The absorption, distribution, metabolism and excretion were studied following a single oral administration of ¹⁴C-TAU-284 to rats and dogs.
1. The blood level of radioactivity increased within 30min, reaching the C_max of 0.27μg eq./ml, and was decreased with a t_1/2 (1-8 hr) of 3 hrs after oral administration of ¹⁴C-TAU-284 to male rats.
2. The level of radioactivity in almost tissue was attained the maximum 30 minutes after oral administration. In these tissues, the levels in liver was highest, followed by kidney, small intestine, stomach, gall bladder, pancreas and adrenal gland. The levels in other tissues were the same as plasma level or lower. The decrease of radioactivity in most tissues was similar to that in plasma.
3. The autoradiograms of pigment rats at 24 hrs after dosing, the distribution of radioactivity in the skin and the uveal-tract of eyes, melanin containing tissues, was observed. The radioactivity in these tissues was disappeared 30 days after dosing.
4. The unchanged drug was major component found in urine and bile. In rat urine, only β-oxidative metabolite was detected. In rat bile, taurine-conjugated metabolite of the unchanged drug and 5 other metabolites were detected. No metabolite was detected in plasma of rat and dog and in the urine of dog.
5. Urinary and fecal excretion were 39.7 and 61.6%, of the dosed radioactivity, respectively, within 120 hrs after oral administration to male rats. Biliary excretion accounted for 40.6% of the dose and its possible that most of it was subjected to entero-hepatic circulation.

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The distribution and excretion of radioactivity was studied following a 21-day period of daily oral administration of ¹⁴C-TAU-284 to male rats. Furthermore, the transfer of radioactivity into the fetus and milk was also studied on the 12th and 18th day of pregnancy in rats, and in lactating female rats.
1. When measured at 24 hrs after each of 21 repeated dosings to male rats with ¹⁴-C-TAU-284, the levels of radioactivity in the blood reached the steady-state by the 16th dosing. The decrease of radioactivity in blood after repeated dosings for 21 days was slower than that after a single dosing.
2. In the distribution of radioactivity after the 21st dosing, the radioactivity in the liver and kidney was higher than that in other tissues. The radioactivity in cerebrum, eye balls, fat, seminal vesicles and testis were low. And radioactivity levels in other tissues were moderate. The tissue levels of radioactivity increased after each dosing during repeated administration.
3. Transfer to blood cells also increased by repeated dosing. Most radioactivity in blood cell was associated with a globin fraction.
4. The total ex cretion of radioactivity in urine and feces during each 24 hrs after daily dosing was almost constant.
5. The levels of radioactivity in the fetal liver 30 minutes after oral administration to 18th day in pregnant rats were about the same as in maternal plasma. The levels of radioactivity in other fetal tissues were 1/3 to 1/10 of that in maternal plasma.
6. The radioactivity level in the milk reached a maximum (0.40 μg eq./ml) at 1 hr after oral administration to 11 day-lactating rats. The radioactivity in milk 48 hrs after dosing was bellow the detection limit. The radioactivity in milk at each measured time was higher than that in plasma of lactating rat.

