Absorption, distribution, metabolism and excretion of Y-516, a new psychotropic drug, were investigated in male and female rats after administration of ¹⁴C labeled compound (¹⁴C-Y-516).
When ¹⁴C-Y-516 was orally administered to rats, approximately 3.2 ?? 9.2 % and 84.9 ?? 99.8 % of ¹⁴C was excreted within 4 days in urine and feces, respectively. No sex, dose and route differences were not observed on urinary and fecal excretion. Percent recovery of ¹⁴C in bile was 62% and 75% in male and female rats, respectively.
The highest blood level of ¹⁴C was observed within 30 min after oral administration of 5 mg/kg. A good correlation was observed between blood concentrations and administered doses.
The highest concentration of ¹⁴C was found in the liver, and relatively high levels were observed in the lung, adrenal, kidney, spleen, thyroid and salivary gland. No significant accumulation of ¹⁴C was observed in any tissue except the liver 24 hours following administration. About 72% of ¹⁴C present in the serum was bound to the proteins. A little transition of ¹⁴C to the blood cell was observed.
The major metabolic pathways of Y-516 in rats are considered to be the hydroxylation at iminodibenzyl ring, and dehydrogenation at the terminal spiroamine moiety, and the hydroxylated derivatives were mainly excreted as glucuronides in the bile. No sex and dose differences were observed in metabolism of Y-516.

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Effects on ¹⁴CO₂ expiratory patterns of nature and administration route of the injection fluid were studied.
1) In case of rapid i.v. injection, no difference in the pattern was found by difference in glucose concentrations and volumes of the aqueous injection fluid.
2) By the same route as mentioned above, lower P₁ height and more longdrawn plateau by the ¹⁴C-glucose-blood mixture than the aqueous injection fluid were recorded for radiorespirometric patterns.
Results indicated that ¹⁴C-glucose molecules in the aqueous fluid infused into the blood vessel could be supplied into organs or tissues before mixing of the aqueous ¹⁴C-glucose solution with the blood fluid in the blood vessel system. And it is suggested that much more amount of ¹⁴C-glucose might be taken up in organs and tissues when the label was resoluble in aqueous solution than in blood.
3) In case of intraduodenal infusion, a tracer of glucose in a small volume such as 0.05 ml of the aqueous solution gave a similar radiorespirometric pattern to that by the aqueous ix. injection fluid. This is an indication that there was fast absorption of glucose by the intestinal mucosa, which might be not rate determining step.
A relatively large volume and very high concentration of glucose in the infusion fluid caused big suppression of the radiorespirometric pattern. This might be suggestive that the above factors might give physical suppression to the peristalsis of the intestine.

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The absorption, distribution, metabolism and excretion of ¹⁴C-nizatidine were studied after a single oral or intravenous administration of 5 mg/kg to rats.
1. The blood levels of radioactivity reached a maximum concentration at 30 min after oral administration, corresponding to 668 and 426 ng equivalent of nizatidine/ml, and then declined within the first 6 hr with half-lives of 1.43 and 1.38 hr in male and female rats, respectively. The half-lives in the ranges of 8-24 hr were 10.3 hr in male, and 15.4 hr in female.
2. The blood level of radioactivity declined biexponentially with half life of 0.66 hr in the first 4 hr and 27.0 hr in the range between 6 hr and 48 hr after intravenous administration in male rats.
3. Male rats excreted 68.0 % of the dose in urine and 27.1 % of the dose in feces until 120 hr after oral administration. Until 120 hr after intravenous administration, male rats excreted 84.2 and 16.2 % of the dose in urine and feces, respectively. The biliary excretion within 48 hr after oral administration was 20.2% of the dose in male rats, while the excretion of the radioactivity reabsorbed, as a percent of the dose, was 5.8% in bile and 30.3% in urine until 48 hr after intraduodenal injection.
Female rats excreted 59.7 % of the dose in urine and 39.1 % of the dose in feces until 120 hr after oral administration.
4. The radioactivity levels in the tissues except the testis reached a maximum concentration at 30 min after oral administration in male rats, and relatively high radioactivity was found the kidney, small intestine, liver, urinary bladder and stomach. The other tissues contained nearly the same concentrations of radioactivity as plasma, or somewhat lower. At 120 hr after oral administration, the radioactivity in most tissues was not detectable.
5. The plasma protein binding in vitro was 12.8-16.9% at concentrations range between 0.1 and 10 μg/ml, and that in vivo was 20.6, 26.2 and 41.8% in the plasma sample collected 0.5, 2 and 6 hr after administration, respectively.
6. In the fractions of plasma and urine collected in male and female rats after oral administration, the unchanged drug, N-desmethyl and S-oxide metabolites were the main components and the other minor compounds, M-3 and M-5, were also detected in the urine. In the fractions of bile in male rats, M-2, M-4, M-5 were detected with the unchanged drug, N-desmethyl and S-oxide metabolites.

