Examination was made of the absorption, distribution and excretion of radioactivity in SpragueDawly rats following a single subcutaneous administration of ¹⁴C-labeled OPB-2045 at 1 mg/kg, and the following results were obtained:
1. Serum concentrations of radioactivity were maximum (C_max) of 0.032-0.033 μg eq./ml at 1 hr after administration in male and female rats. Radioactivity half-life in serum was 77.0 hr as determined at 48 hr to 168 hr postdosing in male and female rats. The area under the serum concentration-time curve (AUC_0→∞) was 0.75 to 0.78 μg eq.·hr/ml. Radioactivity in blood cells accounted for 31.9-77.9% of total radioactivity in the blood. Radioactivity in the blood exceeded that in the serum. AUC_0→∞ in the blood was 1.5 to 2 times that of the serum.
2. Radioactivity was highest in the pituitary gland, followed by the thyroid, adrenal glands, lungs and kidneys in male rats 1 hr postdosing. In tissues, it was 10 to 26 times higher than in the blood. At 8 and 24 hr postdosing, radioactivity in adrenal glands was extremely high, and 100 to 200 times that in the blood. At 72 and 168 hr postdosing, radioactivity was high in the adrenal and pituitary glands and kidneys. Its tissue distribution in female rats was essentially the same as in male rats.
3. Urinary and fecal excretion of radioactivity was 17.2-20.8% and 68.4-71.2% of the administered doses, respectively, with 9.1-9.3% remaining in the carcass at 168 hr postdosing.
4. Biliary and urinary excretion of radioactivity at 24 hr postdosing accounted for 34.1% and 14.2% the administered doses, respectively, in male rats whose bile ducts had been cannulated.

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The absorption, distribution and excretion of radioactivity were investigated in male beagle dogs following a single subcutaneous administration of ¹⁴C-labeled OPB-2045 at 1 mg/kg and the following results were obtained:
1. Blood concentrations of radioactivity reached maximum levels (C_max) of 0.074μg eq. /ml at 30 min after dosing and then declined with half-lives of 29.5 hr and 58.6 hr as determined at 30 min to 12 hr and 12 hr to 168 hr, respectively, postdosing. The area under the concentration-time curve (AUC_0→∞) was 5.40μg eq.·hr/ml. Serum concentrations of radioactivity reached Cmax of 0.084μg eq./ml at 30 min postdosing. The half-life of radioactivity in serum was 34.4 hr and 67.6 hr. AUC was 6.03μg eq.·hr/ml.
2. Radioactivity in blood cells during 30 min to 168 hr postdosing accounted for 28.3-46.5% of total radioactivity in the blood.
3. Radioactivity was highest in kidneys, followed by thyroid, pituitary gland, lungs, heart, liver and adrenal glands, showing 0.084-0.994μg eq./g, at 168 hr postdosing. 2.1% of the administered dose remained at the administration site.
4. Urinary and fecal excretion of radioactivity for 168 hr postdosing accounted for 59.4% and 23.5% of the administered doses, respectively.

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The absorption and tissue distribution of OPB-2045, a new antiseptic antimicrobial drug with a biguanide moiety in the molecule, were studied in male Sprague-Dawley rats with intact or damaged skin following a single and repetitive dermal application of 0.1% ¹⁴C-OPB-2045 in a liquid formulation applied at the dose of 0.3 mg/rat to 6.25 cm² of the skin. Comparative percutaneous absorption was also investigated in rats treated with single doses of 0.04% ¹⁴C-OPB-2045 and ¹⁴C-chlorhexidine in aqueous solution at 0.12 mg/rat to the same area of the skin.
Radioactivity was hardly detected in the serum of rats with intact and damaged skin during a 24-hr period after single topical application of 0.1% ¹⁴C-OPB-2045. Urinary and fecal excretions of radioactivity within 336 hr after single dosing were 1.20/ and 4.1% of the dose, respectively, in rats with intact skin, and 2.4% and 5.0%, respectively, in rats with damaged skin, indicating no significant differences. Percutaneous absorption was estimated to be approximately 1.40/ of the total dose in rats with intact skin following repetitive dermal application of the compound. Radioactivity in various tissues was quite low except the application site of the compound, and the disappearance of radioactivity from the application site was sluggish in intact and damaged skin rats. Percutaneous absorption of ¹⁴C-OPB-2045 and ¹⁴C-chlorhexidine in aqueous solution was 4.20/ and 4.2% of the dose respectively in intact skin, and 7.1% and 3.8% respectively in damaged skin.
The percutaneous absorption of OPB-2045 is thus quite poor, and essentially the same to chlorhexidine. Stratum corneum, an important tissue as a barrier controlling percutaneous absorption of chemicals does not appear to be important to the absorption of either OPB-2045 or chlorhexidine through the skin.