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The absorption, distribution, excretion and metabolism were investigated after a single oral (3 mg/kg) or intravenous (1 mg/kg) administration of ¹⁴C-taltirelin to male rats and dogs.
1. The extent of absorption calculated from the ratio of urinary excretion after or al and intravenous administration of ¹⁴C-taltirelin was 9 and 21% of the dose in rats and dogs. The intestinal absorption ratio in non-fasted rats decreased by 38% compared with that in fasted rats.
2. After oral administration to rats, the plasma level of radioactivity reached the maximum level of 157 ng eq./ml at 1 hr after dosing and then decreased with a half-life of 119 min. After oral administration to dogs, the plasma level of radioactivity reached the maximum level of 508 ng eq./ml at 1.5 hr and then decreased with a half-life of 146 min. The values of bioavailability in rats and dogs were 3.9 and 18.5%, respectively.
3. The ratios of plasma protein binding of radioactive substances in rats and dogs were below 12% both under the in vivo and in vitro conditions.
4. Radioactivity levels afte r oral administration to rats reached a peak at 30 min to 3 hr in most tissues and were high in the liver, kidney, spleen, lung, blood and skin, except for gastrointestinal tract. But at 24 hr radioactivity levels in these tissues decreased remarkably. Radioactivity level in the brain, a target organ of pharmacological effect, was low and decreased slowly.
5. In both rats and dogs, most of the dose wa s excreted within 48 hr after dosing and the absorbed ¹⁴C-taltirelin was excreted mainly in urine.
6. Radioactivity excreted in bile within 24 hr was 1.7 and 5.7% of the dose after oral and intravenous administration to rats, respectively.
7. Two metabolites, (−)-N-[(S)-hexahydro-1-methyl-2, 6-dioxo-4-pyrimidinyl carbonyl]-L-histidyl-L-proline (“Acid”) and (S)-hexahydro-1-methyl-2, 6-dioxo-4-pyrimidinecarboxylic acid (“MDOA”), together with unchanged taltirelin were detected in plasma and urine of both rats and dogs.

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The transfers of ¹⁴C-taltirelin into the fetus and milk and sex-related difference were investigated after a single oral administration of ¹⁴C-taltirelin at a dose of 3 mg/kg to rats. The blood level after repeat ed oral dosing was also studied.
1. In pregnant rats on the 13th and 19th day of pregnancy, the levels of radioactivity in whole fetus reached the maximum levels at 3 hr after oral administration, which accounted for 1/7 and 1/3 of the maternal blood concentration, respectively. At 3 hr, the transfered radioactivity in fetus of 19th day pregnant rats was less than 0.002% of dose per one fetus.
2. In lactating rats on the 14th day af ter delivery, levels of radioactivity in the blood and milk at 1 hr after dosing were 11.0 and 8.9 ng eq./g, respectively. The radioactivity in the milk decreased more slowly than that in blood and the radioactivity level in the milk was about 2 times higher than the corresponding blood level from 6hr after dosing.
3. There were no significant sex-related differences in the pharmacokinetic parameters of blood radioactivity and urinary excretion. MDOA, found in the urine of male and female rats, accounted for approximately 18 and 30% of urinary radioactivity, respectively, but any sex difference in kind of urinary metabolite was not observed.
4. After 15 times repeated oral administrations to male rats, the C_max, t_1/2 and AUC_inf values of blood radioactivity increased by 1.3, 2.2 and 3.1 times compared with those after the first dosing, respectively. The blood level of radioactivity at 1 hr after each dosing reached steady-state within 7 times dosing.

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The transfer, distribution and degradation of taltirelin in the brain were investigated after oral (3 mg/kg) or intravenous (1 mg/kg) administration and injection into cisterna cerebellomedullaris (300 μg/kg) in rats.
1. Taltirelin was hardly degraded for 3 hr in blood, whereas TRH was degraded with a half-life of 5.4 min. Taltirelin and TRH were degraded by the brain homogenate with half-lives of 64.4 and 7.9 min, respectively, suggesting that taltirelin is 8 times more stable than TRH in the brain. In the cerebrospinal fluid taltirelin and TRH were equally stable for 3 hr.
2. Concentration of unchanged taltirelin in the brain decreased more slowly with a half-lives of 55.4 ?? 65.7 min than that in the blood (t_1/2 : 23.1 min) after intravenous administration of taltirelin. After oral administration, the brain concentrations of unchanged taltirelin reached the maximum levels of 135 ?? 364 pg/g and then decreased slowly. The unchanged taltirelin was not detected in the brain at 6 hr after dosing.
3. After injection of ¹⁴C-taltirelin into cisterna cerebellomedullaris, the brain concentrations of radioactivity reached the maximum levels of 2.3 ?? 5.5 μg eq./g at 1 hr after injection and then decreased slowly. These results indicated that taltirelin was transferred from cerebrospinal fluid into the brain, in which taltirelin was retained for a long time.
4. After intravenous adm inistration of ¹⁴C-taltirelin or ³H-TRH, there is a difference in the brain distribution of radioactivity between taltirelin and TRH. Radioactive concentration in pituitary gland, which was target organ of hormonic effect, at 5 min after intravenous administration of ¹⁴C-taltirelin was 1/10 of that after dosing of ³H-TRH.

