H]-enprostil and the levels of volatile tritium were almost equilibrated within 7 days of drug administration. The formation rate of volatile tritium was estimated to be 1-2% of the single dose. The blood levels of non-volatile radioactivity at 1 h after each daily dosing were nearly constant. The levels at 24 h, however, increased with repeated dosing. The levels of non-volatile radioactivity in most tissues at 1 h after the multiple administration (7 and 14 times) were higher than those after the single dose. At 24 h, levels were noticeable after multiple dosing even in the tissues in which levels below the detection limit were found after the single dose. From the comparison of the multiple-dose groups, the levels in most tissues attained steady state within 7 times dosing. The daily excretions of radioactivity in the urine, feces and expired air were constant throughout the period of consecutive administration. The total recovery of administered dose was 92%, which was similar to that achieved in the single-dosing group. As described above, the retention of non-volatile radioactivity was observed in most tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 3rd communication: tissue accumulation after consecutive oral administration of [N-methyl-14C]-imidapril in rats.

Accumulation characteristics of radioactivity in the organs and tissues, metabolism, and excretion of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), an oral angiotensin-converting enzyme inhibitor, were investigated after consecutive oral administration of [N-methyl-14C]-imidapril at a once-daily dose of 1 mg/kg to male rats for 14 days. During the consecutive oral administration, the plasma radioactivity levels at 1 h after each dose reached steady-state following the 3rd to 4th administered dose; this was about 1.4 times higher than the corresponding plasma levels of the first dose. At 24 h after each administration, the plasma levels attained a steady-state at 3-4 days after the beginning of the consecutive dosing. Examination of the time course of plasma radioactivity after the single and multiple (7 and 14 times) oral administration revealed that the Cmax and AUCO-24 h values slightly, but significantly, increased according to repeated dosing and the beta-phase of the t1/2 of disappearance became longer after consecutive dosing. However, these values were not markedly different among consecutive dosing groups. The extent and rate of excretion of radioactivity in the urine and feces were nearly constant during the periods of consecutive oral administration, and were also similar to those after the single oral administration. Total recovery of radioactivity from urine and feces within 96 h after the final dosing was more than 98% of the total dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition and metabolism of [14C]sparfloxacin after repeated administration in the rat.

Disposition and metabolism of [carbonyl-14C]sparfloxacin (SPFX, 5-amino-1-cyclopropyl-7-(cis-3,5-dimethyl-1-piperazinyl)-6,8-difluoro- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid, AT-4140; CAS 110871-86-8), a novel antimicrobial quinolone, were studied in rats during and after 14 consecutive daily oral administrations at 10 mg/kg. Plasma levels after the 1st and 14th administration were similar in terms of tmax (1 h), Cmax (around 1.35 micrograms eq/ml), T1/2 (3-4 h) and AUC (about 7.3 micrograms eq h/ml). Plasma levels at 0.5 h after each administration were virtually constant in the range of 1.25-2.66 micrograms eq/ml for 14 days, but those at 24 h tended to elevate to about 0.06 micrograms eq/ml, which was an apparent steady state level after the 6th administration. Tissue distribution after the repeated administration was also similar to that after single administration: levels in the kidney, liver, pancreas, submaxillary gland, lung and many others were higher than, or similar to those in plasma, and in brain and some others, lower. Composition of radioactive metabolites in urine was not statistically different from that after single administration. About 20 and 73% of dose were excreted in daily urine and feces, respectively, for 14 days and radioactivity was almost completely excreted within 96 h after the last administration.     

Metabolic fate of the new cardiotonic denopamine in animals. 2nd communication: tissue accumulation in the rat after consecutive oral administration of 14C-denopamine

Accumulation characteristics of (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (denopamine, TA-064) in organs and tissues were investigated after oral administration of 14C-denopamine to rats once a day (5 mg/kg/d) for 1, 6 and 10 days. The levels of radioactivity in each organ and tissue were measured at various time intervals after the final dose. The levels of radioactivity at 15 min after administration were generally higher in the consecutive-dose groups than in the single-dose group. However, the levels were equilibrated within 6 days of administration. Radioactivity at 24 h after administration decreased to about the detection limit in each group. In addition, half-lives of disappearance of radioactivity from the body were not significantly affected by the consecutive doses. About 100% of the dose was recovered from the urine and feces during consecutive administration periods. Consequently, it was considered that the drug hardly showed retention and accumulation characteristics in the body.     

