Etoposide {4'-demethylepipodophyllotoxin-9 (4, 6-O-ethylidene-β-D-glucopyranoside)}, an anticancer drug, is a semisynthetic derivative of podophyllotoxin, and it is claimed to be effective in a lung and testis cancer and in lymphoma. We have studied the tissue and organ distribution of [³H]-Etoposide by whole body autoradiography and quantitative determination of radioactivity in the tissues and organs of rats. [³H]-Etoposide distributed mainly in the liver, intestine and kidney. It was in good agreement with the fact that [³H]-Etoposide was mainly excreted into the bile in the case of rat. No [³H]-Etoposide was found in the brain after a single administration, it was regarded that Etoposide almost did not penetrate through the blood-brain barrier. Only a slight radioactivity was found in the brain after the consecutive p.o. administration for 10 days. When [³H]-Etoposide was administered to the pregnant rats, radioactivity was found in the fetus in concentration about 1/10 of maternal blood level. In the consecutive administration, the concentration in most tissues and organs was higher than that after single administration, whereas the half-lives in these organs (β-phase) were not prolonged. One may conclude, concerning the above fact, that Etoposide did not accumulate in tissues and organs.

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Etoposide {4'-demethylepipodophyllotoxin-9 (4, 6-O-ethylidene-β-D-glucopyranoside)}, an anticancer drug, is a semisynthetic derivative of podophyllotoxin, and it is claimed to be effective in a lung and testis cancer and in a lymphoma. We have synthesized a tritium labeled Etoposide ([³H]-Etoposide) for the pharmacokinetics study. The blood concentration of [³H]-Etoposide in dog was decreased relatively fast in a tri-exponential pattern following i.v. injection. The blood level of [³H]-Etoposide in dog reached to a maximum level i.v. or p.o. administration, and then it diminished relatively rapidly in a biexponential manner from the blood. Bioavailability in dog after p.o. administration was 13.1 % calculated from the AUC after i.v. and p.o. administration. Cumulative excretion following i.v. and p.o. administration were 75 and 86 %, respectively. The blood concentration of [³H]-Etoposide was same both in rats and dogs, and bioavailability was 14.1 % obtained from the AUC data. The half-life of β-phase after the consecutive i.v. injection was prolonged to about 2 times than that after a single injection. The total excreted amounts to urine and feces were 95 % during 72 hours after a single and consecutive injection, indicating that excreted amount (% of administered dose) was not changed by the consecutive administration. [³H]-Etoposide was mainly excreted into the bile in rats, and 68.1 and 33.8 % of it was excreted into the bile after i.v. and p.o., respectively, during 72 hours after administration. The reabsorption rate of [³H]-Etoposide in rat was 9.3% of i.v. administered dose and 12.5 % after p.o. administration. The absorption rate of [³H]-Etoposide in rat was about 40 % calculated from the total excretion in urine and bile after p.o. administration. [³H]-Etoposide was also excreted into the milk to higher extent than to the blood. This was regarded to be due to the high lipophilicity of Etoposide.

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Percutaneous absorption and metabolism of halcinonide (21-chloro-9α-fluoro 11β, 16α, 17α-trihydroxy-4-pregnen-3, 20-dione cyclic-16, 17-acetal), a synthetic topical antiinflammatory corticosteroid, were studied in rats with the use of ¹⁴C-labeled compounds. Greater parts of the dermally applied radioactivity were retained in the skin as the parent compound and 4.2 to 8.4 % of the dose was excreted into urine and feces within 5 days after application. When ¹⁴C-halcinonide was injected intravenously, the parent compound did not occur in urine and bile. However, various kinds of dechlorinated metabolites were found. Cell-free, skin and liver perfusion experiments were carried out to examine the site of metabolism of halcinonide. In contrast to the low metabolic activity seen in the skin, a very rapid detoxification rate in the liver tissue was observed. From these results, it is suggested that halcinonide is metabolized to various kinds of dechlorinated and reduced metabolites, and disappears from the body rapidly after absorption from the skin.