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Absorption, distribution, metabolism, excretion, transfer into the fetus and milk were investigated after a single oral administration of ¹⁴C-SS320A 25 mg/kg to rats of both sexes.
1. The blood level of radioactivity in the fasting male rats reached the C_max of 15.03 μg/ml at 0.31 hr and then declined with t_1/2z of 5.7 hr. The AUC_0-∞ was 33.0 μg hr/ml. In the blood, the parameters of radioactivity in the non-fasting rats were as follows, the C_max values was lower, the T_max and t_1/2z were longer and the AUC was 1.3 times larger than those in fasting rats. The blood radioactivity in male and female rats were similar.
2. In a study of gastro-intestinal absorption in situ, the largest amount of ¹⁴C-SS320A was rapidly absorbed from the small intestine.
3. The all of tissues in the fasting male rats showed a maximum level of radioactivity at 0.5 hr after oral administration, and it was eliminated quickly until 24 hr. The high concentration of radioactivity was observed in the kidney, liver, cerebrum and eyeball. However, the radioactivity levels in these tissues were less than 1 % of the maximum level within 120 hr after administration. Also, in majority of tissues of non-fasting rats the T/P were similar, but, the elimination of radioactivity from tissues were slower than fasting rats.
4. The protein binding ratios (in vitro) of radioactivity were low in plasma sample of rats and human at0.2-20 μg/ml. In rats, the protein binding ratios (in vivo) of radioactivity were 4.0 and 2.5 % at 0.5 and 4 hr and then increased 19.5 % at 8 hr after oral administration.
5. The distribution ratio (in vitro) of radio activity in blood cells (fasting) of ¹⁴C-SS320A was about 28 and 35% in blood samples of rats and human, respectively, at 0.2-20 μg/ml. The distribution ratio of radioactivity in blood cells was about 25% from 0.5 hr to 8 hr after oral administration of ¹⁴C-SS320A to male rats.
6. In the urine M1 and M3 were mainly found. In the plasma the SS320A, M1, M3 and M4 were mainly found at 1 hr after oral administration of ¹⁴C-SS320A in fasting and non-fasting rats. M1 was found in cerebrum, eyeball and lung as the main metabolite in fasting rats, the unchanged form, however, was found mainly in liver and kidney.
7. In male rat, 96.8, 0.7 and 0.8% of the dose was excreted in the urine, feces and expired air, respectively, within 120 hr after oral administration of ¹⁴C-SS320A. The same results were obtained after intravenous administration. The sex differences in drug excretion were not observed.
8. The excretion of radioactivity in the bile, urine and feces in male rats was 1.3, 95.4 and 0.1% of the dose, respectively, within 48 hr after oral administration of ¹⁴C-SS320A.
9. On the 12-th and 18-th days of gestation, the level of radioactivity in the fetus after oral administration of ¹⁴C-SS320A was higher than that in maternal plasma.
10. The level of radioactivity in milk, after oral adm inistration of ¹⁴C-SS320A to lactating female rats on the 11-th day after delivery, was lower than that in plasma until 2 hr. Nevertheless, it reached the same concentration at 4 hr, and it was higher than that in plasma after 8 hr.

