Absorption, distribution, metabolism and excretion of [14C]ebastine after a single administration in rats.

Absorption, distribution, metabolism and excretion of ebastine (4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, LAS-90, CAS 90729-43-4), a novel antihistamine, were investigated with 14C-labeled compound in rats after a single oral or intravenous administration, in comparison with [14C]carebastine, an active metabolite of ebastine. After intravenous administration of [14C]ebastine at 2 mg/kg, the plasma level of radioactivity decreased biphasically with alpha-phase half-life (t1/2 alpha) of 1.6 h and beta-phase half-life (t1/2 beta) of 3.1 h. After administration of [14C]carebastine, a similar plasma level-time profile was observed with t1/2 alpha of 0.7 h and t1/2 beta of 2.1 h. Following oral administration of [14C]ebastine at a dose of 2 mg/kg, the plasma level reached the maximum (Cmax) of 102 ng eq./ml at 2 h and decreased monophasically with t1/2 of 3.9 h. At 20 mg/kg, a monophasic decrease was also observed with Cmax of 1110 ng eq./ml at 4 h and with t1/2 of 4.0 h. After oral administration of [14C]carebastine at 2 mg/kg, the plasma level reached Cmax of 129 ng eq/ml at 2 h, followed by a monophasic decrease with t1/2 of 2.9 h. Half-lives after administration of [14C]ebastine were somewhat longer than those after administration of [14C]carebastine. The level of [14C]ebastine radioactivity in the liver was about 36 times higher, and in kidney, mesenteric lymph nodes, lung, adrenal, submaxillary gland or pancreas 2-4 times higher than in plasma at 2 h after oral administration. The brain level was lower than the reliable limit of measurement. Other tissue levels were similar to or lower than plasma level. Radioactivity in most tissues decreased essentially in parallel with that in plasma. In pregnant rats, [14C]ebastine radioactivity level in fetus was about 1/4 of the maternal plasma level 1 h after administration. In lactating rats, milk levels of [14C]ebastine radioactivity were similar to maternal plasma levels over 8 h. Serum protein binding of [14C]ebastine was more than 99.8%. After intravenous administration of [14C]ebastine, about 6% of the dose was excreted in the urine and about 93% in the feces. Similar results were observed after oral administration at 0.2, 2 and 20 mg/kg. Following administration of [14C]carebastine, the recovery of radioactivity in urine and feces were around 2% and 96% of the dose, respectively, irrespective of administration route. In the plasma 2 h after oral administration of [14C] ebastine, carebastine and the polar metabolite(s) were observed as major components, whereas ebastine was hardly detected.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption, distribution and excretion of [carbonyl-14C]mosapride citrate after a single oral administration in rats, dogs and monkeys.

Absorption, distribution and excretion of mosapride citrate ((+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morph oli nyl] methyl]benzamide citrate, AS-4370, CAS 112885-42-4), a novel gastric prokinetic drug, were studied with 14C-labeled drug in male and female rats mainly after a single oral administration. Plasma concentrations and excretion following oral administration of [14C]mosapride were also investigated in dogs and monkeys of both sexes. The main experimental dose was 10 mg/kg. After oral administration, [14C]mosapride radioactivity was rapidly absorbed through the intestinal tract. In male rats, concentration of plasma radioactivity reached the maximum (Cmax; 1410 ng eq./ml) 1 h after administration and decreased biphasically with half-lives of about 2 h in alpha-phase (t1/2 alpha) and in beta-phase (t1/2 beta) of about 8 h. t1/2 beta was virtually constant in the dose range from 1 mg/kg to 100 mg/kg, and the area under the plasma concentration-time curve (AUC) was proportional to the dose. In female rats, biphasic plasma concentration-time profile with similar half-lives was also observed, but Cmax (2070 ng eq./ml) and AUC were larger than those in male rats, suggesting the sex difference in pharmacokinetics. In dogs and monkeys, Cmaxs of plasma concentration were about 1000 ng eq./ml and 2000-3000 ng eq./ml, respectively, and sex difference was not observed. Plasma concentrations declined in a biphasic manner and t1/2 alpha and t1/2 beta were about 4 h and 15 h in dogs and about 3 h and 10 h in monkeys, respectively. The [14C]mosapride radioactivity was distributed to many tissues including the stomach and small intestine at the higher concentration, while to the brain and eye ball at the lower concentration than the plasma in male rats. Radioactivities in most tissues decreased essentially in parallel with those in plasma. In pregnant rats, concentrations of radioactivity in fetus were a little higher than those in the maternal plasma. In lactating rats, milk radioactivity concentrations were about 5 times higher than corresponding plasma concentrations, and both of them decreased with similar half-lives. Mosapride was bound to serum protein of various animal species, albumin and alpha 1-acid glycoprotein, in about 93-99%. After oral administration in rats, about 40% of dosed radioactivity was excreted into urine and about 60% into feces via bile. Neither dose dependency nor sex differences was observed in excretion. In dogs, about 20% of dosed radioactivity was recovered in urine and about 70% in feces.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding of sulfonamides to erythrocyte proteins and possible drug-drug interaction.