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The absorption, distribution, and excretion of KAA-276 were studied in male rats after intratracheal administration of ³H-KAA-276.
1. The radioactivity level in plasma reached a maximum at 5 min after intratracheal administration of ³H-KAA-276 to male rats at a dose of 30μg/kg. The AUC at this dose was 17.8 ng eq. of KAA-276·hr/ml, which accounted for about 100% of the AUC observed after intravenous administration at the same dose. The Cmax and the AUC were increased in a dose-dependent manner at the dose range of 10 to 100 μg/kg.
2. The radioactivity levels in the lungs, trachea, liver, pituitary, kidneys, urinary bladder, and mandibular gland were high after administration of ³H-KAA-276 to the rats. Low levels were detected in the central nervous system, eyeballs, and testes.
3. The excretion of radioactivity in the urine and feces was 17.8% and 82.1% of the dose, respectively, by 168 hr after administration. The excretion of radioactivity in the bile was 75.3% of the dose within 48 hr. Moreover, almost 40% of the biliary excreta was re-absorbed and excreted in the bile and urine.

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We have investigated a linearity and animal species-difference of plasma concentration-time profile of ONO-5046 and its metabolite (M-1) after intravenous administration of ONO-5046·Na to rats and dogs. The following results were obtained.
1. Following intravenous bolus administration of ONO-5046·Na at the doses of 1 and 5 mg/kg to male rats, plasma concentrations of the unchanged drug at 2 min were, respectively, 10.33 and 33.61 μg/ml, and did not increase in a dose-dependent manner. On both doses, t_1/2 (5-30 min) of the unchanged drug was approximately 7 min, but CLtotal and Vss obtained from the plasma concentration-time profile increased with the dose.
2. Following intravenous bolus administration of ONO-5046·Na at the doses of 1 and 5 mg/kg to male dogs, t_1/2 (5-30 min) of the unchanged drug was approximately 5 min. The AUC_0→∞ of unchanged drug increased with the dose.
3. Following intravenous infusion of ONO-5046·Na for 2 hr at the doses of 1 and 10 mg/kg/hr to male rats, plasma concentrations of the unchanged drug reached the steady-state levels within 1 hr, and steadystate levels (C_{120 min}) were 2.29 and 22.05 μg/ml, increased in a dose dependent manner. The plasma concentration (C_{120 min}) of the metabolite (M-1) were 2.02 and 17.81 μg/ml, increased in a dose dependent manner. These results could be explained the linearity at the range of these doses.
4. Following intravenous infusion of ONO-5046·Na for 2 hr at the doses of 1 and 10 mg/kg/hr to male dogs, plasma concentrations of the unchanged drug reached the steady-state levels within 30 min, and steady-state levels (C_{120 min}) were 1.14 and 13.24 μg/ml, increased in a dose dependent manner. CLtotal of the unchanged drug in the dog was approximately twice of that in rats. The plasma concentration (C_{120 min}) of the metabolite (M-1) were 0.40 and 5.40 μg/ml, increased in a dose dependent manner. These results could be explained, similarity to the rats, the linearity at the range of these doses.

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The concentrations of finasteride, an inhibitor of steroid 5α-reductase, and its metabolites in plasma, urine, bile, and tissue was assayed after oral or intravenous administration of ¹⁴C-finasteride to rats using radio-HPLC.
Finasteride accounted for approximately 50% of plasma radioactivity after oral or intravenous administration of ¹⁴C-finasteride to male rats. The major metabolites of finasteride, side-chain hydroxylated (M-1) and 6 α-OH (M-4) finasteride, accounted for 12%-27% of plasma radioactivity. Almost all of the orally administered ¹⁴C-finasteride was excreted into bile and the metabolites accounted for most of the biliary radioactivity. This shows that metabolism was the major route of drug elimination in rats. The side-chain oxidation and ring hydroxylation were the major pathways. At 0.5 hr after oral dosing, approximately 60% of the radioactivity in the liver was attributable to metabolites, and the intact drug accounted for almost half of the radioactivity present in the kidney, suggesting rapid distribution of finasteride.
To identify the metabolites reabsorbed during the entero-hepatic circulation, the small intestine contents, small intestine, portal vein and abdominal aorta plasma, liver, and bile of the rats were assayed for metabolites after intraduodenal injection of the bile samples obtained from other rats orally administered with ¹⁴C-inasteride. Finasteride ω-acetic acid (M-3) was mainly found and was present in all samples except in portal vein plasma. This metabolite as well as ω, 6α-(OH)₂ finasteride (M-5), which was formed in the small intestine during absorption, were converted to glucuronides in the small intestine tissue and then influxed into the portal vein blood. In the liver, these conjugates were hydrolyzed to their aglycones, some of which were further oxidized. The metabolite composition of the bile was comparable to that of the administered bile.
These findings suggest that almost all of the orally administered ¹⁴C-finasteride was metabolized in the liver. The metabolites were excreted into the bile and then reabsorbed into the entero-hepatic circulation. The metabolites M-3 and M-5 were mainly reabsorbed into the entero-hepatic circulation, undergoing glucuronidation in the small intestine and hydrolysis and oxidation in the liver.

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