The absorption, distribution and excretion of terguride, a new anti-hyperprolactinemia drug, were studied in rats.
1. After oral administration of ³H- or ¹⁴C-terguride (0.02mg/kg), the radioactivity in plasma reached the maximum(C_max) at 0.5hr, and then disappeared with a half-life of 5hr. The absorption from gastrointestinal tract was complete.
2. Concentration of terguride in plasma reached C_max at 2hr after oral dosing of unlabelled terguride (0.2mg/kg), and then disappeared with a half-life of 2hr. The bioavailability of terguride after oral administration was about 30%.
3. Binding to plasma protein in vitro was about 80%, and the binding to plasma proteins were 63 and 55% in the samples collected at 1 and 4hr, respectively.
4. The radioactivity in tissues after oral dosing of ³H-terguride (0.02mg/kg) showed higher levels in liver, kidney, submaxillary gland and pituitary than in other tissues. No long-lasting retention and accumulation were observed after single and repeated oral dosing. In pregnant rats, foetus and amniotic fluid at 1hr showed similar radioactivity to that in maternal plasma, and then disappeared almost completely within 72hr.
5. Concentration of terguride in pituitary after oral dosing of unlabelled terguride(0.2mg/kg) was about 5 folds higher than that in plasma and brain.
6. Urinary and fecal excretion within 7days after oral dosing of ¹⁴C-terguride (0.02mg/kg) was 20 and 76%, respectively. After multiple oral dosing for 16days, 25% of the total dose was excreted in urine and 72% in feces within 4days. Biliary excretion after intravenous dosing was 67%, and 15% of the excreted radioactivity was recirculated enterohepatically.
7. Radioactivity in the stomach milk of a neonate was below 0.04% of the dose given to dam. No radioactivity in neonatal plasma was detected.

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The absorption and excretion of terguride in rabbits were studied.
1. After oral administration of ¹⁴C-terguride (1 mg/kg) to female rabbits, the radioactivity in plasma reached the maximum (C_max) at 1hr and disap peared with a half-life of 1.9hr. Concentration of terguride in plasma reached C_max at 0.25 ?? 1 hr and disappeared with a half-life of 1.2hr. Similar plasma kinetics was observed in male rabbits. Urinary and fecal excretion within 7days after oral dosing was 41 and 53%, respectively.
2. The bioavailability of terguride after oral administration was about 39%
3. Food intake before oral administration of unlabelled terguride (0.2mg/animal) decreased (about 30%) the C_max, whereas the increase was induced by neutralization of stomach pH, however, no effect of their treatment on T_max and availability was found.

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After oral administration of ¹⁴C-terguride to rats (0.4mg/kg) and rabbits (1, 100mg/kg), metabolites in biological samples were analyzed by the mean of high performance liquid chromatography. In addition, the main metabolites were isolated from perfusate of rat liver and rabbit urine after high dose administration (100mg/kg). The structural elucidation of the isolated metabolites was carried out by ¹H-NMR spectroscopy and mass spectrometry.
The results showed as follows : (1) In rats, the amount of unchanged substance accounted for 15% of radioactivity in plasma and the other 5 peaks were also detected 4hr after administration. Excreted amount in urine (0 ?? 24hr) was 16% of the dose and 8 peaks were found. Excreted amount in bile (0 ?? 6hr) was 50% of the dose and 2 main metabolites were found. Unchanged substance was detected slightly in both samples. (2) In rabbits, 8 % of radioactivity in plasma 2hr after administration was unchanged substance and the other 8 peaks were found. Excreted amount in urine(0 ?? 24hr) was 38% of the dose, the unchanged substance was detected slightly and the other 7 peaks were found. (3) Although the metabolism rate in rabbits was faster than that of rats, there was no difference in main metabolic pathway between these two species. (4) From the perfusate of rat liver 2 metabolites were isolated, their chemical structures were proposed as N-mono-deethyl-terguride, is a main metabolite in rats plasma and urine of both animals, and oxidative cleavaged form of indole ring. From the rabbits urine mono-deethylated 2-keto-3-hy droxy-terguride was isolated, and it was a main metabolite in plasma and urine of rabbits. (5) The main metabolic pathway was oxidative N-dealkylation and oxidation of double bonds at C₂/C₃.

