RESUMEN
AR177 is a 17-mer oligonucleotide that has anti-human immunodeficiency virus activity in vitro. The disposition of internally labeled 33P-AR177 was studied after the tail vein injection of single and multiple doses (0.7 mg/kg) to rats. After a single dose, the terminal half-life of AR177 in the blood and plasma was 367 and 271 hr, respectively, significantly longer than values reported for other oligonucleotides. Analysis of the AR177 tissue distribution showed that the majority of the dose was distributed to the liver (40%), bone marrow (17%) and renal cortex (15%) at 8 hr after single dosing. Analysis of the AR177 concentrations in tissues showed that the highest concentrations were achieved in the renal cortex (15.0 microg-eq/g), liver (7.4 microg-eq/g), bone marrow (3.9 microg-eq/g), mesenteric lymph node (3.0 microg-eq/g) and spleen (2.4 microg-eq/g) at 8 hr after single dosing. The half-life in these tissues was 9.6, 7.7, 36.8, 10.0 and 30.8 days, respectively. Forty-eight hours after the last of seven i.v. doses given every other day, the concentrations in tissues were as follows: renal cortex, 39.9 microg-eq/g; liver, 33.9 microg-eq/g; bone marrow, 12.7 microg-eq/g; spleen, 9.3 microg-eq/g; mesenteric lymph node, 5.1 microg-eq/g. Twenty-one days after administration of the last dose, tissue concentrations were still high, as follows: renal cortex, 18.6 microg-eq/g; liver, 6.2 microg-eq/g; bone marrow, 12.5 microg-eq/g; mesenteric lymph node, 3.9 microg-eq/g; spleen, 8.1 microg-eq/g. There was low urinary and fecal excretion (urinary excretion of 12.8% and fecal excretion of 6.0% of the total dose over 21 days) after a single dose. Gel filtration and anion-exchange high-performance liquid chromatography and electrophoretic analysis of the radioactivity in tissues indicated that >90% of the radioactivity represented intact AR177 for at least 7 days after drug dosing. These results demonstrate that AR177 has an extended plasma, blood and tissue half-life, is widely distributed and achieves high concentrations in lymphoid and nonlymphoid tissues in rats.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Oligonucleótidos/farmacocinética , Animales , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/orina , Médula Ósea/metabolismo , Cromatografía Líquida de Alta Presión , Heces/química , Inyecciones Intravenosas , Corteza Renal/metabolismo , Hígado/metabolismo , Masculino , Oligonucleótidos/administración & dosificación , Oligonucleótidos/sangre , Oligonucleótidos/orina , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Glycidol (2,3-epoxy-1-propanol), an industrial chemical, has been shown to be a reproductive toxicant in short-term studies and a carcinogen in rats and mice in oncogenicity studies. The reproductive toxicity of glycidol was believed to result from its conversion to alpha-chlorohydrin by the action of HCl in the stomach. The comparative disposition of glycidol was investigated in rats following oral (po) or intravenous (iv) administration at doses of 37.5 and 75 mg/kg. These were the doses used in the National Toxicology Program (NTP) oncogenicity study with glycidol. Approximately 87-92% of the dose was absorbed from the gastrointestinal tract of the rat. [14C]Glycidol equivalents were eliminated in urine (40-48% of dose in 72 h), feces (5-12%), and exhaled as CO2 (26-32%). At both doses, 9-12% and 7-8% (estimated) of the dose remained in tissues at 24 and 72 h following dosing, respectively. In general, the concentrations of glycidol equivalents in tissues were proportional to the dose. The highest concentrations of radioactivity were observed in blood cells, thyroid, liver, kidney, and spleen, and the lowest in adipose tissue, skeletal muscle, and plasma. The pattern of distribution of radioactivity in tissues was similar for both the iv and po routes. The total recovery of radioactivity ranged from 87 to 91% of dose. Urinary radioactivity was resolved by high-performance liquid chromatography (HPLC) analysis into 15 metabolites. There were one major (14-21% of the dose) and four lesser metabolites (each representing 2-8%); the others were minor, each representing 1% or less of the dose. In general, the urinary metabolic profile was similar following either iv or po administration at the two doses studied. Previous studies by other investigators suggested that alpha-chlorohydrin, which was presumably formed from glycidol by the HCl in the stomach, was metabolized and excreted in urine as beta-chlorolactic acid. The results of the present study show that very little, if any, urinary radioactivity coeluted with authentic beta-chlorolactic acid following either iv or po administration. Therefore, it is concluded that the conversion of glycidol to alpha-chlorohydrin is quantitatively insignificant. However, it may be significant with regard to glycidol reproductive toxicity. Also, the NTP oncogenicity study with glycidol was carried out within the dose range in which its disposition characteristics were linear.