Pharmacokinetics and disposition of a new antitumor antibiotic (2'R)-4'-O-tetrahydropyranyladriamycin in rats. Distribution and excretion after multiple administration

The accumulation of (2'R)-4'-O-tetrahydropyranyladriamycin (THP) was studied in rats received intravenous administration of 14C-THP at a dose of 0.5 mg/kg/day for 14 consecutive days by determining blood and tissue levels and the excretion of the radioactivity. The radioactivity levels in plasma and blood cells after the multiple administration were higher than those after single administration. The half-life of the radioactivity after the multiple administration was longer in the blood cells but not in the plasma than the half-life after a single administration. Tissue levels of the radioactivity after the multiple injection were 2 to 4 times as high as the levels after a single injection except for the brain and testes in which a large accumulation of the radioactivity was observed. However, little accumulation of unlabeled THP was found in most tissues when determined by HPLC. The accumulation of radioactivity in tissues, therefore, was due to metabolites of THP. The disposition of 14C-THP was also examined in rats which had previously received unlabeled THP (0.5 mg/kg/day) for 13 days. The pretreatment did not affect the disposition of 14C-THP seriously, although the pretreatment raised tissue levels slightly and a rebound of plasma level of 14C-THP, and lowered the fecal excretion ratio. No induction of hepatic drug metabolizing enzymes was observed in rats after repeated administrations of THP for consecutive 14 days.     

The absorption, tissue distribution and excretion of di-n-octyltin dichloride in rats

In this study the absorption, tissue distribution and excretion of 14C-labeled di-n-octyltin dichloride ([14C]DOTC) in rats were investigated after oral and intravenous (i.v.) administration. Although after i.v. administration with 1.2 mg [14C]DOTC/kg body weight the tissue radioactivity was about 3-4 times higher than after oral administration with 6.3 mg [14C]DOTC/kg body weight, the relative tissue accumulation was found to be the same after the oral and i.v. dosage. The highest amount of radioactivity was found in liver and kidney, and to a lesser degree in adrenal, pituitary and thyroid glands. The lowest activity was recovered from blood and brain. No selective accumulation was observed in thymus, although it has been reported that thymus atrophy is the most sensitive parameter of DOTC toxicity in rats. For all tissues a time dependent decrease in radioactivity was found, except for kidney. The excretion of radioactivity in feces and urine was determined after a single i.v. or oral dose of 1.2 and 2 mg [14C]DOTC, respectively. After i.v. administration most of the radioactivity was excreted in the feces which was characterized by a biphasic excretion pattern. In orally treated rats more than 80% of the radioactivity was already excreted in the feces during the first day after administration. This indicated that only a small part of the DOTC was absorbed, which was calculated to be approximately 20% of the dose. Similar half-life values of 8.3 and 8.9 days were obtained from the fecal excretion of radioactivity after the i.v. and oral administration, respectively. The urinary excretion of radioactivity appeared to be independent of the body burden, since the daily amount of radioactivity excreted in urine was nearly the same independent of the route of administration as well as the time after administration.     

Comparative assessment of ocular tissue distribution of drug-related radioactivity after chronic oral administration of 14C-levofloxacin and 14C-chloroquine in pigmented rats

