Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.

MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Levels of dopamine in blood and brain following nasal administration to rats.

The aim of this study was to investigate the levels of [(3)H]dopamine in blood, the cerebrospinal fluid (CSF) and brain tissue samples in rats and to find out whether the drug is transferred along the olfactory pathway to the central nervous system following nasal administration. [(3)H]Dopamine (50 microCi) was given to male Sprague-Dawley rats either intravenously or nasally to the right nostril. For the absorption study, blood samples were withdrawn from the carotid artery. The CSF samples were taken by cisternal puncture and then brain tissue samples were excised. The presence of unchanged dopamine in the samples was ascertained using thin layer chromatography (TLC). The radioactivity in the samples was measured using liquid scintillation. The greatest amount of the total radioactivity absorbed from the nasal mucosa into the systemic circulation was observed at the first sampling point 15 min after administration. The bioavailability of the total radioactivity was 68+/-30%. The uptake of [(3)H]dopamine in the brain was significantly higher 30 min after nasal administration than after intravenous administration (P<0.01). TLC data showed that approximately 59%, 14% and 68% of the radioactivity in the olfactory bulb, CSF and olfactory mucosa, respectively, coeluted with dopamine. In conclusion, these results show that unchanged dopamine is transferred into the olfactory bulb via the olfactory pathway in rats.     

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

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

Disposition and pharmacokinetics of inhaled dimethylamine in the Fischer 344 rat

The disposition and pharmacokinetics of [14C]dimethylamine [( 14C] DMA) following 6-hr inhalation of either 10 or 175 ppm were determined in male Fischer 344 rats. Seventy-two hours after termination of exposure, the disposition of recovered radioactivity was similar for each airborne concentration, with more than 90% in the urine and feces, 7 to 8% in selected tissues and the carcass, and 1.5% exhaled as 14CO2. Over 98% of the radioactivity in the urine was unmetabolized DMA. Analysis of tissue radioactivity immediately after exposure to [14C]DMA showed that the respiratory nasal mucosa contained the highest concentration of 14C, followed by the olfactory nasal mucosa; concentrations of 14C in liver, lung, kidney, brain, and testes were approximately 2 orders of magnitude less than in the nasal mucosal tissues. Radioactivity in plasma of rats exposed by inhalation to 175 ppm of [14C]DMA decayed in a biphasic manner. The terminal half-life for plasma radioactivity was similar to the half-lives of some plasma proteins, suggesting incorporation of 14C into proteins subsequent to metabolism of [14C]DMA. The results indicate that, while most of the inhaled DMA is excreted unchanged, a small amount of oxidative metabolism of DMA occurs.     

The metabolic disposition of C-labelled carmoisine in the rat after oral and intravenous administration

The absorption, distribution and excretion of the red azo dye carmoisine (Ext. D & C No. 10) was studied in male rats. [14C]Carmoisine was administered in a dose of 200 mg/kg (25 microCi) by gavage or in the same dose (200 mg/kg; 3 microCi) by intravenous injection, and radioactivity was measured in blood, tissue, faeces and urine at different times after dosing. After oral administration of the dye, no radioactivity was detected in the brain, adipose tissue, muscle, testes, spleen or lung, and recovery of the administered activity in faeces and urine was almost complete by 32 hr. The radioactivity profile of the blood indicated rapid but poor absorption of [14C]carmoisine, a maximum radioactivity content corresponding to 0.01% of the dose per ml of blood being reached within 10 min. The decay curve for 14C radioactivity in the blood after iv injection of [14C]carmoisine indicated rapid distribution to the tissues and could be described in terms of a two-compartment mathematical model. The highest levels of radioactivity occurred in the gastro-intestinal tract and liver after the injection but after 24 hr no radioactivity was detectable in these or other tissues. All the radioactivity was recovered in the faeces and urine in the 24 hr following iv injection, the 79% of the dose present in faeces indicating active excretion of the dye and its metabolites in the bile and poor reabsorption from the intestine. The bioavailability of [14C]carmoisine, calculated from the blood-radioactivity curves after oral and iv administration, was less than 10%.     

Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benziosoxazole (AD-810) in Rats, Dogs and Monkeys and of AD-810 in Men

Disposition of 3 - (sulfamoyl[14C]methyl) - 1,2-benzisoxazole ( [14C]AD-810) in rats, dogs and monkeys after oral administration in 20 mg/kg was studied. In preliminary human studies, healthy subjects ingested 200 mg of AD-810. [14C]AD-810 was found to be completely absorbed from digestive tracts in animals, since urinary and biliary excretion accounted for virtually total recovery of dosed radioactivity. Plasma levels reached maxima at several hours after administration in all species examined and decreased exponentially. In rats, tissue levels were virtually similar to plasma levels indicating rather even distribution in the body, and tissue radioactivity disappeared with the similar rate to plasma. Autoradiographic findings on the distribution were consistent with radiometric results. Radioactivity was evenly distributed in fetus in the pregnant rat with the similar level to maternal tissue levels. Like other sulfonamide derivatives, AD-810 was markedly taken up by erythrocytes in all species. [14C]AD-810 radioactivity was mostly excreted within 48 to 72 h after administration and its major route was urine in animals. In men, excretion of unchanged AD-810 and its metabolite in urine was found to be rather slow. No significant differences were found in absorption, distribution and excretion of radioactivity after 7 consecutive daily oral dosings of [14C]AD-810 in rats.     

Transfer of some carboxylic acids in the olfactory system following intranasal administration

The uptake of [14C]benzoic acid, 4-chloro[14C]benzoic acid, [3H]phthalic acid and [14C]salicylic acid in the nasal passages and brain was determined following a unilateral intranasal instillation in mice. An uptake of radioactivity from the nasal mucosa to the ipsilateral olfactory bulb was observed up to 4 h after administration following intranasal instillation of these carboxylic acids whereas the level was low in the contralateral olfactory bulb. Autoradiography of mice given [14C]benzoic acid and [14C]salicylic acid by intranasal instillation showed a preferential localization of radioactivity in the axonal and glomerular layer of the olfactory bulb 1 h after the administration. Four hours after administration the radioactivity was present as a gradient from the axonal layer towards the center of the olfactory bulb. Pretreatment of mice with a compound known to damage the olfactory neuroepithelium resulted in a decreased uptake of [14C]benzoic acid in the olfactory bulb. Thin layer chromatography of supernatants from the ipsilateral olfactory bulbs of mice given [14C]benzoic acid by nasal instillation indicated that the radioactivity in the bulbs represented unchanged compound. These results suggest that there is a transfer of some aromatic carboxylic acids in the olfactory pathways.     

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.     

Localization of 14C-nizatidine in the gastric wall of rats.

Nizatidine (N-[2-[[[2- [(dimethylamino)methyl]- 4-thiazolyl]methyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine , CAS 76963-41-2) has a selective and competitive antagonism against histamine H2-receptors. The localization of 14C-nizatidine to the parietal cells of gastric mucosa which is the effective site of nizatidine, was studied. After oral administration of 14C-nizatidine to rats, the radioactivity was rapidly distributed at higher levels in the gastric mucosa than in the plasma. The mucosal level of nizatidine at 6 h after administration was still 63.3 ng/g tissue, being similar to the effective plasma concentrations in dogs and man. Nizatidine was confirmed to be retained as an unchanged drug in the gastric mucosa, supporting the duration of pharmacological effects of nizatidine. The localization of the drug in gastric wall after intraduodenal administration was examined by means of microautoradiography. The radioactivity of 14C-nizatidine absorbed as the fine developed silver granules was widely localized into the parietal cells in the mucosal layer through the gastric wall at 30 min after administration. Also at 2 h after administration, when the suppression of gastric acid secretion was strongest, the silver granules were almost uniformly localized all over the gastric wall, but the localization was generally less dense than at 30 min.     

