The ocular distribution, absorption and excretion of ¹⁴C-labeled or unlabeled tranilast after a single and repeated ophthalmic instillation were studied in guinea pigs and rabbits.
After a single administration in rabbits, the excretion ratio of radioactivity in urine, feces and expiration were similar both after an ophthalmic and oral administration ; and accumulated for approximately 30, 15 and 50% in urine, feces and expired air, respectively.
After a repeated ophthalmic instillation in rabbit eyes, the excretion ratio of radioactivity in urine, feces and expiration were nearly of the same pattern as that after a single ophthalmic instillation. After a single ophthalmic instilation in guinea pig and rabbit eyes, the radioactivity was high in the extraocular tissues, conjunctiva and cornea, than that in the intraocular tissues.
And the levels of tranilast in plasma were much lower than that in conjunctiva and in cornea.
The radioactivity of the ocular tissues during the repeated ophthalmic instillation in rabbit eyes was much higher in conjunctiva and in cornea than in other tissues, and continued to increase till the final dosing. The elimination ratio from these tissues after final dose of repeated ophthalmic instillation were comparative to the values after a single ophthalmic instillation. These results suggested that tranilast accumulated in the ocular tissues by consecutive instillation of 0.5% tranilast ophthalmic solution, but it did not remain in the ocular tissues after the cessation of instillation.

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The plasma levels, tissue distribution, metabolism and excretion of ¹²⁵I-rhIGF-I were studied in rats after a single intravenous or subcutaneous administration. ¹²⁵I-rhIGF-I used in this study was eluted at a different position to native rhIGF-I as determined by the reversephase HPLC and its biological activity was confirmed by a proliferation test of BALB/c 3T3 cells. The amino acid analysis of the radioactive peaks revealed that the iodination site of ¹²⁵I-rhIGF-I was at the Tyr-24 and Tyr-60.
After a subcutaneous administration of ¹²⁵I-rhIGF-I at the dose 1 mg/kg to male and female rats, the maximum concentrations of total and trichloroacetic acid (TCA)-insoluble radioactivity were reached at 3h and 1h, respectively. AUC of total and TCA- insoluble radioactivity and C_max of total radioactivity were slightly lower in male rats than female rats, but C_max of TCA-insoluble radioactivity, T_max and T_1/2 of both radioactivity were similar in male and female rats. Until 1h after a subcutaneous administration, the highest radioactivity (5 ?? 8 times higher than that of the plasma level) was observed in the kidney, but radioactivity in other tissues except the thyroid gland and stomach were below the plasma level. These results are in good agreement with those of whole body autoradiography. The major excretion route of ¹²⁵I-rhIGF-I is urine and there is no difference related to the routes of administration and sex. Most of radioactivity in the urine consisted of free iodine, similar results were observed in the case of bile. The kidney might also play the major role in metabolism of ¹²⁵I-rhIGF-I.

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The transfer of ¹²⁵I-rhIGF-I to the fetus or into the milk after a single subcutaneous administration was investigated in pregnant rats on 12th and 18th day of gestation and in lactating rats.
The level of radioactivity in the fetus on the 18th day of gestation was higher than that on the 12th day of gestation, but was at least six times lower than that in maternal plasma. The level of radioactivity in fetal tissues disappeared parallelling the maternal plasma except that in thyroid gland, which might be due to free ¹²⁵I.
Most of radioactive substances of high molecular weight, which were found in the milk of lactating rats, might be on endogenous proteins which had in corporated a free iodine, otherwise the permeability of rhIGF-I into milk was thought to be low.

