The absorption, distribution, metabolism and excretion of S-1452, a new thromboxane A₂ receptor antagonist, were studied after a single oral or intravenous administration of ¹⁴C-labelled compounds at a dose of 5mg/kg to fasted and non-fasted rats. Also, using ³H-(+)-S-145·Na, in vitro binding to serum protein was investigated in experimental animals and humans.
1. After oral administration, ¹⁴C-S-1452 was almost completely absorbed in both fasted and non-fasted rats, and approximately 90% of the dosed radioactivity was excreted into the bile.
2. Plasma concentration profiles of radioactivity, (+)-S-145 and its metabolites after an intravenous administration to fasted rats were similar to those found with non-fasted rats.
3. The bioavailability of (+)-S-145 after an oral administration of ¹⁴C-S-1452 was estimated to be approximately 70% in fasted and 30% in non-fasted rats. This suggests that the hepatic first-pass effect of (+)-S-145 in rats is extensive and that it is influenced by the gastric emptying rate.
4. After oral administration of ¹⁴C-S-1452, the plasma concentration of dihydrobisnor was higher than bisnor. This suggests that the reduction of the ethylene bond at the α-side chain of (+)-S-145 occurs predominantly rather than β-oxidation.
5. The major metabolites excreted in urine were 5-OH-tetranor and 6-OH-tetranor, which were hydroxylated at the 5- or 6-position of bicyclo ring, respectively. In the bile, main fraction of the radioactivity was excreted as conjugated metabolites, with more taurine conjugates than glucuronides.
6. The in vitro binding to serum protein of (+)-S-145 accounted for more than 95% in all species studied.

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The absorption, distribution, metabolism and excretion of S-1452 were studied after a single oral or intravenous administration of ¹⁴C-labelled compounds at a dose of 5mg/kg in beagle dogs and cynomolgus monkeys.
1. After a single oral or in travenous administration to dogs, taurine-conjugated metabolites were detected in plasma. In monkey plasma at the same dose regimens, high concentrations of glucuronides were found.
2. S-1452 was metabolized mainly by β-oxidation at the α-side chain, hydroxylation of the 5- or 6-position of the bicyclo ring and taurine or glucuronic acid conjugation in dogs and monkeys as well as in rats.
3. The half-lives (t_1/2β) of (+)-S-145 in plasma were calculated to be 60min in dogs and 30min in monkeys. These were larger than that observed in rats.
4. The bioavailability of (+)-S-145 after oral administration of ¹⁴C-S-1452 was estimated to be approximately 43% in dogs and 5 % in monkeys. The result for dogs suggests that almost no first-pass effect occurred, because absorption after the oral administrtion was estimated to be 40 ?? 50% of the dose in dogs in this study. In contrast, the low bioavailability in monkeys suggests that the first-pass effect of (+)-S-145 in liver or intestinal tracts is very extensive.

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Transfer of radioactivity into the fetus and milk were studied after a single oral administration of ¹⁴C-S-1452 at a dose of 5mg/kg in pregnant rats on 19 days of gestation and in lactating rats.
1. In whole body autoradiography, distribution patterns of radioactivity in maternal tissues were similar to those found in male rats.
2. The distribution of radioactivity in a fetus at 1 hr after administration was estimated to be 0.04% of the administered dose. This result suggests that fetal transport of S-1452 is relatively low in rats.
3. At 24hr after administration, the radioactivity in maternal tissues and in the fetus had been almost completely eliminated.
4. The level of radioactivity in the milk was one-third of that in the plasma at 30 min after administration. From 2 to 6hr after administration, higher levels were found in the milk. However, at 24hr after administration, the level was similar to that in the plasma.

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The tissue distribution and excretion of S-1452 were studied in rats after a single and repeated oral administration of ¹⁴C-S-1452 at a dose of 5mg/kg or 5mg/kg/day for 10 days.
1. The level of radioactivity in the liver was markedly higher than those in other tissues after both single and repeated dosing.
2. Whole body autoradiography after a single or repeated administration demonstrated that the radioactivity in the hepatic vein was markedly weaker than that in the portal vein. This phenomenon suggests that the hepatic first-pass effect of (+)-S-145 in rats was the extensive one.
3. The daily excretions of radioactivity in urine and feces were constant during repeated administration. Within 168hr after the last dosing, 8.3% and 89.2% of the administered radioactivity were recovered from the urine and feces, respectively.
4. After both single and repeated administration, the radioactivity tended to disappear slowly from the whole blood, spleen and bone marrow.
5. After repeated administration of ¹⁴C-S-1452 for 10 days, no accumulation of radioactivity in the tissues was observed.

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The metabolism of S-1452, calcium (5Z)-7-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate hydrate, a new TXA₂ receptor antagonist, in rats was studied. Twelve unconjugated metabolites including the unchanged free acid of S-1452, (+)-S-145, and three α-chain-shortended metabolites, bisnor-, dihydrobisnor- and tetranor-(+)-S-145, and four pairs of their regioisomeric metabolites, hydroxylated at the 5- or 6-position of the bicyclo ring, were isolated from plasma after oral administration of ¹⁴C-S-1452 or unlabelled S-1452. Two of the hydroxylated metabolites, 5-OH-tetranor- and 6-OH-tetranor-(+)-S-145, were also isolated from urine. Furthermore, four taurine-conjugated metabolites, (+)-S-145, bisnor-(+)-S-145, dihydrobisnor-(+)-S-145 and tetranor-(+)-S-145 taurine, were isolated from bile. The structures of these metabolites were identified by means of GC/MS, LSIMS and ¹H-NMR analyses in comparison with their synthesized reference compounds. The stereochemistry of 6-OH-(+)-S-145, the exo configuration of its hydroxy group, was confirmed by comparison of its retention time on HPLC with those of endo and exo reference standards. Other hydroxylated metabolites also were considered to be of the exo configulation. Tentative metabolic pathways in rats are presented and discussed.