Fluoroquinolones have been reported to have a high affinity for melanin. The ocular tissue distribution and accumulation of radioactivity was compared after repeated oral administration of 14C-levofloxacin and 14C-chloroquine at daily doses of 20 mg (0.054 mmol) kg(-1) and 28 mg (0.054 mmol) kg(-1), respectively, in pigmented rats for 84 days. The mean serum level at 24 h following each dose of 14C-levofloxacin was almost constant in the range of 0.33-0.45 nmol equiv mL(-1) after the 14th dose and thereafter. The melanin-containing ocular tissues, such as iris ciliary body and stratum pigment chorioides sclera, showed a much higher concentration of radioactivity than other non-pigmented ocular tissues. The respective concentration in iris ciliary body and stratum pigment chorioides sclera after the 1st dose was 126.47 and 74.91 nmol equiv g(-1), and gradually increased with increasing dose number, reaching 1261.81 and 447.45 nmol equiv g(-1) after the 84th dose, which was ca. 10 and 6 times higher, respectively, than after the 1st dose. The mean serum level following each dose of 14C-chloroquine was almost constant in the range 0.51-0.87 nmol equiv mL(-1) after the 7th dose and thereafter. The respective concentration in iris ciliary body and stratum pigment chorioides sclera after the 1st dose was 572.10 and 709.41 nmol equiv g(-1), and gradually increased with increasing dose number, reaching 33 317.92 and 12 322.90 nmol equiv g(-1) after the 84th dose, which was ca. 58 and 17 times higher, respectively, than after the 1st dose. The concentration in aqueous humour, cornea, lens, vitreous body and retina after the 84th dose was 1.84, 6.33, 0.48, 5.60 and 11.42 nmol equiv g(-1) for 14C-levofloxacin and 18.84, 264.99, 27.26, 158.43 and 1020.89 nmol equiv g(-1) for 14C-chloroquine (ca. 10, 42, 57, 28 and 89 times higher, respectively, than for 14C-levofloxacin). Especially, the concentration in the retina was markedly higher after 14C-chloroquine administration than after 14C-levofloxacin administration. The concentration and the extent of accumulation of radioactivity not only in melanin-containing ocular tissues but also in other non-pigmented ocular tissues, such as retina, after chronic oral administration of 14C-levofloxacin once daily for 84 days were much lower than those after multiple dosing with 14C-chloroquine under the same conditions. These results indicate that levofloxacin would have a much lower risk for ocular toxicity than chloroquine after chronic dosing.     

The absorption and excretion of butylated hydroxyanisole in beagle dogs

Recent studies have indicated that administration of [14C]butylated hydroxyanisole (BHA) to rats, either orally or by intraperitoneal (i.p.) injection, resulted in high retention of radioactivity in the forestomach. The present study was undertaken to investigate the fate of [14C]BHA in non-rodents. 2 Groups of 5-mth-old male beagle dogs were fed a diet containing either 3% or 0.03% BHA for 7 days, and were injected i.p. with 3-tert-[methyl-14C]butyl-4-hydroxyanisole (Amersham International) at a dose of 30 muCi/kg. On the 7th day after [14C]BHA injection, all dogs were killed after fasting overnight, and the liver, kidney, heart, fat tissue and stomach were collected for radioanalysis. An additional 3 beagles served as control group. The fate of BHA after the single i.p. injection of [14C]BHA was examined by the determination of 14C-radioactivity in whole body, blood, urine, feces and several tissues. Blood, urine and feces samples were collected daily for 7 days. Blood samples were collected at intervals for 24 h. BHA was rapidly taken up in the bloodstream, and 50-80% of the total radioactivity was recovered in the urine within 2 days. 15-30% Appeared in the feces within 2 days. The tissue distribution of radioactivity 7 days after [14C]BHA injection showed only a small portion remaining in the stomach (0.16-0.19% of dose/g), liver (0.3-1.7%) and other tissues (0.02%). The radio-activity was almost evenly distributed in the three parts of the stomach (cardia, corpus and pylorus). These findings are in contrast with the previous data in rats that BHA can accumulate in high concentrations in the forestomach.     

Study on the metabolic fate of catena-(S)-[mu-[N alpha-(3- aminopropionyl)histidinato(2-)-N1,N2,O:N tau]-zinc]. 2nd communication: absorption, distribution, metabolism and excretion after repeated administration to rats.