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Transfer of ¹⁴C-nizatidine into the fetus and milk after oral administration to pregnant or lactating rats, and the absorption, distribution, metabolism and excretion of ¹⁴C-nizatidine after repeated administration to male rats were studied.
1. On day 13 and 18 of gestation, the radioactivity in the fetus was lower than that in the maternal blood based on autoradiography. On day 18 of gestation, the radioactivity levels in the fetal liver and kidney were higer than that in the maternal plasma, but at 48 hr after oral administration the radioactivity levels decreased to 5 % and 2 % of the highest concentration, respectively.
2. The concentrations of radioactivity in the milk were higher than that in the maternal plasma until 6 hr after administration, however the disappearance of radioactivity from the milk was significantly faster and was not detected at 48 hr after administration.
3. In the study with repeated administration, blood levels of radioactivity until 24 hr reached the steady state after the 14 th dose. Cumulative excretion ratios with urine and feces were constant after the 3rd administration. The concentrations of radioactivity in the tissues at 24 hr reached the steady state after the 14th dose, but the disappearance of radioactivity from tissues after the 21 th dose was relatively slow.
4. In the plasma and urine after the 21 th dose, the unchanged drug, N-desmethyl and S-oxide metabolites were detected as major component and M-3 and M-5 were also detected in the urine, however at low concentrations.

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The absorption, metabolism and excretion of ¹⁴C-nizatidine were studied after a single oral administration of 5 mg/kg to male dogs.
1. The blood levels of radioactivity reached a peak level (1876 ng eq./ml) at 1 hr after administration and then declined with a half life of 2.05 hr until 12 hr.
2. Within 120 hr after administration, the excretion of radioactivity into urine and feces was 88.4 % and 8.1 % of the dose, respectively.
3. The in vitro plasma protein binding to dog plasma was 11.0-18.6% and that to human plasma was 23.9-45.4 % at concentrations range between 0.1 and 10 μg/mt. The plasma protein binding in dog plasma collected at 2, 4 and 8 hr after administration was 7.6, 5.8 and 15.7%, respectively.
4. In plasma and urine, unchanged drug, M-3 and S-oxide metabolites were mainly detected.
5. M-3 was identified nizatidine N-oxide by MS and NMR.

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The absorption, distribution and excretion of ethan-l-hydroxy-1, 1-diphosphonate (EHDP, SM-5600) were investigated in mice, rats and dogs after single oral or intravenous administration of ¹⁴C-SM-5600.
1. When ¹⁴C-SM-5600 was orally administered (50 mg/kg), the absorption from gastro-intestinal tract was very low. In each animal species, 8-16 % of radioactivity was excreted in urine and 82-88 % in feces during 48 hr period after administration. Only a trace amount of radioactivity (0.2 %) was excreted in bile of rats.
2. Serum levels reached maxima (C_max) at 0.5 hr in mice and rats and at 2 hr in dogs. The Cmax levels were 7.5, 7.3 and 26.0 μgeq/ml in mice, rats and dogs, respectively.
3. High levels of radioactivity were detected in bones in all animal species, but in other tissues the levels were rather low and rapidly decreasing.
4. There were no sex-related-differences in the disposition of SM-5600 in rats.
5. A dose dependency of absorption (C_max and AUC) was observed in rats given lower doses than 50 mg/kg of ¹⁴C-SM-5600.