Asunto(s)
Compuestos Epoxi/metabolismo , Compuestos Epoxi/farmacocinética , Propanoles , 1-Propanol/administración & dosificación , 1-Propanol/metabolismo , 1-Propanol/farmacocinética , Administración Oral , Animales , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Compuestos Epoxi/administración & dosificación , Inyecciones Intravenosas , Absorción Intestinal , Masculino , Ratas , Ratas Endogámicas F344 , Distribución TisularRESUMEN
After intradermal administration of 3.7 mg/kg of 14C-labeled 5'-TTGCTTCCATCTTCCTCGTC-3' (14C-labeled ISIS 2105) to rats, a phosphorothioate oligodeoxynucleotide, absorption was rapid. Approximately 65% of the administered dose was absorbed within 1 hr after the dose and peak blood levels were achieved within 30 min. After the initial rapid phase of absorption, a slower absorption phase ensued that resulted in more than 95% of the dose being cleared from the injection site. Slow metabolism of 14C-labeled ISIS 2105 occurred at the injection site. The rate and characteristics of metabolism in the skin were similar to those observed in other tissues. Once absorbed, the pharmacokinetics, distribution and metabolism of 14C-labeled ISIS 2105 after intradermal administration were comparable to those after an i.v. dose. The distribution and terminal half-lives were 0.5 and 53 hr, respectively. Levels of 14C-labeled ISIS 2105 in the blood were found in the plasma and the drug distributed broadly to all peripheral tissues; the liver, renal cortex and bone marrow accumulated the highest levels of drug. The 14C-labeled ISIS 2105 was eliminated principally by metabolism. Approximately 50% of the dose was found in expired air and 15% and 5% were found in urine and feces, respectively. No intact oligonucleotide was found in urine or feces at any time.
Asunto(s)
Antivirales/farmacocinética , Tionucleótidos/farmacocinética , Absorción , Animales , Antivirales/sangre , Antivirales/metabolismo , Secuencia de Bases , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Heces/química , Femenino , Inyecciones Intradérmicas , Datos de Secuencia Molecular , Ratas , Piel/metabolismo , Tionucleótidos/clasificación , Tionucleótidos/metabolismo , Distribución TisularRESUMEN
Based on its epidermal growth factor receptor-mediated tyrosine kinase inhibitory activity, (Z)-alpha-[(3,5-dichlorophenyl)methylene]-3- pyridylacetonitrile (RG 14620) is undergoing evaluation as a topical drug for psoriasis. Disposition studies were conducted in rats and rabbits, using [14C]RG 14620, primarily to investigate percutaneous absorption. Plasma radioactivity and the unchanged drug along with material balance were determined following intravenous administration (2.5 mg/kg) of a solution in PEG 400 or dermal application (50 mg/kg) of a 5% petrolatum ointment. Following an intravenous dose, initial (5-min) plasma radioactivity concentrations were comparable (approximately 1700 ng-eq/ml) in both species, but the decline was slower in rabbits. After dermal application, maximum plasma concentrations were attained at 12 hr in rats and 24 hr in rabbits, and corresponded to approximately 160 and 90 ng-eq/ml, respectively. Overall, the unchanged drug represented < 22% of the total plasma radioactivity in both species, suggesting extensive metabolism. In the rat, fecal route was the major route of excretion, whereas in the rabbit, urinary and fecal excretion contributed to about similar extent. Based on dose-adjusted ratios of plasma radioactivity AUC0-24 hr values, extent of percutaneous absorption appeared to be 1.9% in rats and 0.6% in rabbits. The estimates were 0.6% and 1.2%, respectively, when AUCs were determined for the unchanged drug in plasma. However, based on cumulative excretion of radioactivity up to 96 hr, percutaneous absorption was 12.0% in the rat and 2.0% in the rabbit. The differences in estimates of absorption were attributed to slow but continued absorption of the drug from skin, even after removal of the dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Nitrilos/farmacocinética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Piridinas/farmacocinética , Tirfostinos , Administración Tópica , Animales , Heces/química , Inyecciones Intravenosas , Nitrilos/administración & dosificación , Piridinas/administración & dosificación , Conejos , Ratas , Ratas Sprague-Dawley , Absorción CutáneaRESUMEN