After repeated administration of 14C-Z-103 (catena-(S)-[mu-[N alpha-(3- aminopropionyl)histidinato(2-)-N1,N2,O:N tau]-zinc], CAS 107667-60-7) to rats for 21 days, the accumulation of radioactivity in the blood and tissues was proportional to the number of doses given. Following treatment of the terminal blood, plasma, liver and kidney samples with trichloroacetic acid (TCA) or protease, the radioactivity in these tissues was demonstrated to be TCA-insoluble and solubilized by the protease treatment. Thus, the accumulation of radioactivity after repeated administration of 14C-Z-103 was considered to be due to the utilization of the metabolites of L-carnosine, the constituent of Z-103, into a protein. The cumulative ratios of radioactivity excreted into the urine, feces and expired air and the radioactivity remaining in the carcass after repeated administration of 14C-Z-103 for 21 days were similar to those values obtained after a single administration, suggesting that repeated administration did not influence the excretion profile of Z-103. During the period of repeated administration of non-radioactive Z-103 to rats for 21 days, the fecal content of zinc was higher than that in nontreated rats, whereas it returned to the control level at 48 h after the final administration. There was no significant difference in the urinary concentration of zinc between treated and non-treated animals during the period of repeated administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption, distribution and excretion of 14C-pirenzepine in rats. Accumulation characteristics after multiple dose regimen

Absorption, distribution and excretion of 14C-labelled 5,11-dihydro-11-[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one-dihydrochloride (pirenzepine, LS-519 Cl2) were studied in SD-JCL rats. After a single i.v. injection of the drug (2 mg/kg), the concentration of radioactivity in the blood decreased bi-phasically with half-lives of 1 and 8 h. After s.c. administration of the same dose, the drug was very rapidly absorbed and it was shown that the concentrations and the elimination pattern were almost identical to that observed following i.v. injection. After oral administration of 20 mg/kg, absorption was relatively slow, taking 3 h to reach Cmax. The concentrations of radioactivity distributed in most tissues reached their maximum 3 h after a single oral administration, well comparable with that in the blood. In the study with multiple administration (5mg/kg once a day up to 14 days), 24 h after withdrawal of 7-day administration, the concentration in the liver, kidneys and testes were two times those at a 1-day administration. This ratio, however, did not increase furthermore over a 10- to 14- day administration period. All tissue levels gradually decreased with time after the final administration. Thus, no specific or considerable accumulation was demonstrated. The drug found excreted into urine was about 46% and into feces about 53% of the administered dose 96 h after i.v. injection. After single oral administration, urinary excretion was found extremely low, i.e., 8%, while 91% was excreted via feces.     

Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 4th communication: tissue distribution, placental transfer and milk secretion of radioactivity in rats after a single oral administration of 14C-NS-49, and effects of repeated administration on its pharmacokinetics.

The tissue distribution, placental transfer and milk secretion of 14C-NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoro-methanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, have been studied after a single oral administration (1 mg/kg) of a suspension formulation to rats. Radioactivity concentrations in tissues were generally highest 1 or 4 h, and for most tissues, exceeded those in the corresponding plasma. Concentrations were generally similar in male and female rats and persisted for at least 24 h. Radioactivity concentrations in most tissues declined in parallel with those in plasma. Placental transfer of radioactivity was low accounting for < 0.1% of the maternal dose. In milk, concentrations were of a similar order to those in the plasma but reached a peak later: the data implied that 14C-NS-49 readily diffused from the plasma into the milk. The absorption, distribution and excretion of 14C-NS-49 have been studied after the repeated administration (1 mg/kg) of a suspension formulation to rats for up to 21 days. At 21 days, radioactivity concentrations in plasma reached a peak 1 h and declined with a terminal half-life of 67 h. Steady state concentrations were reached during 14 days. Peak concentrations in tissues occurred 1 h and, in most tissues exceeded the plasma value. Radioactivity concentrations in tissues appeared to reach steady state during the 21-day dosing period. Tissue and blood cell concentrations declined more slowly than those in the plasma. Radioactivity excretion was relatively constant during the repeated administration and similar in urine (mean 45.8% total dose) and feces (mean 48.2% total dose). At 7 days after the last of 21 daily oral doses, only 0.2% of the total dose remained in the body, indicating that there is no marked accumulation of radioactivity in the tissues. The results obtained in these studies indicated that rats receiving NS-49 at 24 h intervals during chronic and reproductive toxicity studies would be continually exposed to the parent compound and/or its metabolites.     