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The absorption, distribution and excretion of ¹⁴C-HY-770 in mice, rats and dogs were studied after single oral and intravenous administrations.
1. After oral administration of ¹⁴C-HY-770 to male mice (50 mg/kg), male rats (50 mg/kg) and male dogs (5 mg/kg), the maximal blood concentration of radioactivity appeared at 0.5-1 hr, followed by a decline with half-lives (T_1/2) of 2.55 hr in mice, 2.84 hr in rats and 3.80 hr in dogs. After intravenous administration to declined with T_1/2 of 2.40 hr. The serum level of unchanged HY-770 in rats was much lower than that determined as a total radioactivity.
2. After oral administration of ¹⁴C-HY-770 to male and female rats, the radioactivity was rapidly and well distributed to many organs, including brain and spinal cord. The concentrations of unchanged HY-770 in many organs were much higher than that in serum.
3. After oral administration of ¹⁴C-HY-770 to male mice, male rats and male dogs, the radioactiyity excreted into urine and feces within 7 days was 82.1-91.8% of dose and 6.9-16.1% of dose, respectively. The radioactivity excreted into bile during 24 hr in male rats was 23.1 % of dose.
4. In vitro protein binding to rat, dog and human serum was 75.7, 70.6 and 85.5% respectively. In vivo protein binding at 0.5 hr was 31.6% in rats and 36.5% in dogs.
5. After oral administration of ¹⁴C-HY-770 to pregnant rats (50 mg/kg), the concentration of radioactivity in fetus was lower than that in the maternal blood.
6. After oral administration of ¹⁴C-HY-770 to lactating rats, the milk level of radioactivity was about twice higher than that in blood. The milk concentration of unchanged HY-770 was about 7 times higher than that in serum.

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The absorption, distribution and excretion of ¹⁴C-HY-770 in male rats were studied following a 21 day period of daily oral administration at a dose of 50 mg/kg.
1. During repeated administration, the blood level of radioactivity reached the steady state between the 4th and 7th dosing. The maximal concentration of radioactivity was obtained at 2 hr (11.13 μg equivalent of HY-770/ml) after the final dosing and decreased with similar half-life (3.29 hr) to that after single administration.
2. During repeated administration, the tissue concentrations of radioactivity were nearly constant. After repeated administration, the tissue concentration of radioactivity decreased rapidly. Neither a accumulation nor a residue of radioactivity occurred in any tissue.
3. Excretion profile did not change during repeated administration. The cumulative urinary and fecal excretion of radioactivity were 79.9 and 18.1% of dose, respectively, within 7 days after final dosing. The overall cumulative (urinary plus fecal) excretion was 97.9% of dose.

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1. After oral administration of ¹⁴C-HY-770 (50 mg/kg) to rats, the urinary excretion of unchanged HY-770 within 24 hr was only 0.89 % of administered dose and several metabolites were detected. These results suggested that HY-770 was extensively metabolized.
2. Six main metabolites were identified. These metabolites were derived from following pathways. (I) Oxidation of the ethyl group, i.e. the side chain of benzene ring. (II) Reduction of the ketone group. (III) Oxidative cleavage of the pyrrolidine ring.
3. The pathway (I), oxidation of the ethyl group, was found to be main metabolic pathway, all other intensively excreted metabolites originated from this metabolic route.

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Prednisolone has been widely used in different disease states with limited understanding on its broad pharmacological and toxicological properties. This is due to difficulty in considerations why the pharmacokinetics cannot be related with the effect of the drug and how to control the dosages on the basis of pharmacodynamics of drug efficacy. This article attempts to review recent studies on pharmacokinetics, pharmacodynamics in vitro and in vivo, and clinical pharmacology of the drug to attaining better therapeutic effect on the survival of kidney allograft and preventing acute rejection reaction after renal transplantation. As a result, the inhibitory effects of prednisolone on mitogen-activated preoperative blastogenesis of lymphocytes from patients in vitro and on postoperative hypothalamus-pituitary-adrenal axis in vivo play a role of clinical markers for prospective diagnosis of acute allograft rejection and/or fatal diverse effects during long-term drug administration. Pharmacodynamics under the category of such lymphocyte or systemic sensitivities to prednisolone have never been established well. However, these studies on prednisolone in kidney transplantation seem to be a first example of clinical pharmacology of glucocorticoids. The methodology "used in these studies shoud be applied to altered disease states and other corticosteroids in future. The literature is reviewed 1980 through 1988.

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