The blood level profile and urinary excretion of meclomen (MCM) and its metabolites after single and repeated oral administrations to healthy human volunteers have been investigated.
When MCM was orally administered in single doses of 75, 150 and 300 mg to human volunteers, the blood level of MCM and its main metabolite, M-1, reached the maximum at 1-1.5 and 1.5-2 hr and then decreased with half lives of 0.9-1.1 and 5.3-12.1 hr, respectively. The area under time-concentration curve (AUC) and maximal plasma concentration of MCM were closely correlated with doses in the range of 75-300 mg. In 24 hr after the administration of MCM in the three doses, the total urinary excretions of MCM and its metabolites including M-1, M-2, M-3 and M-4, were 31, 28 and 27 %, respectively. The excretion ratio of the metabolites was almost the same in each dose.
When MCM was given three times per day in doses of 50, 100 and 200 mg for 5 days to healthy human volunteers, the maximal blood levels of MCM were nearly equal in the respective doses and in 14-15 hr after the third administration in each day. The blood concentrations of MCM and M-1 decreased to 1/15-1/100 and 1/20-1/40 of the corresponding maximum in the 6 th day while the maximal level of M-1 gradually increased depending on the dose. On the other hand, the total urinary excretion of MCM and its four metabolites during 6 days after the administration appeared to correlate closely in the three doses as well as in the case of a single administration but the excretion ratio of M-1 increased slightly in all doses. These results imply that no significant amounts of MCM and M-1 would be accumulated in human beings.

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FO-1561 (S-adenosyl-L-methionine, disulfate, tosylate) labeled at three different positions with ¹⁴C([CH₃-¹⁴C]FO-1561, [Met-2-¹⁴C]FO-1561 and [Ade-8-¹⁴C]FO-1561) was administered intravenously to dogs (10 mg as S-adenosyl-L-methionine (SAMe[/kg) to examine the blood and plasma levels, excretion of radioactivity and the plasma and urinary metabolites. Radioactive phosphatidylcholine in some tissues were also quantified after intravenous administration of [CH₃-¹⁴C]FO-1561.
The blood and plasma radioactivity rapidly decreased biphasically until 4 hour and no difference was observed in pharmacokinetic behavior among the three differently labeled FO-1561 compounds. HPLC analysis also showed that the radioactivity in the plasma until 2 hour was unchanged SAMe.
More than 85 % of the administered radioactivity was excreted in the urine until 168 hour after administration of each type of labeled FO-1561. The excretion of radioactivity in feces was less than 5 % until 168 hour. Thus, the main excretory route was shown to be. renal excretion.
Urinary metabolites were 5′-deoxy-5′-methylthioadenosine (MTA) and methionine after administration of [CH₃-¹⁴C]FO-1561, homoserine, homoserine lactone and methionine after administration of [Met-2-¹⁴C]FO-1561, and MTA, adenine and S-adenosylhomocysteine after administration of [Ade-8-¹⁴C]FO-1561. However, unchanged SAMe accounted for more than 80 % in urine until 48 hour. The brain, liver and plasma contained radioactive phosphatidylcholine after administration of [CH₃-¹⁴C]FO-1561.
From these results, the following two major metabolic pathways of exgeneous SAMe was demonstrated: 1) cleavage of C-S bond in SAMe resulting in the formation of homoserine, homoserine lactone and MTA, 2) transmethylation of S-methyl group to endogenous methyl acceptors such as phosphatidylethanolamine.

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Inclusion complexes of 1-hexylcarbamoyl-5-fluorouracil (HCFU) with β-cyclodextrin (β-CyD), heptakis (2, 6-di-O-methyl)-β-CyD (DM-β-CyD) and heptakis (2, 3, 6-tri-O-methyl)-β-CyD (TM-β-CyD) in the molar ratio of 1 : 1 were prepared and their antitumor activities against P-388 leukemia were examined in mice. Antitumor activities of the test compounds against the tumor were evaluated by the increase in lifespan [ILS (%)] of P-388 leukemia-bearing mice. ILS after per oral administration of HCFU (150 mg/kg) to P-388 leukemia-bearing mice, for example, was 25.5 % while after administration of β- and DM-β-CyD complexes was 57.5 and 76.5 %, respectively. However, TM-β-CyD complex was rather toxic to mice. The concentration of HCFU in the ascitic fluid, following oral administration of DM-β-CyD complex to mice was significantly higher than that after administration of the drug alone. The results indicate that the increased antitumor activity of HCFU following complexation with DM-β-CyD may allow to reduce the dose, which is a promising advantage to decrease the side effects of this antitumor agent.

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The blood and plasma levels, distribution and excretion of S-adenosyl-L-methionine sulfate tosylate (FO-1561) were studied in rats afer intravenous administration of [CH₃-¹⁴C] FO-1561.
1. After intravenous administration of 10 mg/kg to rats, the blood and plasma levels of radioactivity decreased biphasically until 2 hr, and then kept steady state until 24 hr. After intravenous administration of 100 mg/kg to rats, the blood and plasma levels of radioactivity decreased biphasically until 4 hr, increased slightly until 8 hr, and then decreased slowly. The biological half life of radioactivity at early time period after administration was slightly shorter in plasma than in blood. The dose dependence in the biological half life was not observed.
2. The main excretory route of radioactivity was in urine (31.30 %) and expired air (29.72 %) at a dose of 10 mg/kg, and in urine (74.39 %) at a dose of 100 mg/kg. The excretion of radioactivity in feces or bile was slight. At 120 hr after administration, the residual of radioactivity in carcass was 33.41 % of dose in the group administered at 10 mg/kg, and 11.39 % of dose in the group administered at 100 mg/kg.
3. At 6 hr after administration, the increase of radioactivity was observed in the gastro-intestinal wall and several tissues, and in the skeletal muscle at 48 hr. These results suggest that [CH₃-¹⁴C] may be incorporated into endogenous substance. The high level of radioactivity in the kidney was observed during 120 hr after administration.
4. The binding of radioactivity to plasma protein increased gradually after 1 hr and at 24 hr later, more than 90 % of radioactivity was bound to protein. The binding of radioactivity to blood cell increased gradually after 6 hr, and the binding rate of radioactvity was 69.64 % at 120 hr.

