Simvastatin is a lactone prodrug whose hydroxy acid (SVA) is a potent competitive inhibitor of HMG-CoA reductase. Disposition and metabolism of the drug were investigated in male rats after administration of [¹⁴C] simvastatin.
1. After oral dosing of [¹⁴C] simvastatin at doses of 3, 10 and 30mg/kg, plasma radioactivity increased proportionally to administered dose with peak plasma concentration at 2hr and declined with half-lives of 3.8 ?? 5.2hr.
2. Radioactivity was rapidly and widely distributed to tissues, reaching maximum levels at 2hr in many of the tissues. The radioactivity was high in the gastrointestinal tract and liver, secondary in the kidney. At 96hr, the level in each tissue was very low when compared with the maximum value. Similar distribution characteristics were observed by whole body autoradiography.
3. Excretion of radioactivity was 8.1% and 83.3% of the dose in urine and feces, respectively, within 96hr after oral administration. In bile-duct cannulated rats, radioactivity excreted into bile and urine represented 45.3% and 3.9% of the dose, respectively. Gastrointestinal absorption of radioactivity was estimated to be about 50% During the enterohepatic circulation study, 31% of the radioactivity excreted in bile was reabsorbed.
4. Hydroxy acid of simvastatin(SVA) was highly bound to serum protein(>90%). After oral administration, the extent of binding of radioactivity to rat plasma protein was 33 ?? 37 %, and red-blood cells to plasma concentration ratio was 0.34 ?? 0.53.
5. Simvastatin was extensively metabolized in rats after oral dosing, and systemic bioavailability estimated on the basis of HMG-CoA reductase inhibitor equivalents was 4%.
6. Plasma radioactivity was comprised mainly of 2, 2-dimethylbutyric acid (DMB), 2, 2-dimethyl-3-hydroxybutyric acid (DMHB) and SVA. In the liver, SVA was the main metabolite. In bile, 3'-hydroxy metabolite of SVA, 6'-caboxylic acid of SVA and a number of unknown metabolites were present. DMHB, DMB glucuronide and the glycine conjugate of DMB were the three major species found in the urine. Simvastatin was difficult to detect in the tissues and excreta examined.

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Absorption, distribution and excretion of [¹⁴C] simvastatin were studied in male rats after 21-day consecutive daily oral administration at the dose of 10 mg/kg.
Plasma levels of [¹⁴C] simvastatin at 1hr after each administration did not increase during and after repeated administration. The radioactivity levels-time curve after the final administration was similar to that after the first dosing.
The cumulative excretion of radioactivity in urine and feces accounted for 9.0% and 91.4% of the total dose, respectively, within 96hr after the final administration.
After the final administration, radioactivity was concentrated in the gastrointestinal tracts, liver and kidney. The distribution pattern was similar to that observed after the single administration. There was no accumulation of the drug and its metabolites in the tissues of rats after the consecutive oral administration of [¹⁴C] simvastatin.
Foeto-placental transfer and excretion of radioactivity into milk were studied in pregnant and lactating rats after single oral administration of [¹⁴C] simvastatin.
Whole body autoradiograms of rats on day 12 and 18 of gestation showed low distribution and rapid elimination of radioactivity from the fetus. On day 18 of gestation, the concentration of radioactivity in the placenta, amniotic fluid and fetal tissues were nearly equal to or less than those in the maternal plasma. The amount of radioactivity transferred into a fetus was about 0.02% of the oral dose.
The concentrations of radioactivity in the milk were about 20-54% of those in maternal plasma.

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The absorption, distribution, excretion and metabolism of recombinant human interleukin-2 (S-6820) were studied following intravenous or subcutaneous injection at a dose of 5×10⁵U/kg to rats. Concentrations of S-6820 in serum, tissues and other body fluids were measured by a bioassay and an enzyme immunoassay.
1. After intravenous injection of S-6820 to rats, serum levels of S-6820 decreased biphasically and the half-lives of the α phase and β phase were 2. 4 min and 16min, respectively.
2. Absorption ratio after subcutaneous injection of S-6820 was about 37%.
3. After repeated intravenous injection of S-6820 once a day for 5 days, the levels of S-6820 in serum and tissues reached the same levels as after single administration. No accumulation was observed.
4. After intravenous injection of S-6820, especially high level was observed in the kidney, however, it decreased rapidly (t_1/2=11min). The levels of S-6820 in the other organs (spleen, lung, heart and liver) were lower than the serum level.
5. After intravenous injection of S-6820 to 20-th day pregnant rat, S-6820 in the amniotic fluid and fetus was not detected.
6. After intravenous injection to lactating rats, the transfer of S-6820 from blood to milk was minimal.
7. A little of S-6820 was found in the bile by EIA. S-6820 was not detected in the urine by EIA method.
8. The disappearance rates of S-6820 in rats changed from t_1/2(β)=0.41hr in sham operated rats to t_1/2(β)=1.57hr in rats with renal excision. The kidney appeared to be the main metabolic site.