Pharmacokinetics and tissue distribution of a novel PDE5 inhibitor, SK-3530, in rats

Aim： To investigate the pharmacokinetic profile and tissue distribution of a novel phosphodiesterase type 5 inhibitor, 5-ethyl-2-{5-[4-（2-hydroxy-ethyl）-piperazine- 1-sulfonyl]-2-propoxy-phenyl }-7-propyl-3,5-dihydro-pyrrolo（3,2-d）pyrimidin-4- one （SK-3530）, in rats after administration of the ^14C-labeled compound. Methods： The pharmacokinetic parameters of SK-3530 were measured based on the total radioactivity and parent SK-3530 concentration in rat plasma after intravenous and oral administration. The tissue distribution of total radioactivity after a single oral administration of [^14C]SK-3530 at a dose of 40 mg/kg was assayed. The plasma protein binding rates of SK-3530 were assessed by in vitro and ex vivo assay. Results： The total radioactivity profiles showed linear pharmacokinetics. The maximum plasma concentration and area under the curve of the parent SK3530 were 10%-20% compared to those of the total radioactivity. After the oral administration of [^14C]SK-3530, the radioactivity was widely distributed in all tissues, and the tissue/plasma ratio of the radioactivity 1 h after administration was calculated as 0.5-2.6 with the exception of excretory organs. A relatively high penetration was shown in the adrenal glands, liver, and lung. In vitro and ex vivo plasma protein binding assay by ultrafiltration showed a considerably high binding rate of more than 97%. Condusion： SK-3530 was relatively well absorbed in the gastrointestinal tract and showed linear pharmacokinetics over the investigated dose range. SK-3530 had low oral bioavailability due to a high, first-pass metabolism.     

Di-(2-ethylhexyl)adipate: absorption, autoradiographic distribution and elimination in mice and rats

Whole-body autoradiography was used to study the tissue distribution of the plasticizer di-(2-ethylhexyl) adipate (DEHA), labelled in the acid [carbonyl-14C] or alcohol [2-ethylhexyl-1-14C]moiety, after iv or ig administration to male mice and rats and pregnant mice. With both DEHA preparations, during the first 24 hr after administration high levels of radioactivity were observed particularly in the body fat, liver and kidneys (after iv and ig administration) and in the intestinal contents (after ig administration) of both species. After administration of [carbonyl-14C]DEHA, radioactivity was also registered in the adrenal cortex, corpora lutea of the ovary, bone marrow, forestomach mucosa, salivary glands and Harder's gland in both species. [2-ethylhexyl-1-14C]DEHA derived radioactivity was found in the bronchi in male mice. Radioactivity was observed in the foetal liver, intestine and bone marrow during the first 24 hr after iv or ig administration of [carbonyl-14C]DEHA to pregnant mice. There was very little accumulation of [2-ethylhexyl-1-14C]DEHA in the mouse foetus but some was found in the urinary bladder, liver and intestinal contents as well as in the amniotic fluid. In an absorption/elimination study in rats of doses of 25 microCi/kg body weight of [14C]DEHA administered ig, dissolved in corn oil or dimethylsulphoxide, blood levels of radioactivity increased somewhat faster and were two or three times higher when DMSO was the vehicle indicating poor absorption of DEHA from the corn oil solution which more accurately reflects human contact with DEHA. Little radioactivity from [carbonyl-14C]DEHA was recovered in the bile, whereas [2-ethylhexyl-1-14C]DEHA was excreted in the bile in significant amounts particularly when DMSO was the vehicle. There was evidence of enterohepatic circulation of DEHA. Radioactivity was also excreted in the urine. As shown by autoradiograms obtained 4 days after the administration of [14C]DEHA there was no retention of DEHA and/or its metabolites in the tissues of mice.     

Pharmacokinetics of [14C]ciclesonide after oral and intravenous administration to healthy subjects