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Quinotolast sodium, a new anti-allergic drug, was studied in six healthy male volunteers to evaluate its pharmacokinetics in steady-state conditions after oral dosing. The subjects were given a single dose of 5mg, and after a two-day washout period, followed by 5mg every 12 hours in the morning and evening for six days and once in the next morning. The pharmacokinetics of quinotolast were well described by a linear model fitting to a biexponential equation with first-order absorption. The steady state was reached by the second day of multiple dosing with terminal half-life of 8.4 hours. The in vivo plasma protein binding was as high as 98.7%. Quinotolast was hardly excreted unchanged in the urine, while 22.6 and 19.0% of the dose were excreted as its glucuronide and hydroxy metabolite, respectively. The trough concentrations in the morning were significantly higher than those in the evening. The difference was mostly related to the slower absorption in the evening. The pharmacokinetic calculations suggest that quinotolast is hardly subjected to first-pass hepatic metabolism.

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The effect of food intake on the bioavailability of quinotolast sodium, a new anti-allergic drug, was studied in six healthy male volunteers. Each volunteer was subjected to the experiment designed according to a Latin-square with two-way crossover, and was given a single 5-mg oral dose of quinotolast sodium after overnight fasting or 30 minutes after a standard breakfast. There were no significant differences in the area under the plasma concentration-time curve, the maximum plasma concentration or the time to reach the maximum plasma concentration between the fasting and fed states. These results showed that the bioavailability of quinotolast sodium may be affected by food only in a small extent.

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The pharmacokinetics of quinotolast sodium, a new anti-allergic drug, were studied in six elderly and six young healthy male volunteers after single oral dosing with 5mg of the drug. The mean maximum plasma concentration of unchanged drug increased significantly from 171ng/ml in the young to 284ng/ml in the elderly volunteers. However, the time to reach the maximum plasma concentration, area under the plasma concentration-time curve, elimination half-life and apparent oral clearance did not differ between the two groups and were as follows : 1.7 and 1.5hours ; 1399 and 1293ng·hr/ml ; 9.2 and 8.1 hours ; 57.0 and 61.5ml/min in the elderly and young, respectively. Quinotolast was hardly excreted unchanged in the urine, while 16.7 and 20.3% of the given dose were excreted in the urine as its glucuronide and hydroxy metabolite, respectively, in the elderly, and 20.6 and 26.5%, respectively, in the young. The urinary excretion of glucuronide in the elderly did not differ from that in the young, but hydroxy metabolite was significantly reduced in the elderly. The results of this study suggest that although possible reduction in the metabolism of hydroxylation or reduction in absorption might occur in the elderly, such a reduction was slight and would not affect the overall plasma concentration of unchanged drug.

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The metabolic fate of L-carnosine in rats was studied after administration of [¹⁴C-U-histidine]-L-carnosine (¹⁴C-(his)-L-carnosine) or [¹⁴C-β-alanine]-L-carnosine (¹⁴C-(ala)-L-carnosine).
1. The blood level of radioactivity reached the maximum concentration (C_max) at 4hr after oral administration of ¹⁴C-(his)-L-carnosine in rats, and the level was almost constant thereafter up to 120hr. On the other hand, the blood levels of radioactivity reached the C_max at 0.5hr after oral administration of ¹⁴C-(ala)-L-carnosine, and declined with a half-life of 3.9hr within the first 6hr and the half-lives in the periods between of 6-24hr and 24-120hr were 19.7hr and 91.9hr, respectively.
2. Male rats excreted 7.9% of administered dose in urine, 6.3% in feces and 37.0% with expired air during 120hr after oral administration of ¹⁴C-(his)-L-carnosine. On the other hand, after administration of ¹⁴C-(ala)-L-carnosine the excretion of radioactivity into the urine, feces and expired air were 5.4%, 1.8% and 80.2%, respectively.
The radioactivity in the carcass after administration of ¹⁴C-(his)-L-carnosine and ¹⁴C-(ala)-L-carnosine were 44.4% and 9.6%, respectively.
3. The blood concentrations and excretion of radioactivity of [¹⁴C-U]-L-carnosine were similar to those after administration of ¹⁴C-(his)-L-carnosine.
4. The disappearance of unchanged L-carnosine in plasma followed first-order kinetics with the half-life of 15min after intravenous administration of ¹⁴C-(his)-L-carnosine to rats, and then the appearance of L-carnosine (the metabolite of L-carnosine) was very rapid and reached the C_max at 0.5hr. When the plasma sample after intravenous administration was treated with sulfosalicylic acid (SSA), the radioactivity of SSA supernatant declined as a function of time.
5. In vitro, L-carnosine was converted to L-histidine in the presence of human plasma within 15min at room temperature.
6. The present studies indicade that L-carnosine was converted to L-histidine and β-alanine in rats and humans, of which L-histidine was further utilized for the incorporation of endogenous high molecular substances.