Metabolism and disposition of the flame retardant tris(2,3-dibromopropyl)phosphate in the rat

The metabolism and disposition of the flame retardant, tris(2,3-dibromopropyl)phosphate (Tris-BP), were studied after po and iv administration of the 14C-labeled compound to the male rat. Tris-BP was readily absorbed from the gastrointestinal tract and rapidly distributed throughout the body. The distribution and excretion of Tris-BP derived radioactivity were similar after either po or iv administration. The only effects of route of administration on tissue distribution were slightly higher concentrations in liver after po administration and in lung after iv administration. The initial elimination of Tris-BP derived radioactivity in urine, feces, and as CO2 accounted for approximately 50% of the dose in 24 hr. An analysis of Tris-BP derived radioactivity remaining in the tissues one day after administration indicated that most of the radioactivity in all tissues was in the form of various metabolites rather than the parent compound. The terminal clearance of Tris-BP derived radioactivity from most of the tissues studied was best described by a single component exponential decay with a half-life of approximately 2.5 days. Clearance from liver and kidney was somewhat slower having a half-life of approximately 3.8 days. Approximately 33% of the radioactivity excreted in urine and approximately 50% of the radioactivity excreted in bile were identified by cochromatography with synthesized standards on high performance liquid chromatography (HPLC). Six metabolites and a trace of the parent compound were identified in urine and bile by this method. The six metabolites products of dealkylation and dehydrobromination of the parent compound. The metabolites of Tris-BP isolated from urine and bile were also formed in vitro by NADPH-dependent microsomal enzymes from rat liver. The soluble enzymes from liver metabolized Tris-BP to at least three unidentified polar metabolites.     

The fate of ultra-low viscosity 14C-hydroxypropyl methylcellulose in rats following gavage administration

The disposition of 14C-Hydroxypropyl methylcellulose (HPMC) with a viscosity of 2.25 centipoise was studied in male and female Sprague-Dawley rats following a single 500 mg/kg body weight gavage dose, or five consecutive daily doses. Recoveries for the single dose were: feces, greater than 99%; urine, approximately 1%; carcass and tissues, approximately 0.2%; expired air, 0.07%; and bile, 0.05%. Plasma radioactivity had a monophasic excretion half-life of approximately 2 hours for either sex. The majority of the residual radioactivity in the tissues was found in the gastrointestinal tract. The absorbed radioactivity in the urine, based on thin layer chromatography (TLC) analyses, represented methyl ethers of glucose and oligomers; this amounted to 0.56% recovered in a study in which urine samples were isolated from possible contamination by radioactivity in the feces. The 0.56% correlated well with the 0.53% portion of the original dosing solution which consisted of cellulose units with an average molecular weight of less than 1000. Recovery of radioactivity in the feces of rats on the 5-day dosing regimen was 97% and 102% for males and females, respectively, without any evidence for accumulation in tissues. Approximately 1% was recovered in the urine. Thus, the results of this work show that ultra-low viscosity 2.25 centipoise HPMC was only minimally absorbed with essentially all of a single 500 mg/kg gavage dose, or 5 daily consecutive doses, being excreted unabsorbed in the feces.     

The Fate of Ultra-Low Viscosity 14C-Hydroxypropyl Methylcellulose in Rats Following Gavage Administration

ABSTRACT

The disposition of ¹⁴C-Hydroxypropyl methylcellulose (HPMC) with a viscosity of 2.25 centipoise was studied in male and female Sprague-Dawley rats following a single 500 mg/kg body weight gavage dose, or five consecutive daily doses. Recoveries for the single dose were: feces, >99%; urine, ～1%; carcass and tissues, ?0.2%; expired air, 0.07%; and bile, 0.05%. Plasma radioactivity had a monophasic excretion half-life of approximately 2 hours for either sex. The majority of the residual radioactivity in the tissues was found in the gastrointestinal tract. The absorbed radioactivity in the urine, based on thin layer chromatography (TLC) analyses, represented methyl ethers of glucose and oligomers; this amounted to 0.56% recovered in a study in which urine samples were isolated from possible contamination by radioactivity in the feces. The 0.56% correlated well with the 0.53% portion of the original dosing solution which consisted of cellulose units with an average molecular weight of < 1000. Recovery of radioactivity in the feces of rats on the 5-day dosing regimen was 97% and 102% for males and females, respectively, without any evidence for accumulation in tissues. Approximately 1% was recovered in the urine. Thus, the results of this work show that ultra-low viscosity 2.25 centipoise HPMC was only minimally absorbed with essentially all of a single 500 mg/kg gavage dose, or 5 daily consecutive doses, being excreted unabsorbed in the feces.     