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A new hypnotic, 450191-S, is a ring-opened benzodiazepine derivative. It is knownthat the unchanged drug is not detected in plasma and urine after oral administration ofthis drug to humans, and that the metabolites of 450191-S, M-1, M-2, M-A, M-3, and M-4are found in plasma and mainly M-4 is excreted in urine. Some papers have shown thatthe main active metabolites of 450191-S are M-1, M-2, M-A, and M-3.
This paper deals with the pharmacokinetics of 450191-S in healthy volunteers . Plasmahalf-lives of metabolites of 450191-S were M-1, 1.2±0.5hr;M-2, 3.2±0.8hr;M-A, 5.0±1.2hr;M-3, 8.5±1.Ohr;and M-4, 1.7±0.1hr (mean±SD).The half-life of total activemetabolites (the sum of the plasma concentration of M-1, M-2, M-A, and M-3) was 10.5±2.6hr.Plasma concentration of each metabolite after administration of 0.5, 1, 2, 4mgof 450191-S was approximately proportional to the dose. Mean urinary excretion ratio of M-4 was 62. 3% of the dose. Effect of food on the pharmacokinetic parameters was notfound. Plasma concentration of each metabolite after multiple administration showed asimilar time course to the simulation curve calculated using pharmacokinetic parametersestimated from observed plasma concentrations after the first dose. Plasma protein binding ratios measured by ultrafiltration at 37° were M-1, 79.3%;M-2, 81.2-87.5%;M-A, 76.8-78.7%;M-3, 80.8-81.4%;and M-4, 88.9-89.7%.

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Rilmazafone Hydrochloriode (RZ), a prodrug of benzodiazepine derivatives, is used clinically as a sleep inducer.
The pharmacokinetics of RZ in patients were studied to determine the clinical dose for patients with chronic renal failure.
Five patients (2 male, 3 female, aged 44-62yr) who participated in this study were undergoing hemodialysis. They were given RZ (1mg, p. o.) one time on the day of dialysis, and 5-7 days later on the day of non-dialysis. Blood samples were collected for 48hr after each administration to determine the concentrations of metabolites of RZ (M1, M2, MA, M3, M4). Pharmacokinetic profiles of RZ in these patients were compared with those in healthy volunteers (2mg, p. o.). Despite the dose difference and body weight difference (patients, 53kg (mean), volunteers, 60kg), C_max's of M1 and M4 in patients were double and AUC's were five times those in healthy volunteers. T_1/2's of M1, M2, M4 in patients were two to four times longer than those in healthy volunteers. The pharmacokinetic profiles of total active metabolites in patients were not significantly different. However, plasma concentration-time curves of potent active metabolites (M1, M2) in patients would probably be higher than those in healthy volunteers, if both were given the same dose of RZ.
These results may indicate that dosage of RZ in patients with chronic renal failure should be started from 1mg, because of the reduction of hepatic metabolism and renal excretion of RZ in these patients.

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¹⁴C-6315-Sの雄性ラットにおける単回ならびに反復静脈内投与後の組織分布, 妊娠ラットにおける組織分布および胎仔移行性, 乳汁中濃度について検討した。
¹⁴C-6315-S, 20mg/kg単回静脈内投与後, 放射能は速やかに全身に分布し, 投与後5分の濃度は腎臓が最も高く (289μg equiv.of 6315-S/g), 以下, 血漿 (67), 肝臓 (60), 肺 (36), 心臓 (12) 等の順であった。これらの放射能は以後急速に減少し, 24時間後にはすべての組織で1μg/g以下に低下し, 残留性を示すような組織は認められなかった。
反復投与 (20mg/kg, 1日1回, 7日間) での組織中濃度は, 最終回投与後早い時間は単回投与の値とほぼ一致していたが, 24時間後の値は単回投与よりも2～5倍高かった。しかし, これらも168時間後にはすべて1μg/g以下に低下したので, 蓄積性は低いと判断された。
反復投与期間中の日内排泄率は。尿に65%, 糞に35%でいずれも一定した値であり, 反復投与による排泄の変動はみられなかった。
¹⁴C-6315-S, 20mg/kgを妊娠ラットに投与したとき, 5分後の胎仔組織中放射能濃度は母獣血漿濃度の1/20以下であった。
¹⁴C-6315-S, 20mg/kgを哺育中雌性ラットに投与したとき, 乳汁中濃度は血漿濃度と同じかやや低い値であった。

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A new hypnotic, 450191-S, was administered to five elderly patients [cerebral thrombosis: two patients (81 yr and 78 yr), gastric cancer: one patient (61 yr); chronic hepatitis: twopatients (78 yr and 70 yr)]. Pharmacokinetic behaviors of this drug in these patients werecompared with those in healthy volunteers reported in a previous study.
Plasma protein binding ratio of each metabolite and urinary excretion ratio of M-4 inelderly patients were similar to those in healthy volunteers. However, some differencesin plasma concentration time course of metabolites were found between elderly patientsand healthy volunteers. In healthy volunteers, C_max of M-1 was lower than that of M-2and M-A whereas in elderly patients C_max of M-1 was higher than M-2 and M-A. Fromthe results of various investigations of the phenomenon, it seems that the higher plasmaconcentration of M-1 in elderly patients may be ascribed to a decrease of first-pass effect.

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