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¹²⁵I-rhIGF-I was administered subcutaneously to rats at the dose of 1 mg/kg for 7 consecutive days.
After seventh subcut aneous administration of ¹²⁵I-rhIGF-I, the plasma levels of total and trichloroacetic acid (TCA)precipitable radioactivity declined more slowly than those after a single administration. However, it might be caused by an endogenous proteins which had incorporated a free ¹²⁵I and low molecular weight fragments of ¹²⁵I-rhIGF-I and the plasma levels of rhIGF-I itself were thought not to be changed after repeated administration.
Except the thyroid, the permeability of rhIGF-I to tissues did not change, and no accumulation of ¹²⁵I-rhIGF-I in any particular tissue was observed after repeated administration.
During repeat ed administration, the excretion of radioactivity in urine and feces was almost similar to that after a single administration, and 80% and 9 % of the administered dose was excreted within 168 hours after the last dosing to urine and feces, respectively.
Most of radioactivity in t he urine consisted of free ¹²⁵I which indicates that ¹²⁵I-rhIGF-I was well metabolized. Thus, it appears that ¹²⁵I-rhIGF-I does not accumulate in tissue.

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Distribution, accumulation, foeto-placental transfer and excretion of ¹²⁵I-SNB-5001 into the milk were studied after intravenous (iv) or subcutaneous (sc) administration at a dose of 50 U/kg to male, pregnant and lactating rats, respectively.
1. After single iv administration to male rats, high level radioactivity was distributed rapidly in thyroid, blood, lymph, kidney, liver, bone marrow and lung and thereafter the radioactivities in most tissues, except thyroid and skin, disappeared rapidly as revealed by whole body autoradiography. After sc administration, the radioactivity was slowly distributed in the tissues at a low level, but distribution patterns were similar to those after iv administration. Distribution of radioactivity in brain and spinal cord was extremely low.
2. After repeated iv and sc administration to male rats for 7 days, distribution patterns of radioactivity were not changed compared with those after single administration. Accumulation of radioactivity in the tissues was scarcely observed except in thyroid and skin.
3. After iv administration to pregnant rats (19th day of gestation), a very small amount of radioactivity was distributed in fetal tissues except thyroid and gastric contents. TCA-insoluble radioactivity in fetus was about 30% at the early times after administration, indicating that most of the radioactivity was free ¹²⁵I and ¹²⁵I-compounds of low molecular weight. These results suggest that SNB-5001 is scarcely transfered into the fetus.
4. The radioactivity in the milk was increased gradually and reached the maximum of the higher level than that in maternal plasma at 6hr after iv administration to lactating rats. Afterwards, the radioactivity in milk disappeared rapidly similar to that in plasma, however, the ratio of TCA-insoluble radioactivity in milk was increased with time.

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The absorption, distribution, metabolism, excretion and identification of metabolites of E6123, (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8, 11-dimethyl-2, 3, 4, 5-tetrahydro-8H-pyrido [4', 3' : 4, 5]thieno[3, 2-f][1, 2, 4]triazolo[4, 3-a][1, 4]diazepine, were studied in beagle dogs after a single oral administration.
1. After oral administration, the radioactivity in the blood, plasma and hematocytes reached their C_maxs at 2.3h, 3.0h and 2.0h, respectively. And then the radioactivity decreased two-exponentially with their t_1/2^λ₁ and t_1/2 of 6.3h and 33.9h in blood, 4.9h and 38.7h in plasma, 3.0h and 18.7h in hematocytes, respectively. The AUCs in blood, plasma and hematocytes were 3952, 3745, 4167ng eq. ·h/ml, respectively.
2. After oral administration, C_max of unchanged drug in plasma was reached at 1.3h and then decreased rapidly with t_1/2 of 1.7h. The AUC was 330ng·h/ml.
3. In vitro plasma protein binding of ¹⁴C-E6123 varied from 57 to 59% at the range of concentration from 10 to 1000ng/ml. After oral administration, the in vivo plasma protein binding of radioactivity was approximately 59 and 85% for plasma samples collected at 0.75 and 8h, respectively.
4. After oral administration, the radioactivity in almost all tissues were the same or higher than that of plasma ; indicating that ¹⁴C-E6123 had an increased high affinity for tissues. The radioactivity in the tissues, except eye, disappeared fastly.
5. The level of radioactivity in the lung as the target organ was 1.8 times higher than that in plasma at 2h after administration. And more, the composition of metabolites of E6123 in plasma and lung was almost the same and the unchanged drug was a main compound.
6. Approximately 42 and 47% of radioactivity was excreted in urine and feces during 48h after oral administration, respectively. At least, seven metabolites were found in urine and feces respectively, with a minor quantities of unchanged drug.
7. Main metabolic pathways were shown to be as follows ; (1) oxidation of methyl group at the 11-position (M1B), (2) oxidation of carbon 2 and (3) hydrolysis of side chain (M3). After the oxidation of carbon 2, M1A was formed. And then M1A was metabolized to M2 by reduction and to M4 by oxidation.