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The absorption, distribution, metabolism and excretion of ¹⁴C-SS320A were investigated during and after repeated oral administration to male rats at a daily dose of 25 mg/kg for 10 days.
1. The level of radioactivity in the blood (24 hr after daily dosing) did not change with the number of repeated dosing. The C_max after 10-th dosing was 1.9 times higher than that in the single dosing. The half life was 1.8 times longer than that found in the single dosing.
2. The radioactivity levels in the tissues within 0.5 hr after the 5-th and 10-th dosing were similar to that in the 1-st dosing, but the radioactivity levels within 24 hr after the 5-th and 10 th dosing were increased by the repeated dosing. The radioactivity accumulated in the fat and brown fat.
3. The protein binding ratios of radioactivity at 0.5, 4 and 8 hr after the 10 th dosing were 9.6, 13.4 and 50.9%, respectively.
4. The distribution ratio of radioactivity in blood cell at 0.5, 4 and 8 hr after the 10-th dosing were 24.7, 28.3 and 32.1%, respectively.
5. The relative amounts of metabolites in the plasma at 1 hr after the 10-th dosing were mainly M4 and unchanged form, and followed by Ml, M3 and M2 in that order. In the urine, main metabolite was M1 followed by M3 and minor amount of M2. In the cerebrum and liver, metabolite M3 was mainly found. In the eyeball and lung, metabolite M1 was mainly found. In the kidney metabolite Ml and M3 were mainly found.
6. The excretion of radioactivity in the urine and feces reached a plateau level (about 96%) until the 3rd dosing.

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The absorption, metabolism and excretion of SS320A were investigated in male dogs after a single oral administration (25 mg/kg).
1. The blood level of rad ioactivity in male dogs reached the C_max of 23.44 μg/ml at 3.33 hr and then declined with t_1/2Z of 15.8 hr. The AUC_0-∞ was 415.5 μg·hr/ml. The radioactivity level in the plasma was same as that in blood.
2. The protein binding ratios (in vitro) of radioactivity were 0.0% in plasma sample of dogs at 0.4-40 μg/ml. The protein binding ratios (in vivo) of radioactivity was 0.4-2.5%.
3. The distribution ratio of SS320A radioactivity in blood cells was 2.5-9.3% in the in vitro conditions. The distribution ratio of radioactivity were 1.0% at 0.5 hr, and then increased 26.9 and 27.2% at 8 and 24 hr after administration to male dogs.
4. In the plasma, M1 (25. 6-37.6%), M4 (7.9-12.3%) and M3 (5.9-12.3%) were mainly found. In the urine, M1 (55.7%), M3 (19.6%), M2 (12.6%) and M4 (5.9%) were mainly found. The unchanged form in plasma was 32.7-49.9% from 0.5 to 8 hr.
5. In male dogs, 92.9 and 2.2% of the dose was excreted in the urine and feces, respectively, within 168 hr after administration.

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Evidence has been accumulating that oxidative stress plays important roles in pathogenesis of various acute and chronic diseases. A wide variety of drugs and chemicals have been shown to produce reactive oxygen species by their oxidative metabolism in the body, thus may cause oxdative stress and lead to cellular and tissue damages. In order to response to such oxidative insults, many antioxidative defense systems are constitutively expressed in mammalian cells the body. Of these antioxidative defense systems, heme oxygenase-1 (HO-1), a first and rate-limiting enzyme of heme degradation, has recently been shown to be highly responsible enzyme against oxidative stress. HO oxidatively cleaves heme into carbon monoxide (CO), Fe²⁺ and biliverdin, the latter is readily reduced to bilirubin. These degradative byproducts of heme by HO has currently been characterizing their physiological importance. Namely, CO, as just like NO, may play as a gaseous messenger; bilirubin acts as an antioxidant; Fe²⁺ is a modulator of ferritin. Therefore, the induction of HO-1 produced by physiological and pathophysiological states, and by drugs and chemicals may play vital roles in the adaptive and/or protective response to oxidative stress as a whole. Accumulated evidence demonstrates that HO-1 is induced by not only the substrate heme but also a wide variety of divergent drugs and chemicals, such as hormones, heavy metals, organic compounds including glutathione depletors, cytokines, prostaglandins and so on. Although a detailed mechanism of the induction of HO-1 by these compounds remains to be determined, most of them produce the enzyme induction through oxidative stress. Additionally, it is well established that HO-1 induction in liver or kidney is generally followed by the decrease in cytochrome P-450 content, important enzyme(s) which metabolizes endogenous substances and exogenous drugs and chemicals.
This review will describe partly on the current understanding of physiological and/or pathophysiological significance of HO-1, and mainly focus on the significance of this enzyme induction in response to oxidative stress produced by drugs and chemicals. I hope that this review will stimulate interest and understandings in HO-1 and its potential roles in response to oxidative stress.

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