Chlophentermine-induced abnormalcytoplasmic inclusions in peripheral blood cells of rats and guinea pigs.

The metabolic fate of [¹⁴C]gossypol was studied in the pig following a single oral dose of 6.7 mg/kg (3.7 μCi). Radioactivity was rapidly excreted from the animal body via feces. After 20 days, the total radioactivity recovered in the feces was 94.6% of the administered dose. A total of 2.1% of the radioactivity of administered dose was recovered in the expired CO₂ collected continually for 20 days. This indicates that decarbonilation of gossypol is not a major route of gossypol metabolism in the pig. Radioactivity was least excreted via urine; only 0.7% of the administered dose was recovered in the urine. One day after the administration, the tissues had 32.9% of the administered dose, which was decreased to 1.2% at 20 days. The conceptration of gossypol and its metabolites in the tissues (as indicated by radioactivity) was highest in the muscle, followed by liver, adipose tissues, and the blood. The half-life for the disappearance of radioactivity from the animal body following the administration of [¹⁴C]gossypol was 78 hr. Identification of metabolites was carried out by ultraviolet, infrared, and mass spectrometry in connection with thin-layer autoradiography. Compounds isolated from pig liver were characterized as gossypol, gossypolone, gossypolonic acid, demethylated gossic acid, and presumably apogossypol. Gossypol and metabolites may be conjugated to form glucuronides, sulfates, or hybrids.     

The distribution, metabolism, and elimination of clofarabine in rats.

The distribution, metabolism, and elimination of intravenous [14C]clofarabine was studied in Fischer 344 male rats under a once daily for 5 days dosing schedule of 25 or 50 mg/kg/day. Also, the in vitro metabolism in rat, dog, and human hepatocytes was studied. Plasma radioactivity (of which clofarabine accounted for 63% to 93%) exhibited three phases of exponential elimination, with half-lives of 0.3, 1.3, and 12.8 h after administration of the 25 mg/kg/day regimen. Unscheduled deaths occurred after one to three doses with the 50 mg/kg regimen, possibly due to nonlinear pharmacokinetics; therefore, mass balance and radiokinetic profiles could not be obtained. A total of 77.1% (of which 87.2% was clofarabine) and 10.8% (of which 6.9% was clofarabine) of the dose was recovered in urine and feces, respectively. 6-ketoclofarabine, believed to be formed via adenosine deaminase, was the metabolite of greatest concentration found in urine and feces, but in each matrix, it accounted for only 7% of the daily recovery of radioactivity. 6-ketoclofarabine was also found in myocardium and liver but accounted for less than 2% of the total radioactivity in those tissues. Clofarabine was the major analyte found in myocardium (>97% region of integration) and liver (>94% region of integration). Whole body autoradiography demonstrated that the highest postdistributive concentrations of radioactivity were in the excretory organs, kidney, bladder, and gastrointestinal tract, with no remarkable suborgan distribution. In rat, dog, and human hepatocytes, 95, 96, and 99.8% [14C]clofarabine remained, respectively, after 6 h of incubation. Eleven metabolites were observed, with the largest constituting 2.5% of the radioactivity.     

Paraffin-stimulated excretion of 2,4,6,2'4'-pentachlorobi[14C]phenyl by rats.