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Q-35, (±)-1-Cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methylaminopiperidine-1-yl)-4-oxoquinoline-3-carboxylic acid, is a new pyridone carboxylic acid antibiotic(NQ). Certain NQs have been reported to inhibit theophylline (TP) metabolism in vivo and in vitro. We investigated the effect of Q-35 on TP metabolism by rat liver microsomes. TP was incubated with rat liver microsomes in the presence of Q-35, enoxacin, ofloxacin or ciprofloxacin. The effect of NQ was evaluated in terms of the formation of main TP metabolite, 1, 3-dimethyluric acid. Enoxacin strongly inhibited this formation while Q-35 showed the lowest inhibitory effect among four NQs.
Relationship between the structure and inhibitory effect of the Q-35 derivatives was studied. 3'-amino substituents in 7-pyperidinyl group showed a strong inhibitory activity, while the 3'-methylamino and 4'-amino substituents were weak inhibitors. Little enantiomeric effect was observed at the 3'-position. The methoxy group in the 8-position reduced inhibitory effect.
From these results, the Q-35 has little effect on TP metabolism and the effects of Q-35 derivatives on TP metabolism depends on the stereochemical stsucture of 7- and 8- substituents.

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Antipsychotic drugs have been widely used in humans for the treatment of schizophrenic psychosis. It is widely accepted that the pharmacological activities of antipsychotic drugs are best associated with its dopamine D₂ receptor blockade. The usual therapeutic doses vary to a high extent among the antipsychotic drugs with the maximum of about 500-fold difference, despite of the same clinical improvement. In order to clarify the mechanism of this difference, we analyzed retrospectively the pharmacotherapeutic effects of antipsychotic drugs based on the receptor occupancy theory. Since the antipsychotic drugs readily transfer across the brain cell membranes, the dopamine D₂ receptor occupancies of various drugs were calculated by using both their unbound concentrations in plasma and dissociation constants(K_d) for dopamine D₂ receptor, and then compared with those determined by PET. The calculated dopamine D₂ receptor occupancies of antipsychotic drugs which had no active metabolites were almost constant (76.4±15.0%) and corresponded to those determined by PET (80.0±7.6%). On the other hand, the calculated receptor occupancies of antipsychotic drugs which had active metabolites varied between 0.8 to 35% because of no consideration of active metabolites. However, those determined by PET were stable (79.8±4.1%). This finding indicated that the usual doses of antipsychotic drugs allowed to get about 79% as the optimum dopamine D₂ receptor occupancy. Furthermore, the simulation of effect-receptor occupancy curves based on the ternary complex model indicated that the large receptor occupancy was necessary for sufficient therapeutic effect of antipsychotic drugs. Based on these findings, we could develop a methodology for estimating the rational usual dose of a newly developed drug by using K_d and data on pharmacokinetics in phase I clinical study.

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The vagina is an important area of the reproductive tract. The vaginal route of administration of drugs may be a viable alternative to oral theraphy. But the vaginal preparations on the market are exclusively restricted to those are topically effective. Most of agents in vaginal preparations act directory on the vaginal membrane. Vaginal absorption is characterized by the avoidance of hepatic first pass effect, prolonged retention of the blood level and the variation throughout the reproductive cycle. In this minireview, the vaginal absorption of several drugs with low molecular weight is introduced from the standpoint of chemical structure, first pass effect and transport process. In addition, we discuss the vaginal absorption of prasterone sulfate(PS)in rats. PS is almost completely absorbed from the vagina. PS may be transported through vaginal membranes by both paracellular route and carriermediated process.

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