5'-TTGCTTCCATCTTCCTCGTC-3' (ISIS 2105) is a phosphorothioate oligodeoxynucleotide currently being evaluated as an intralesional antiviral drug for the treatment of genital warts that are caused by the human papillomavirus. ISIS 2105, labeled with 14C (at the carbon-2 position of thymine) was administered as a single i.v. injection (3.6 mg/kg) to female Sprague-Dawley rats to assess the disposition of the drug. After i.v. administration of [14C]2105, blood radioactivity disappeared in a multiexponential manner with the half-lives of the phases equal to 0.4, 1.9, 7.1 and 5.1 hr. The initial volume of distribution was 22 ml and the postdistribution volume of distribution was 1076 ml, which indicated an extensive distribution of radioactivity. The apparent blood clearance was 14.7 ml/hr. The radioactivity in the expired air accounted for 51% of the administered dose over the 10-day period. Urinary and fecal radioactivity accounted for 15% and 5% of the administered dose, respectively. The major sites of radioactivity uptake were the liver (up to 22.6% of the dose), kidneys (renal cortex, up to 14% of the dose), bone marrow (up to 14% of the dose), skin (up to 13% of the dose) and skeletal muscle (up to 9% of the dose). Other tissues contained approximately 1% or less of the dose. The overall recovery of radioactivity 10 days postdosing was 95.1 +/- 7.5% (mean +/- S.D.) of the administered single dose. The radioactivity in the blood was almost completely in the plasma during the course of the study. In the plasma, the radioactivity was extensively bound to proteins, as assessed by size-exclusion high-performance liquid chromatography (HPLC), in samples up to 8 hr postdosing. Retention data on size-exclusion HPLC and in vitro incubations using purified proteins suggested that the plasma proteins that bound [14C]2105 were albumin and alpha 2-macroglobulin. The complex formed between the plasma proteins and [14C]2105-derived radioactivity was dissociated on anion-exchange HPLC to indicate that the great majority of plasma radioactivity coeluted with intact [14C]2105 in samples that contained sufficient radioactivity for analysis. There was a time-dependent decrease in the proportion of hepatic and renal radioactivity that coeluted with the intact [14C]2105 during the course of the study. The urine did not contain radioactivity that eluted with intact [14C]2105 on anion-exchange HPLC.
Asunto(s)
Tionucleótidos/farmacocinética , Animales , Secuencia de Bases , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Heces/química , Femenino , Datos de Secuencia Molecular , Ratas , Ratas Sprague-Dawley , Tionucleótidos/sangre , Tionucleótidos/orina , Distribución TisularRESUMEN
The absorption, disposition, and metabolism of [14C]thiophene was investigated in rats following nose-only inhalation exposure at 8000 ppm for 1 h. Under these exposure conditions, it was estimated that approximately 16.3% (493 mumol) of the inhaled thiophene was absorbed from the respiratory system. Within 72 h following exposure, a total of 488 mumol of thiophene equivalents (99% of that retained) was excreted, of which 360.4 mumol (73.9% of the total excreted radioactivity) was in expired air, 120.7 mumol (24.8%) was in urine, 3 mumol (0.6%) was in feces, and 3.7 mumol (0.8%) was in the cage wash. Excretion took place primarily within the first 8 h, during which 91% of the total radioactivity excreted was collected. The thiophene equivalents remaining in tissues at 72 h were estimated to total 5.1 mumol (1.0% of the retained radioactivity). Exhaled radioactivity was identified as thiophene. No 14CO2 was detected in the expired air. After 1 h following exposure, the elimination of thiophene equivalents from plasma was monophasic, with a half-time of 3.6 h. The elimination of thiophene equivalents from blood cells was biphasic, with half-times of 2.9 h and 9.1 d. The blood cells/plasma concentration ratios of thiophene equivalents ranged from 3 to 13, with the higher ratio observed at the 12-h time interval. At 72 h after exposure, blood cells contained the highest concentration of thiophene equivalents, approximately fourfold higher than that of the liver, which contained the second highest concentration. Kidney, heart, and lung contained similar but lower concentrations than liver, while brain, fat, and skeletal muscles contained the lowest concentrations. In summary, this study demonstrates that thiophene was absorbed from the respiratory system, and the majority of the absorbed thiophene was eliminated unchanged in the exhaled air, while a smaller fraction was metabolized and eliminated in urine.