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The plasma levels, tissue distribution, metabolism and excretion of KRN5702 after a single subcutaneous administration were investigated in the rats using ¹²⁵I-KRN5702 and/or a double-antibody radioimmunoassay (RIA) and in vivo bioassay.
After subcutaneous administration of KRN5702 at a dose of 200IU/kg in male rats, the plasma concentration reached the maximum concentration (C_max) during 8 to 12 hours, and then declined slowly. C_max after subcutaneous administration was below 10% of the concentration observed at 10 minutes after intravenous administration of the same dose. However, in the elimination phase, the plasma concentration after subcutaneous administration maintained to be relatively higher than that after intravenous administration. The profiles of biological activity in sera, determined by exhypoxic polycythemic mouse bioassay, was almost same as compared with those determined by RIA, and also same as immunoreatcive radioactivity of ¹²⁵I-KRN5702.
Dose-dependent increase was observed in Cmax, but not observed in half-lives. The half-life and mean residence time (MRT) obtained from subcutaneous administration had been longer when compared with intravenous administration. The bioavailability after subcutaneous administration as estimated by the area under the plasma concentration vs time curve(AUC) accounted for 35.5-54% of the value obtained from intravenous injection. There was no difference in AUC, half-life and other pharmacokinetic parameters between make and female rats.
The majority of tissues both in male and female rats showed a maximum level of radioactivity at 8 hours after administration of ¹²⁵I-KRN5702, and then decreased in parallel with plasma level in any time interval. High level of radioactivity same as in plasma, were observed in bone marrow, kidney, thyroid and in bladder. Radioactivity in most of other tissues was lower than that in plasma. These results were in good agreement with those of whole body autoradiography. Same distribution profiles of radioactivity were also observed in female rats with the exception of genital organs.
Within 168 hours after subcutaneous administration, most of the administered radioactivity was excreted in urine in the form of free iodine.
These results suggest that KRN5702 adm inistered subcutaneously are slowly transferred into general circulation without degradation at the site of injection. We considered that subcutaneous administration might be advantageous route, since it provides a possibility to maintain the effective plasma concentration of KRN5702.

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The plasma levels, tissue distribution and excretion of ¹²⁵I-KRN5702 after repeated subcutaneous administration were investigated in male rats.
After seventh subcutaneous administration of ¹²⁵I-KRN5702 at a dose of 200IU/kg, no difference in the plasma level profiles of total and trichloroacetic acid (TCA) precipitable radioactivity was observed, whereas immunoreactive radioactivity showed relatively low level when compared to that after a single administration. Both the area under the plasma concentration vs time curve (AUC) and the maximum level (C_max) of immunoreactive radioactivity after repeated administration were 17 and 16% lower than that after single administration, respectively. We consider that the increase in utilization of this material by target organs might be responsible for increased plasma clearance.
In the majority of tissues, the levels of radioactivity at 8 hours after each dose during repeated administration were same or slightly higher than those after initial administration. High levels of radioactivity were observed in the plasma, kidney and at the site of administration, independently of the numbers of injection. Whereas those in the spleen, bone marrow and thyroids were relatively higher as compared with those of the initial administration. After final administration, the most of tissues showed a maximum level of radioactivity at 8 hours after administration and then decreased in parallel with plasma level in any time interval. Beyond 48 hours after final administration, the radioactivity in the site of injection decreased to below 2 % of that at 2 hours after administration, and no accumulation in any particular organs or tissues was observed in repeated administration of ¹²⁵I-KRN5702.
Excretion of radioactivity in urine and feces was almost constant, i. e. 80 ?? 90% and 4 ?? 60% of each administered dose, respectively, during repeated administration. Finally, within 7th days after final administration, radioactivity excreted in urine and feces were 96.2% and 8.0% of total dosing, respectively.