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The influence of age and sex on the metabolism of tiaramide was studied in young (1 month), young-adult (2 months), middle-aged (12 months) and old (24 months) rats. Formation of the N-dealkylated metabolite by hepatic microsomes was highest in the young-adult males and decreased with aging. In the females, the formation was also maximal in the young-adults, became minimum in the middle-aged and reached the intermediate level in the old. Formation of the N-oxide metabolite by the microsomes was highest in the young-adult and middle-aged males and decreased with aging. In the females, the formation was low in the young-adults, increased to maximum in the middle-aged and decreased slightly from the maximal level in the old. The formation of two metabolites by the microsomes was higher in the young-adult and middle-aged males than in the corresponding females. Formation of tiaramide O-sulfate by hepatic 105, 000 g supernatants was maximal in the young males, decreased markedly in the young-adult and middle-aged males and increased again to the intermediate level in the old males. In the females, the sulfate formation by the supernatants was highest in the young-adults, decreased to minimum in the middle-aged, which was similar to the young, and increased again to the intermediate level in the old. The formation by the supernatants was higher in all females than males. Changes in urinary excretion of the metabolites exhibited age- and sex-related changes nearly similar to the formation by the rat liver. These results suggest that age- and sex-related changes in the hepatic metabolism of tiaramide reflect the changes in the urinary excretion of the metabolites in rats.

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The metabolic fate of ¹⁴C-geranylgeranylacetone (GGA), a newly developed antiulcer drug, was investigated in rats. Radioactivity was mainly absorbed by a lymphatic route after the oral administration of ¹⁴C-GGA. The recoveries of radioactivity in thoracic lymph were 38 % (administered dose of 1 mg/kg) and 28 % (10 mg/kg) during 8 hr after dosing, and 27 % (125 mg/kg) during 24 hr post dosing. Radioactivity in the lymph collected for 24 hr (125 mg/kg) was present as unchanged GGA (85 %) and two metabolites. These metabolites were isolated in liver extract other as esterified GGA-OH. Tissue and plasma levels or GGA and its metabolites were estimated by TLC after oral or intravenous administration. GGA was rapidly metabolized in liver to GGA-OH, esterified GGA-OH, and other polar metabolites. The tissue concentration of GGA in liver was low, whereas the level of GGA-OH was higher than in plasma. In contrast, the concentration of GGA in the target tissue, stomach, was higher than that in plasma and liver. The concentration of GGA-OH in the stomach was much higher than the plasma level. These results indicate that GGA is distributed systemically in the mucosal cells without a first pass effect owing to its absorption route.

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The peroxisome is an intracellular granule characterized by the presence of catalase, carnitine acetyltransferase and several hydrogen peroxide-generating enzymes, including the enzyme system involved in the β-oxidation of long-chain fatty acids. Clofibrate, as well as other potent hypolipidemic agents, causes massive hepatomegaly when administered to rodents, chickens and other species. This hepatomegaly is characteristically associated with a marked increase in the number and volume densities of peroxisomes in the liver. Furthermore, several studies have now established that certain chemicals (hypolipidemic peroxisome proliferators) induce hepatocellular carcinoma in both mice and rats. However, whether there is a direct interrelationship between the drug action, peroxisome proliferation and carcinoem genecity is yet to be established. In this revi, I have summarized recent publications concerning the effects of many chemicals on the characteristics of hepatic peroxisomes. The effects of these chemicals on peroxisomes (number, size and emzyme composition) are species-, sex-, and dose-depend. For example, clofibrate, nafenopin, Wy-14, 643, DEHP, etc induced hepatic peroxisome proliferation in the rodeuts. However, any damage of the liver and hepatic poroxisome proliferation in the human freintest with clofibrate or fenofibrate, were not found. On the other hand it is impotant finding for developing a new drug that certain hypolipidemic peroxisome proliferators induce hepatocarcinoma in rodents. However the species difference of the effect on hepatic peroxisomes is extremely marked, and also there is no report concernimg hepatocarcinogenesis by these drugs in human and other primates. As seen in this review, althongh there are many works concerning peroxisome protiferation, serum lipids level, hepatotoxicity, the interrelationship of these phenomena has not yet been elucidated. Then to understand the meanings of the changes in hepatic peroxisomes, it is essential for taking a new turn of the meanings of the changes in hepatic peroxisomes to analyze in detail many data for the mode of action, species difference and sexdiffernce of the effect of these drugs including the drugs other than hypolipidemic peroxisome proliferator.

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The application of a highly sensitive immunoassay, using chemi- or bioluminescent reaction is reviewed. Their advantages of these reactions are that they can be quantiated rapidly, are relatively stable, possess high specific activity, and can take part in an amplification reactions.
They can be employed in the immunoassay in three different ways.
1. The label can be a chemiluminescent substances such as luminol derivatives.
2. Product from label enzyme can be monitored using chem- or bioluminescent reaction. Examples of these application of a luminescence in the immunoassay are for instance, the use of oxidase enzyme or dehydrogenase enzyme labels that produce hydrogen peroxide or NADH.
Those products are monitored using chemi- or bioluminescent reaction.
3. The label can be a catalyst or cofactor for bioluminescent reaction.

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