Asunto(s)
Pulmón/metabolismo , Tiofenos/farmacocinética , Absorción , Administración por Inhalación , Animales , Células Sanguíneas/metabolismo , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Heces/química , Semivida , Hígado/metabolismo , Masculino , Intercambio Gaseoso Pulmonar , Ratas , Ratas Endogámicas F344 , Tiofenos/administración & dosificación , Tiofenos/sangre , Tiofenos/orina , Distribución TisularRESUMEN
[14C]1,2-Bis(2,4,6-tribromophenoxy)ethane (FF-680) was administered at 0.05, 0.5, or 5% in the diet for 1 day to three groups (four rats per group) of rats, and daily at 0.05% in the diet for 10 days to another group of five rats. In addition, another group of four rats were given a single oral gavage dose of 200 mg/kg of [14C]FF-680 in corn oil and were used for bile collection. At all dose levels, [14C]FF-680-derived radioactivity was excreted almost totally via the fecal route (> 99% of the total excreted 14C), with < 1% recovered in the urine. No radioactivity was detected in the expired air, and very little radioactivity was excreted in the bile (ca. 0.04% of the dose). At 4 days after the start of administration of the dosed diet for 1 day, no radioactivity was detected in any tissue analyzed, except adipose tissue, skin, and thymus, in which trace concentrations of radioactivity were detected in some animals. At 10 days after the start of administration of dosed diet to rats dosed for 10 days, trace but detectable levels of radioactivity were observed in all tissues analyzed except the brain of some animals. Excluding the gastrointestinal tract, adipose tissue contained the highest concentration of 14C radioactivity, followed by kidney, skin, and thymus, whereas brain, testes, and spleen contained the lowest concentrations of radioactivity. No parent compound was detected in the urine, while fecal radioactivity was identified as the parent compound. Mean recovery of radioactivity ranged from ca. 86-101% of the [14C]FF-680 consumed. The data indicate that FF-680 was very poorly absorbed from the gastrointestinal tract. However, following daily administration for 10 days, trace amounts of radioactivity accumulated in tissues to provide detectable levels.
Asunto(s)
Bromobencenos/farmacocinética , Retardadores de Llama/farmacocinética , Animales , Bilis/metabolismo , Bromobencenos/administración & dosificación , Cromatografía de Gases , Cromatografía Líquida de Alta Presión , Dieta , Heces/química , Retardadores de Llama/administración & dosificación , Absorción Intestinal , Masculino , Ratas , Ratas Endogámicas F344 , Distribución TisularRESUMEN
The effect of dose on the dermal absorption of 2- and 4-chloronitrobenzene (2- and 4-CNB) has been investigated in rats following nonocclusive protective dermal application on an area of 4 cm2 per animal at approximately 0.0325, 0.325, and 3.25 mg/cm2 (0.65, 6.5, and 65 mg/kg, respectively). At the three-dose levels, 33-40% and 51-62% of the dose of 2- and 4-CNB, respectively, was absorbed from the skin within 72 hr. The balance of the dose was recovered in the protective device and the organic trap (i.e. that portion unavailable for dermal absorption). The absorbed radioactivity was excreted in urine (21-28% of dose, 2-CNB; 43-45%, 4-CNB) and feces (11-15%, 2-CNB; 5-12%, 4-CNB). The extent and rate of dermal absorption and urinary and fecal excretion of 2-CNB were linear over the 0.65-65 mg/kg dose range; for 4-CNB they were linear over the 0.65-6.5 mg/kg dose, and nonlinear at the 65 mg/kg dose.