The absorption, distribution and excretion of Y-24180 were investigated in male rats after a single oral administration of ¹⁴C labeled Y-24180 (¹⁴C-Y-24180). It was found that orally administered ¹⁴C-Y-24180 was absorbed from the small intestine. The absorption from the small intestine was relatively slow, and the time to reach maximum radioactivity concentration in plasma following administration was 2 and 4 h under the non-fasting condition and the fasting condition, respectively. The extent of absorption from the digestive tract was estimated to be at least 70% of dose. The extent of absorption from the digestive tract and disappearance rate from the body were not influenced by food, but bile enhanced the absorption of Y-24180 from the digestive tract. The concentrations of radioactivity in tissues were highest 1-6 h after oral dosing. Distribution of the radioactivity to tissues was lower when compared with the plasma level. The highest radioactivity level after oral dosing was observed in the liver, and its level was 10 times higher than those in the other tissues except the digestive tract. Clearance of radioactivity from each tissue was fast, and no accumulation of radioactivity in the body was observed. Whole body autoradiograms correlated with tissue radioactivity levels and also showed no accumulation of radioactivity in the tissues whose radioactivity levels were not examined. Distribution of radioactivity into blood cells was observed, however, it was assumed that metabolites of Y-24180 present in the blood distributed into blood cells. Serum protein binding of radioactivity at 1 and 6 h after oral dosing was 86.6 and 72.6%, respectively. Most (96.6% of dose) of the administered radioactivity was excreted in feces within 120 h and mostly within 48 h after oral dosing. Fecal excretion after intravenous dosing was comparable to that after oral dosing. After oral administration to bileduct cannulated rats, 69% of the administered radioactivity was excreted in bile within 72 h. This result strongly suggests that fecal radioactivity is mainly due to the radioactivity excreted via the bile. At least 29.3% of the radioactivity in bile was reabsorbed from the digestive tracts via entero-hepatic circulation in rats.

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TA-0201 is a novel orally active non-peptide antagonist for endothelin receptors. Metabolism and pharmacokinetics of TA-0201 were investigated in rat. Animal and human liver microsomes were used to investigate the metabolism of TA-0201 in vitro.
1. The structures of main metabolites were identified to be carboxylic acid form (CA) and diol form (Diol) by comparison with authentic sample using LC/MS/MS. Intrinsic clearances (CLint) for the conversion of TA-0201 to CA by liver microsomes of different species were in the following order of monkey>>dog>human>rat. The isozyme catalyzing the metabolic reaction of TA-0201 to CA and Diol was determined. It was supposed that CYP3A family contributed mainly to these metabolic reactions.
2. Pharmacokinetic studies of TA-0201 in the rat were investigated, the bioavailability (BA) in male rats was calculated as 60%. More than 90% of TA-0201 was disappeared from the body by metabolism. Hepatic and gastro intestinal extractions were 0.21 and 0.11, respectively. Contributions of the two organs in the first-pass extraction of TA-0201 after oral administration were of the same degree.

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Tissue distribution of total radioactivity and the unchanged compound was studied following a single and multiple oral administration of [¹⁴C]D0870 to rats.
1. Tissue levels of radioactivity after a single oral administration to male rats reached the maximum level within 6 hours, then decreased to undetectable level in most tissues within 168 hours after dosing. The tissue levels of radioactivity much exceeded the corresponding plasma level in the liver, adrenal, kidney, lung and other tissues.
2. The distribution of radioactivity in female rats showed a similar pattern to that in male rats. Slight sex differences were observed in liver and adrenal level.
3. Tissue levels of radioactivity in male rats at 24 hours after a daily oral administration for 7 days were much higher than those after a single administration, while those after daily administration for 14 and 21 days were close to those after a daily administration for 7 days.
4. The levels of radioactivity in male rats after a daily administration for 21 days reached the maximum level in most tissues at 6 hours, then declined slower than in the case of single administration study.
5. The most part of radioactivity in plasma and main tissues after both single and multiple administration was composed of the unchanged compound.

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A basic study was carried out in order to improve the detection accuracy of radioluminography (RLG) in drug evaluation studies. Back ground value of photo-stimulated luminescence (PSL_BG) of an imaging plate (IP) was proven to decrease exponentially in proportion to the wall thickness of exposure vessels without any improvement of SD of PSL_BG. This unexpected result was attributed to the fact that a nonuniformity in shielding occurred. PSL_BG was estimated in terms of β-particles from ³²P. When IP was exposed in a shield box, a clear periodicity was observed in the PSL_BG. A method for directly measuring the PSL_BG of each area was developed, which involved exposing IPs simultaneously and assessing PSLBG of the IP in contact with a ¹⁴C sample from the PSL_BG of the corresponding area of the other IPs.

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