BACKGROUND: Ciclesonide is a novel inhaled corticosteroid developed for the treatment of asthma. OBJECTIVE: To investigate the extent of oral absorption and bioavailability of ciclesonide referenced to an intravenous infusion. This information provides an estimate for the contribution of the swallowed fraction to systemic exposure to ciclesonide after oral inhalation. METHODS: In a randomised crossover study, six healthy male subjects (age range 19-40 years) received single doses of 6.9 mg (oral administration) and 0.64 mg (intravenous administration) of [14C]ciclesonide, separated by a washout period of at least 14 days. Total radioactivity was determined in whole blood, plasma, urine and faeces. Serum concentrations of ciclesonide and its major metabolite, the pharmacologically active desisobutyryl-ciclesonide (des-CIC), were determined in serum by high-performance liquid chromatography with tandem mass spectrometry detection. RESULTS: After a 10-minute intravenous infusion, the mean half-life for total radioactivity was 45.2 hours. Elimination of des-CIC was fast with a mean elimination half-life of 3.5 hours. After oral administration, the mean half-life for total radioactivity was 27.5 hours. On the basis of a comparison of dose-normalised areas under the curve of total plasma radioactivity versus time, 24.5% of orally administered [14C]ciclesonide was absorbed. The parent compound ciclesonide was not detected in any of the serum samples after oral administration; serum concentrations of des-CIC were mostly near or below the lower limit of quantification. Thus, systemic bioavailability for des-CIC is <1% and the absolute bioavailability of ciclesonide is even less than this. [14C]Ciclesonide showed no retention in red blood cells. The mean cumulative excretion of total radioactivity was almost complete by 120 hours after oral and intravenous administration. Faecal excretion was the predominant route of excretion for total radioactivity after both routes of administration. Single oral and intravenous administration of ciclesonide was well tolerated. CONCLUSIONS: Because of an almost complete first-pass metabolism, ciclesonide is undetectable in serum after oral administration. Thus, any ciclesonide swallowed after oral inhalation does not contribute to systemically available ciclesonide or to its active metabolite. Drug-related metabolites are excreted mainly via the faeces, and overall recovery of administered radioactivity is virtually complete after an extended sample collection period.     

Transplacental and mammary passage of radioactivity in rats treated vaginally and orally with [14C]propranolol

The milk transfer, maternal-fetal distribution, and disposition of the antihypertensive/spermicidal agent propranolol were studied in pregnant and lactating rats. Single doses (10 mg/kg) of an aqueous solution of [14C]propranolol were administered either orally (po) or intravaginally (ivg) on gestational d 15, or on postpartum d 7-10. Upon ivg administration, [14C]propranolol was quickly transferred to systemic circulation and the mean blood [14C] concentrations were significantly greater during the first 0.25-2 h than in po dosed counterparts. About 98% of the ivg applied dose was absorbed after 6 h in gravid rats, and the combined 6-h excretions of radioactivity in the urine (ivg = 24.6%; po = 22.9%) and feces (ivg = 16.8%; po = 14.6%) were equivalent in both groups. At the end of 6 h, the levels of [14C] in the urinary bladder, adrenal, uterus, ovary, spleen, skeletal muscle, brain, heart, lung and fat were significantly higher in ivg treated rats than po dosed animals. Compared with the maternal plasma (ivg = 0.76; po = 0.88 microgram/ml), the mean concentrations of [14C] in the placentas were similar in both groups, while the amounts of [14C] were three to five times lower in the amniotic fluids and the fetuses of both po and ivg treated dams. In lactating rats, over 99% of the administered radioactivity was absorbed from the vagina within 6 h. The blood concentrations of [14C] were significantly elevated at 0.5 and 1 h in the per vaginam treated animals, and afterward the disappearance rate of [14C] followed a similar course in both groups. Following ivg application, the milk radioactivity peaked at 0.5 h and declined rapidly. However, the appearance of [14C] in milk was rather slow after oral dosing: the milk [14C] peaked between 2 and 3 h posttreatment and remained steady thereafter. The milk to blood (M/B) [14C] concentration ratios were markedly greater during 0.5 to 1 h in the ivg group than in their po dosed counterparts. At 6 h, the [14C] levels in the whole blood, plasma, milk, and mammary gland were virtually equivalent in the ivg and po treated females. Comparison of the areas under the milk [14C] concentration-time curves (AUCs) indicated that the milk availability of [14C] was about 31% more in dams dosed vaginally. These data suggest that route of administration alters the disposition and milk excretion of [14C]propranolol-derived radioactivity in pregnant and lactating rats.     

