The absorption, distribution and excretion of ONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate)after single oral or intravenous administration were investigated in male or female rats.

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The absorption, distribution and excretion of ONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate) after repeated oral administration were investigated in rats. Also the influence on the hepatic drug metabolizing enzyme activities was examined.
1. When ³H-ONO-1078 was orally and repeatedly administered at the dose of 2mg/kg/day for 15 days, the plasma level of radioactivity at 24hr after each administration reached nearly steady state by 5-7th day.
2. Repeated oral administration of ¹⁴C-ONO-1078 at the dose of 2 mg/kg/day for 7 days was not associated with any accumulation of radioactivity in organs or tissues, the radioactivity was quickly eliminated after final administration.
3. When ³H-ONO-1078 was orally and repeatedly administered at the dose of 2mg/kg/day for 7 or 15 days, radioactivity reached nearly steady state in many organs such as liver and kidney. On the other hand, the radioactivity in white and brown fat did not reach steady state by 15-day repeated administration.
4. After repeated oral administration of ¹⁴C-ONO-1078 or ³H-ONO-1078 at the dose of 2mg/kg/day, the excretion of radioactivity into urine or feces were same to those after single administration.
5. Repeated oral administration of ONO-1078 at the dose of 1.0g/kg/day for 15 days did not have any effect on microsomal protein content and hepatic drug metabolizing enzyme activities, but liver weight rose 1.08-fold heigher than normal control.

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The absorption, distribution and excretion of ONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate) were investigated in male beagle dogs.
1. Plasma levels of unchanged drug after oral administration at the doses of 8 or 30mg/kg reached C_max of 69 and 238ng/ml at 1.7 and 2.7hr after administration, respectively. Significant difference was not observed in T_1/2. Bioavailabilities, calculated on the basis of AUC obtained after intravenous administration at the dose of 4mg/kg, were 4.8 and 2.7%, respectively.
2. Plasma levels of radioactivity after oral administration of ¹⁴C-ONO-1078 at the dose of 4mg/kg reached C_max of 28ng eq./ml at 1.3hr after dosing, and declined with T_1/2 of 7.2hr. Bioavailability, calculated on the basis of AUC obtained after intravenous administration at the dose of 4mg/kg, was 2.8%.
3. A slight tissue levels of radioactivity at 120hr after oral administration of ¹⁴C-ONO-1078 (4mg/kg) were detected in liver, kidney, thyroid gland and blood. No significant level of radioactivity was detected in all other tissues.
4. Within 120hr after oral or intrave nous administration of ¹⁴C-ONO-1078 at the dose of 4mg/kg, 99.7 and 99.6% of administered radioactivity were excreted into feces, respectively, indicating fecal excretion was main excretion route in both administration route.
5. Within 48hr after oral administration of ¹⁴C-ONO-1078 at the dose of 4mg/kg, 4.9% of administered radioactivity was excreted into bile and 0.3% of administered radioactivity was excreted into urine.
6. ONO-1078 was absorbed from intestinal tract for many hours, and mostly excreted into feces via bile.

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The metabolism of ONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate) was examined in rats, guinea-pigs and dogs. The binding to plasma (or serum) protein and interaction with reference drugs in binding to human serum protein were also investigated.
1. Metabolites in rats were almost all those with a hydrolized amido-bond in ONO-1078 molecule, except unchanged drug which was not absorbed and excreted into feces. Besides, metabolites in rat were quite different from those of dog. In this manner, species-difference was observed.
2. MC-0 and MH-0, hydrolized metabolites of ONO-1078, and besides MH-1 and MH-2, taurine conjugates of MH-0 and hydroxylated MH-0, respectively, were identified as main metabolites in rats. Moreover a part of MH-0 was incorporated into the adipose tissue as triglycerides.
3. Similarly to rats, the metabolite which had hydrolized amido-bond in ONO-1078 molecule was observed in guinea-pigs.
4. The amido-bond of ONO-1078 was not hydrolized in dogs. Main metabolites were M-1, as mono-hydroxylated form, M-2, as di-hydroxylated form of ONO-1078, and M-3, as sulfoconjugates of M-1 and M-2.
5. ONO-1078 was rapidly hydrolized in liver microsomal fraction obtained from rat and guinea-pig. The enzyme hydrolizing compound in rat liver was identified as carboxylesterase. But, in dog liver microsomal fraction, ONO-1078 was not hydrolized.
6. In the presence of carboxylesterase inhibitor, the formation of M-1 and M-2 in rat liver microsomal fraction was observed.
7. In vivo binding to plasma (or serum) protein after oral administration varied 97.1 ?? 98.9% in rats, 76.1 ?? 84.1% in dogs. All the binding to rat, dog and human serum proteins in vitro were more than 99.7%.
8. The examination of interaction with reference drugs in the binding to human serum protein revealed that ONO-1078 and every reference drugs tested did not affect to the binding ratio of each other.

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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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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 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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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 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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(R, R)-N, N'-Diisopropyltartramide and its a nalogue show enantioselectivity toward mamy compounds possessing at lest two hydrogen bond sites. The addition of (R, R)-N, N'-diisopropyltartramide to the nonaqueous mobile-phase solvent of a silica gel chromatography as well as the use of a silica-based chiral stationary phase derived from (R, R)-tartramide thus make possible the direct resolution of a wide range of enantiomers. Such enantiomers contain α-hydroxy carbonyl derivatives, β-hydroxy carbonyl derivatives, N-acyl derivatives of primary amines, amino esters, and β-amino alcohols, glutarimides, barbiturates, α-hydroxy ketoximes, bi-β-naphthol and 1, 2-diols. The mode of comp lexation for the observed enantioselction was found to be dual hydrogen bonding between(R, R)-tartramide derivatives and the solute enantiomers to be resolved. This mode of hydrogen bonding leads to the formation of a pair of transient diastereomers differing in stability. The broad scope of application of the (R, R)-tartramide derivative as a chial selector may possibly be due to conformational changes involving the formation and/or scission of intramolecular hydrogen bond (s)at the time of complexation. By such conformational reorganization of the (R, R)-tartramide derivative, this molecule is able to provide dual hydrogen bond sites complementary to those of the versatile enantiomers listed above. Dual hydrogen bonding was observed in an X ray crystal structure of the complex of (R, R)-N, N'-diisopropyltartramide with(S, S)-9, 10-dimethyl-9, 10-dihydrophenanthrene-9, 10-diol. In the complex, intermolecular hydrogen bonds are formed between hydroxyls of the diol and amide carbonyls of (R, R)-tartramide. Dual hydrogen bonds in this complex are characterized by relative orientation of the set of bonding sites of each component showing a twist, rotational sense of which reflects the absolute configuration.

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