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The distribution, excretion and metabolism of recombinant human interleukin-2 (S-6820) were studied using ¹²⁵I-labeled compound (¹²⁵I-S-6820)
1. At 5min after intravenous injection of ¹²⁵I-S-6820 to male and female rats, high radioactivity was observed in the kidney. Radioactivities in the other organs were lower than the serum level. Results obtained by whole-body autoradiography showed that high concentrations of radioactivity were found in the cortex renis.
2. At 5min after intravenous injection of ¹²⁵I-S-6820 to 20-th day pregnant rats, no radioactivities were detected in the amniotic fluid and fetus.
3. Within 24hr after intravenous injection of ¹²⁵I-S-6820, 78% and 1 % of administered radioactivity were excreted in the urine and feces, respectively. However, 98% of excreted radioactivity in the urine was not precipitated with trichloroacetic acid.
4. In the kidney after intravenous injection of ¹²⁵I-S-6820, a low molecular weight degradation products of ¹²⁵I-S-6820 were observed as revealed by gel filtration radio-chromatography. In addition, micro-autoradiogram of cortex renis after intravenous injection of ¹²⁵I-S-6820 showed that S-6820 was likely to be ultrafiltrated by the glomerulus and absorbed by proximal tubules. S-6820 appeared to be degraded in the kidney.

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The distribution and localization of OPC-7251(zinofloxacin), a new synthetic antibacterial agent, within the skin was examined by measurement of radioactivity and microscopic autoradiography at the application site in guinea pigs, following a percutaneous administration of a single dose (1.4mg/kg).
The distribution of radioactivity in the skin was measured by scintillation counting of skin sections. Radioactivity gradually penetrated into the skin with time, and was localized rather higher in the hair shaft, hair root and sebaceous glands.
The localization of radioactivity in the skin was also determined by microscopic autoradiography.
Consequently, OPC-7251 distributed in hair (modulla of hair, hair roots) and sebaceous glands and is compatible with the treatment of acne vulgaris.

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To examine the drug interaction between LC9018 and tegafur, the tegafur was administered to LC9018 treated or control mice and plasma concentrations of tegafur and its active metabolite, 5-fluorouracil (5-FU) were monitored.
1. In 300μg LC9018/animal (intravenous, i.v.) treated group, the maximum plasma level(Cmax) of 5-FU and the area under the curve (AUC)decreased to 43% and 64% of control values, respectively. On the other hand, no change was observed in tegafur level, suggesting that LC9018 inhibited the conversion of tegafur to 5-FU at this dose.
2. In 300μg LC9018/animal (intrapleural, i. pl.) treated group, 5-FU level decreased to 55% of the control at 30min after administration. But the influence on the metabolism of tegafur was smaller compared to the intravenous treatment of LC9018.
3. In 180μg/animal (i.v.), 150μg/animal (i.pl.) and 300μg LC9018/animal (subcutanous, s.c.) treated groups, both tegafur and 5-FU level did not alter compared to the control.
4. From above results, influence of LC9018 on the metabolism of tegafur depends on the dose and the administration route (i.v.> i.pl.> s.c.). It is considered that LC9018 slightly affects the metabolism of tegafur at clinical dose (200μg/animal i.pl.).

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The metabolism of azuletil sodium (AZE, KT1-32, sodium 3-ethyl-7-isopropyl-l-azulenesulfonate 1/3hydrate), a novel anti-ulcer agent, was studied after oral administration of ¹⁴C-KT1-32 to male rats. The intact KT1-32 and six metabolites were found in the urine of male rats and were identified by high performance liquid chromatography (HPLC) using a radioisotope detector. The sum of radioactivities of these identified metabolites accounted for 94% of the total radioactivity in the urine. These metabolites were isolated by various solid extraction cartridges. The structural elucidation of the isolated metabolites was carried out by ¹H-NMR spectroscopy and mass spectrometry with electron ionization mode after converted them into the n-propylester-dimethyl ethylsilyl ether derivatives, especially mass spectrometry was very useful to characterize each of these metabolites. M3, only one conjugate, was found to be as the sulfate of the ω-1 hydroxylated metabolite of the ethyl group in KT 1-32. All of these metabolites, except M3, were identified by the comparison of their spectral data with those of the authentic compounds, indicating that the preferential ω-1 hydroxylations of KT1-32 took place on the alkyl groups in 3 and 7 positions and did not on the azulene ring itself.