The mode of binding of sulfonamides to erythrocyte proteins and possible drug-drug interaction between those compounds in erythrocytes resulting in changes in tissue levels were studied in rats using zonisamide (a novel antiepileptic agent possessing a sulfonamide group), several other sulfonamides and some antiepileptics without a sulfonamide group. In Michaelis-Menten plottings, the sulfonamide was found to be concentrated into erythrocytes in vitro and in vivo in a saturable high-affinity mode and in a linear low-affinity mode at ordinary therapeutic plasma levels through a simple diffusion process. Concentration in erythrocytes was affected by the presence of albumin in the extracellular medium. The cellular sulfonamide was readily replaced by extracellular sulfonamides in vitro. Even in vivo, erythrocyte levels of zonisamide were lowered by administration of other sulfonamides, although the plasma and tissue levels were not significantly changed since the plasma and tissue compartments of zonisamide were large relative to the erythrocyte compartment at ordinary therapeutic dose levels of zonisamide in animals and man. Therefore, disposition of zonisamide was not significantly influenced by other sulfonamides, but it is suggested that drug-drug interaction affecting the tissue levels may occur for a combination of sulfonamides with extremely different affinities for erythrocytes and low therapeutic plasma levels.

Mode of antitumor action of recombinant human tumor necrosis factor on the sarcoma Meth A transplanted in the mouse.

The mode of antitumor action of rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation with respect to time course, dose-response relationships and selectivity of the effects. The maximal cytotoxic effect on tumor cells revealed by inhibition of DNA synthesis and maximal lesional effect on tumor vasculature revealed by change in blood pool-size in the tissue were detected at 30 min and 1 h after administration of rHu-TNF, respectively. The dose-response relationship between cytotoxic and tumoricidal effects of rHu-TNF was irrespective of administration route. ED50s of these antitumor effects after i.v. administration of rHu-TNF were about 50 times as high as ED50s after i.t. administration. ED50 of i.t. given rHu-TNF for vascular effect was about 20 times as high as that for cytotoxicity while ED50 of i.v. rHu-TNF for vascular effect was only 2-3 times as high as that for cytotoxicity. The whole body autoradiographies with [125I]HSA given i.v. to see the blood influx into tumor tissue and [14C]thymidine given i.v. to see DNA synthesis in the whole body after administration of rHu-TNF revealed that the distribution of radioactivity was markedly changed in the tumor alone without any detectable change in other whole body tissues. In conclusion, the in vivo antitumor effect of rHu-TNF given i.t. or i.v. appears to be exerted through the direct action on Meth A sarcoma rather than indirectly on tumor vasculature. Under present conditions, the effect of rHu-TNF in the whole body tissues seems rather selective on cells and vasculature of the tumor.

Disposition of 125I-labeled recombinant human tumor necrosis factor in the tumor-bearing mouse.

Disposition of [125I]rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation. After i.v. administration, [125I]rHu-TNF measured by radioactivity and immunoreactivity biphasically decreased in plasma. Tumor level of [125I]rHu-TNF was the maximum at 1 h, then decreased and finally remained essentially constant. After i.t. administration, plasma level reached the maximum at 1 h. Tumor level decreased quickly and then became essentially constant. [125I]rHu-TNF was suggested to be degraded to small fragments in the tumor. Significant distribution of [125I]rHu-TNF was found in the kidney, lung, liver and tumor. Most tissue levels decreased with time in parallel with plasma levels. [125I]rHu-TNF radioactivity was found in proximal convoluted tubules of kidney and in those areas of tumor consisting of degenerating cells with pyknotic nuclei. Urine contained most of administered radioactivity, which being neither immunoreactive nor protein-bound.

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)