Transfer of Some Carboxylic Acids in the Olfactory System Following Intranasal Administration

Abstract

The uptake of [¹⁴C]benzoic acid, 4-chloro[¹⁴C]benzoic acid, [³H]phthalic acid and [¹⁴C]salicylic acid in the nasal passages and brain was determined following a unilateral intranasal instillation in mice. An uptake of radioactivity from the nasal mucosa to the ipsilateral olfactory bulb was observed up to 4 h after administration following intranasal instillation of these carboxylic acids whereas the level was low in the contralateral olfactory bulb. Autoradiography of mice given [¹⁴C]benzoic acid and [¹⁴C]salicylic acid by intranasal instillation showed a preferential localization of radioactivity in the axonal and glomerular layer of the olfactory bulb 1 h after the administration. Four hours after administration the radioactivity was present as a gradient from the axonal layer towards the center of the olfactory bulb. Pretreatment of mice with a compound known to damage the olfactory neuroepithelium resulted in a decreased uptake of [¹⁴C]benzoic acid in the olfactory bulb. Thin layer chromatography of supernatants from the ipsilateral olfactory bulbs of mice given [¹⁴C]benzoic acid by nasal instillation indicated that the radioactivity in the bulbs represented unchanged compound. These results suggest that there is a transfer of some aromatic carboxylic acids in the olfactory pathways.     

Disposition and metabolism of the novel antihypertensive agent alacepril in rats

Disposition and metabolism of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) in rats were studied and compared to those of 1-[(S)-3-mercapto-2-methylpropanoyl]-L-proline (captopril), using 14C-labeled compounds. Some tissue homogenates and plasma of rats were incubated in vitro with [14C]alacepril or [14C]captopril at the concentration of 50 nmol/ml. For in vivo studies, radioactive agents were orally or intravenously administered to rats in doses of 46 mumol/kg (18.7 and 10 mg/kg for alacepril and captopril, respectively) or 460 mumol/kg. In vitro studies revealed that [14C]alacepril is converted to captopril via desacetyl-alacepril (DU-1227) in the liver, kidney and intestine homogenates, but not in the lung homogenate and plasma where deacetylation alone occurred. DU-1227 and captopril formed were found to be partly bound with endogenous -SH compounds i.e. cysteine, glutathione and probably, protein. 1 h after oral administration of [14C]alacepril, plasma levels of total radioactivity reached a maximum of 8 nmol/ml and disappeared with t1/2 of 2.6 h. [14C]Captopril radioactivity was maximum (13 nmol/ml) at 40 min with the disappearance t1/2 of 1.9 h. Similarly to total radioactivity, levels of radioactivity unbound and bound to plasma protein after [14C]alacepril were lower at maximum and disappeared more slowly than those after [14C]captopril. After oral administration of [14C]alacepril, DU-1227, captopril and mixed disulfides of captopril with cysteine and glutathione were detected in the plasma unbound fraction. The three metabolites except for DU-1227 were commonly detected after [14C]captopril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tissue distribution and plasma protein binding of [14C]phenol in rats

The tissue distribution of [¹⁴C]phenol was examined in the rat after oral administration. High concentration ratios between tissues and plasma were found in liver, spleen, kidneys, adrenal gland, thyroid gland, and lungs. Brain, testes, and skeletal muscle had the least concentrations of radioactivity. The total amount of [¹⁴C]phenol in the body reached a peak 0.5 hr after dosing, with only a trace left at 16 hr. Liver was the tissue that accumulated phenol most significantly; 42% of the body phenol was in liver. In blood, 67 to 85% of the ¹⁴C was in the plasma, with 41 to 50% of the radioactivity in plasma bound to plasma protein and/or other macromolecules.     

Distribution of [14C]-tofenacine in rat brain after intravenous, intraperitoneal and multiple oral dosage.