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The absorption, distribution, metabolism and excretion of ¹⁴C-KT1-32 were studied after a single oral and intravenous administrations in the doses of 4-100mg/kg to male and female rats, and male mice.
1. The radioactivity in plasma reached a maximum concentration at 4.5hr (48μg equivalent KT1-32/ml) after oral administration of ¹⁴C-KT1-32 to male rats in a dose of 20mg/kg and then declined with half-life of 3.9hr.
2. The levels of radioactivity in plasma reached a maximum concentration at 3.3hr after oral administration of ¹⁴C-KT1-32 to female rats in a dose of 20mg/kg and then declined with half-life of 3.7hr.
3. The excretion of radioactivity amounted to 57% of the dose in urine and 43% of the dose in feces within 96hr after oral administration to male rats in a dose of 20mg/kg, while after intravenous administration to male rats, the excretion of radioactivity were found to be 81% and 17% of the dose in urine and feces, respectively.
4. The biliary excretion within 48hr after oral administration of 20mg/kg corresponded to 7.7% of the administered dose to male rats, while the excretion of the radioactivity reabsorbed, amounted to 5.3% of the dose in the bile within 48hr after intraduodenal injection.
5. After 20mg/kg oral administration, the female rats excreted during 96hr 73% and 28% of the dose in urine and feces, respectively.
6. The radioactivities in the tissues, except the gastro -intestinal tract and fat, reached the maximum concentration at 3hr after oral administration of 20mg/kg to male rats and relatively high radioactivities were found in the blood, liver, kidney and lung. The radioactivities in all tissues were decreased to less than 17% of the highest concentration at 72hr after oral administration.
7. In female rats, after oral administration of a dose of 20mg/kg, the concentrations in the tissues were lower than that in male rats.
8. After oral administratrion of a dose of 20mg/kg, Ml, M2, M4 metabolites and the intact drug were the major components and M-3, M-5 and M-6 were also detected, however as the minor compounds, in the 0-24hr urine collected from male rats.
9. The M1, M2 metabolites and intact drug were also found in the 0-24hr fractions of bile in male rats.

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The absorption, distribution and excretion of ¹⁴C-KT1-32 were studied after repeated oral administration to male rats. Transfer of radioactivities into the fetus and milk after oral administration of ¹⁴C-KT1-32 to pregnant or lactating rats were studied. The induction of the hepatic drug-metabolizing enzymes was studied after repeated oral administration of KT1-32 to male rats.
1. On day 13 and 18 of gestation, the autoradiography revealed that the radioactivity in the fetus was lower than that in the maternal blood. On day18 of gestation, the radioactivities in the fetal liver and kidney were lower than that in the maternal plasma.
2. The radioactivity in the milk was lower than that in the maternal blood within 8hr after administration. The disappearance of radioactivity from the milk was slower than that from the blood.
3. After repeated administration, the radioactivity in the blood reached the steady state within 24hr following the 1st administration. Cumulative excretion ratios in urine and feces reached a constant value after the 3rd administration. The radioactivities in the tissues at 24 hr reached the steady state after the 7th administration, but the disappearance of radioactivity from the tissues after the 21st administration was quite similar to that after single administartion.
4. In the plasma and urine after the 21st administration, the Ml, M2 metabolites and the intact drug were detected as major components and M4, M3, M5 and M6 were found in the urine as the minor ones.
5. After repeated oral administration of KT1-32 to male rats, there was no induction of the hepatic drug-metabolizing enzymes.

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This minireview describes some physiological factors affecting the metabolic reduction of drugs having a ketone group and the properties of enzymes responsible for the metabolic reduction of these drugs. Acetohexamide and befunolol were chosen as model drugs having a ketone group. Species differences of acetohexamide reductase activity in the liver and kidney were observed among animals tested. The acetohexamide reductase activity in 10000xg supernatant of rat liver was higher in male than in female, and streptozotocin-induced diabetes caused a disappearance in the sex difference. Furthermore, befunolol reductase was purified to homogeneity from the cytosolic fraction of rabbit liver by various chromatographic techniques. On the basis of the substrate specificities and some properties, befunolol reductase was classified as a carbonyl reductase. The reduction of befunolol catalyzed by befunolol reductase proceeded in an ordered Bi Bi mechanism. These observations will provide a better understanding for the metabolic reduction of drugs having a ketone group. The role of the heart in acetohexamide reduction and the product stereoselectivity of acetohexamide reduction are also discussed.

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