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Absorption, distribution, metabolism and excretion were investigated after a single oral administration of ¹⁴C-fadrozole hydrochloride (¹⁴C-CGS 16949A) to rats, mainly females.
1. The plasma levels of radioactivity in non-fasted female rats reached the peak (C_max) of 379ng eq. of CGS 16949 (the base of CGS 16949A)/ml at 2hr after administration and then declined with a half-life of 6.8hr from 4hr to 24hr. The AUC was similar to that after intravenous administration. The plasma concentration in non-fasted male rats reached the C_max of 295ng eq. of CGS 16949/ml at 2hr and then declined with a half-life of 8.2hr from 4hr to 24hr. While the AUC were similar in non-fasted and fasted female rats, the C_max was 1.3 times higher in fasted females. The C_max and AUC increased in dose dependent manner at the doses of 0.2, 1 and 5mg/kg.
The plasma concentration of unchanged CGS 16949 reached the C_max of 269ng eq. of CGS 16949/ml at 30min and then declined with a half-life of 3.1hr from 4hr to 12hr after a single oral administration of ₁₄C-CGS 16949A 1mg/kg to non-fasted female rats.
2. In non-fasted female rats, 89.3 and 10.2% of the dose was excerted within 168hours in the urine and feces, respectively. In the bile an urine of bile-duct cannulated female rats, 24.9 and 59.4% of the dose, respectively, were excreted within 48hr. The intraduodenal administration of biliary radioactive materials resulted in excretion within 48hours of 31.0 and 56.9% to the bile and urine, respectively.
3. The majority of tissues in female rats showed a maximal levels of radioactivity 2hr after administration. At the maximum, adrenal gland, stomach and liver exhibited high radioactivity. Radioactivity of all the tissues decreased to less than 5% of the maximum 168hr after administration.
4. In rat plasma, the unchanged compound (CGS 16949), trans-8-hydroxy metabolite (CGP 45383), cis-8-hydroxy metabolite (CGP 45384) and 8-oxo metabolite (CGP 45385) were mainly found, and the metabolite with hydantoin-type structure (MP2) accounted for the major fraction of radioactivity 24hr after administration. The relative amount of CGS 16949, CGP 45383 and CGP 45384 accounted for 18.1, 34.8 and 25.0% of urinary radioactivity, respectively, and the major metabolite in bile would be the glucuronide of CGP 45383.

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The absorption, distribution, metabolism, and excretion of ¹⁴C-fadrozole hydorochloride (¹⁴C-CGS 16949A) were investigated during and after repeated oral administration to non-fasted female rats at a daily dose of 1mg/kg for 21days.
1. The levels of radioactivity in the plasma ( 24hr after daily dosing) reached a steady state after the 15th dosing and was 3. 1times higher than that found after the 1st dosing. The peak concentration (C_max) and the half-lives after 21st dosing were 477ng eq. of CGS 16949 (the base of CGS 16949A)/ml and 10hr from 4hr to 24hr and 65hr from 48hr to 168hr.
2. The excretion ratio of radioactivity in the urine and feces reached a steady state after the 4th dosing and the excretion ratio after the 21st dosing was similar to that after single dosing.
3. The levels of radioactivity in the tissues after the 7th dosing increased in comparison with those after single dosing and the radioactivity levels after the 14th dosing were similar to those after the 7th dosing. The radioactivity in aorta after the 21st dosing was 8.9times higher than that after single dosing.
4. The relative amount of unchanged CGS 16949 in the plasma after the 21st dosing decreased and that of the metabolite with hydantoin type structure, MP2 increased, compared with those after single dosing. There were no significant differences between the concentration of CGS 16949 after single and the 21st dosing.
5. The relative amount of CGS 16949 and its metabolites in the urine for 24hours after 21st dosing was not significantly different from that after single dosing.

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Sulfation or sulfoconjugation is well kn own as a major metabolic pathway of medical drugs, pesticides and other environmental chemicals. This reaction is catalyzed by cytosolic sulfotransferase in mammals. Several forms of sulfotransferase have been isolated from experimental animals and humans, and these are classified into 4 to 6 different groups from their substrate specificities.
Despite usefuln ess of this classification, exact identification of sulfotransferase form was hampered by the overlapping substrate specificity and instability after purification. Recent progress on the cDNA cloning overcomes this situation. From the deduced amino acid sequences, sulfotransferases involved in the sulfation of lipophilic chemicals become clear to consist of two major groups, arylsulfotransferase and hydroxysteroid sulfotransferase.
Arysulfotransferase may be subdivided into subgroups including phenol and estrogen sulfotransferases, while hydroxysteroid sulfotransferases share broadened substrate specificity for steroids, alcohols and bile acids within groups. In this context, properties of sulfotransferases are discussed in relation to their primary structures.

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