The distribution of radioactivity in the rat brain at 5 min after 10 mg/kg of 14C-labelled N-methyl-2[(o-methyl-a-phenylbenzyl)oxy]ethylamine, [14C]-tofenacine-hydrochloride, the active constituent of Elamol? and Tofacine?, i.v. showed a heterogeneous pattern correlating well with what is known about perfusion and capillarization of brain areas. With the passage of time total brain radioactivity decreased rapidly and radioactivity was redistributed. Both processes occurred simultaneously so that a nearly homogeneous pattern was found at 1 h after i.v. administration. The outer layers of the hippocampus were then the only brain areas with a higher concentration of radioactivity. On i.p. administration of 25 mg/kg of [14C]-tofenacine-hydrochloride maximum brain radioactivity was observed at 30 min, the distribution pattern resembling that seen at 5 min after i.v. dosage. Its further time course corresponded to that of the i.v. series. On multiple oral administration of [14C]-tofenacine-hydrochloride (4 doses of 25 mg/kg at 3-h intervals), maximal radioactivity in the rat brain was observed at 120 min after the last dose. Again the distribution was heterogeneous. Areas of high and low radioactivity were very similar to those seen in the i.v. series at the first intervals, although the contrasts were less pronounced. An exception was the hippocampus where the distribution of radioactivity, -- with high levels in the outer layers as the principal feature -- was similar to that at the last intervals after i.v. administration. A model comprising a central compartment and two brain compartments, representing areas of high and low perfusion, respectively, allows a quantitative explanation of the phenomena observed.     

Pharmacokinetics of acarbose. Part II: Distribution to and elimination from tissues and organs following single or repeated administration of [14C]acarbose to rats and dogs

Acarbose (O-4,6-dideoxy-4-[[1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)-2-cyclohexen-1-yl]amino]-alpha-D-glucopyranosyl- (1----4)-O-alpha-D-glucopyranosyl-(1----4)-D-glucopyranose, Bay g 5421) labelled with 14C was administered to male rats, pregnant and lactating rats as well as to female dogs with single intravenous or oral doses (2 or 4 mg.kg-1) and with repeated oral doses of 2 mg.kg-1 to male rats for 3 weeks. The distribution of radioactivity to organs and tissues, the placental transfer and the secretion into milk was studied using whole-body autoradiographic methods and/or quantitative determination of total radioactivity after autopsy. Unchanged [14C]acarbose was distributed predominantly in the extracellular space, as observed after intravenous dosing to rats. According to the main excretion route, high concentrations were found in kidneys and urine and additionally in blood, lung, and connective tissue or interstitial space. The permeability of the blood/brain barrier for [14C]acarbose and/or its metabolites was very low. No indication was found for distinct differences in the distribution patterns in rats and dogs after intravenous and also in dogs after oral administration. In contrast, in rats after oral dosing the distribution pattern of radioactivity was different with relatively high concentrations in liver, kidney, adrenal gland, spleen, and intestinal mucosa. Due to the slow absorption of the microbial degradation products of [14C]acarbose from the intestine maximum concentrations in the different tissues were reached 8-24 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative study on the disposition of a new orally active dopamine prodrug, N-(N-acetyl-L-methionyl)-O,O-bis(ethoxycarbonyl)dopamine (TA-870) and dopamine hydrochloride in rats and dogs

The pharmacokinetics of a dopamine derivative, TA-870, and dopamine (DA) after oral administration are compared in rats and dogs. The maximum concentrations of free DA in plasma after oral administration of TA-870 were 150 ng/ml in the rat (30 mg/kg) and 234 ng/ml in the dog (33.5 mg/kg). On the contrary, the maximum plasma concentrations after oral administration of DA at an equimolar dose to TA-870 were 12 ng/ml in the rat (12 mg/kg) and 36 ng/ml in the dog (13.5 mg/kg). The AUC values of free DA in plasma after oral administration of TA-870 (30 or 33.5 mg/kg) were 4-6 times higher than those after DA in both animal species. The peak tissue levels of radioactivity in rats after oral administration of [14C]TA-870 (30 mg/kg) were also 5.5 times higher in the liver and 1-2 times higher in other tissues than those after [14C]DA dose (12 mg/kg). In rats, the main excretion route of radioactivity after oral administration of [14C]TA-870 or DA was via the urine. The total recoveries of radioactivity in the urine and feces were 91-96% of the dose within 24 hr for both compounds. Biliary excretion in rats accounted for 19.8% of the dose of [14C]TA-870 and 12.6% of the dose of [14C]DA within 24 hr. These results demonstrate that TA-870 was well absorbed from the digestive tract, extensively metabolized to dopamine, and proved to be an orally usable dopamine prodrug.