Previous studies have shown long-term paraffin treatment to enhance the elimination of organochlorine xenobiotics from the rat body. The purpose of the present study was to determine the effect of paraffin feeding on the persistence of a polychlorinated biphenyl (PCB) isomer in the rat. Male rats housed in metabolism cages were fed a diet containing 1.2 ppm 2,4,6,2′,4′-pentachlorobi[¹⁴C]phenyl (PentaCB) for 1 week. After 1 day on a control diet one-half of the animals received a food ration containing 8% light liquid paraffin. The remaining animals served as controls. Four weeks after discontinuing the PentaCB-fortified diet all animals were sacrificed. Organ weights and hematocrit values were determined. Twenty different tissues were analyzed for radioactivity. The total amount of radioactivity excreted with urine and feces was measured daily. Paraffin treatment slightly depressed body weight gain and feed efficiency. During the PentaCB feeding period 31.7 and 4.8% of the radioactivity ingested were excreted with feces and urine, respectively. After 4 weeks on PentaCB-free diet the paraffin-treated rats excreted significantly more of the radioactivity (54.20±5.38%) compared to controls (42.68±5.62%). The half-lives of the second compartment of a two-compartment open model for the elimination of radioactivity from rat body were 51±11 and 141±62 days for treated and control rats, respectively. Control rats had higher residues in most of the tissues analyzed. The concentration of radioactivity in abdominal fat was 20 times higher than in any other tissue. These results suggest that administration of paraffin or possibly of other nonabsorbable lipid-like substances could be useful in the therapy of PCB poisoning.     

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate in rats, dogs and monkeys

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) were studied in rats, dogs and monkeys after administration of [14C]-MN-1695. MN-1695 was found to be well absorbed from the small intestine after oral administration in all species examined. Plasma level of unchanged MN-1695 reached a maximum at 1 to 4 h after oral administration of [14C]-MN-1695 in rats, dogs and monkeys. The mean elimination half-life of unchanged MN-1695 from plasma was about 3, 4 and 50 h in rats, dogs and monkeys, respectively. Tissue levels of radioactivity after oral administration of [14C]-MN-1695 in rats indicated that [14C]-MN-1695 was distributed throughout the body and the radioactivity in tissues disappeared with a rate similar to that in plasma. A stomach autoradiogram after intravenous administration of [14C]-MN-1695 in the rat revealed the radioactivity localized in the gastric mucosa where MN-1695 was assumed to exert its pharmacological activity. In pregnant rats, [14C]-MN-1695 was distributed to the fetus with levels similar to maternal blood levels. After oral administration of [14C]-MN-1695 in rats, 39 to 46% of the dose was excreted into the urine and 50 to 63% of the dose into the feces, within 96 h. In dogs, about 40% of the dose was excreted into the urine and about 50% of the dose into the feces, within 6 days after oral administration. In monkeys, within 14 days after oral administration, about 60 and 30% of the dose were excreted into the urine and feces, respectively, and the main excretion route was the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Absorption, distribution, metabolism and excretion of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)- 1,4-dihydropyridine (PP-1466) in rats

In this experiment, the absorption, excretion, distribution and metabolism of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1, 4-dihydropyridine (PP-1466) were investigated following oral or intravenous administration, single dose or repeated dose administration using male SLC-Wistar rats and the results of this investigation were summarized as follows: After oral administration of 14C-PP-1466 to rats, the blood level reached the maximum at 1 h and decreased with the biological half-life of about 5 h. The unchanged drug concentration in plasma was 30% of total concentration in plasma and disappeared at 6 h. The high radioactivities in the liver, kidney, fat, lung and adrenal gland were observed after oral and intravenous administration. After oral and intravenous administrations, the excretion in feces and urine during 48 h was 63.0 and 32.4, 58.6 and 41.6%, respectively. Biliary excretion amounted to 57.6 and 46.2% during 48 h, respectively. Six metabolites were found in the urine of rats. Three of them were identified as 2,6-dimethyl-3-carbomethoxy-4-(2-difluoromethoxyphenyl)-5-carboxylic acid pyridine, 2-methyl-3-carbomethoxy-4-(2-difluoromethoxyphenyl)-5-carboxylic acid-6-hydroxymethyl pyridine and its lactonizing analogue. These three metabolites covered 54% of total urinary metabolites. After oral repeated administration for three weeks, the excretion ratio of radioactivity in urine and feces was constant during the administration and no accumulation was observed in rat tissues.