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The biotransformation of S-adenosyl-L-methionine sulfate tosylate (FO-1561) was studied in rats after intravenous administration of ¹⁴C-labeled FO-1561 at a dose of 10 mg (as S-adenosyl-L-methionine)/kg.
1. After intravenous administration of [Ade-8-¹⁴C] FO-1561 to rats, allantoin, uric acid and unchanged S-adenosyl-L-methionine were identified in the urine as major metabolites. Homoserine, cystathionine and methionine were identified after intravenous administration of [Met-2-¹⁴C] FO-1561. After intravenous administration of [CH₃-¹⁴C] FO-1561, the radioactive methyl group was incorporated into creatine and creatinine in the skeletal muscle, and into phosphatidylcholine and N-methylated phospholipids of the brain, liver and kidney. These results suggest that exogenous S-adenosyl-L-methionine is metabolized through purine metabolic pathway and transmethylation.
2. After intravenous administration of [Met-2-¹⁴C] FO-1561 to rats, there was high concentration of S-adenosyl-L-methionine in the plasma, but it almost disappeared within 6 hr. On the other hand, there were low concentrations of S-adenosyl-L-methionine in the brain and liver, and then these levels decreased gradually. There was extremely high concentration of S-adenosyl-L-methionine in the kidney, and its maximum concentration was reached at 1 hr, and then it disappeared within 120 hr. In addition, there was high concentration of S-adenosylhomocysteine in the kidney.
3. After administration, the S (−) ratio of S-adenosyl-L-methionine in the plasma decreased with time, and markedly decreased in the liver and kidney. Therefore it was suggested that S (−) form of S-adenosyl-L-methionine could be utilized selectively in the tissue.
4. On the basis of these results, the metabolic pathways of FO-1561 in rats were discussed.

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Nabumetone, 4-(6-methoxy-2-naphthyl) butan-2-one, is a non-acidic, nonsteroidal anti-inflammatory drug. This is a kind of pro-drug, because nabumetone itself exists shortly in the plasma while its main metabolite, 6-methoxy-2-naphthyl-acetic acid (6 MNA), exerting anti-inflammatory effect remains in the plasma for a long period of time.
Nabumetone, 6 MNA and 4-(6-methoxy-2-naphthyl) butan-2-ol (MNBO) which is an intermediate compound between nabumetone and 6 MNA(10 mg/kg equivalent of nabumetone) were administered intravenously or orally to rats, and the serum levels of these 3 compounds were determined. The following conclusions were obtained by comparison of their serum levels.
1. Nabumetone itself was well absorbed from the gastrointestinal tract, and mostly metabolized by first-pass metabolism after oral dosing.
2. 6 MNA peaked in the serum 1 hr after oral dosing of nabumetone and was eliminated with 1.8 hr half-life.
3. After oral and intravenous dosing, 31 % and 36 %, respectively of nabumetone was converted to 6 MNA.
4. We then investigated the route of conversion and comfirmed the existence of 2 metabolic pathways from nabumetone to 6 MNA; one is via MNBO to 6 MNA (60 %) and the other to 6 MNA (40 %).
5. Nabumetone was metabolized not only in the liver but also in the other organs.

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Blood or plasma concentration, distribution, metabolism and excretion of rt-PA were investigated in male and female rats after single intravenous administration of ¹²⁵I-rt-PA.
1. After intravenous administration of ¹²⁵I-rt-PA, plasma levels of unchanged rt-PA, immunoreactive rt-PA and fibrinolytic activity decreased rapidly. In the plasma, complexes of ¹²⁵I-rt-PA with α₂-macroglobulin or α₂-antiplasmin were observed.
2. After intravenous administration of ¹²⁵I-rt-PA, high radioactivities were observed in the liver, spleen, bone marrow, adrenal gland, kidney and plasma. Radioactivities in the other organs were lower than that in the blood. Most of the radioactivities in these organs were precipitated with TCA, and radioactivities in TCA precipitate were decreased more rapidly than total radioactivity. At 5 min after dosing, immunoreactive rt-PA was observed in the liver and kidney, but its decline was as rapid as that from blood.
3. Within 120 hr after intravenous administration of ¹²⁵I-rt-PA, 89 % and 5-6 % of the administered radioactivity were excreted into urine and feces, respectively. Biliary excretion rate of radioactivity was 15 % of the dose within 48 hr after intravenous administration of ¹²⁵I-rt-PA.

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Blood or plasma concentration, distribution, metabolism, excretion and accumulation of rt-PA were investigated in male rats after repeated intravenous administration of ¹²⁵I-rt-PA for 15 days.
1. During the repeated intravenous administration of ¹²⁵I-rt-PA, blood or plasma total radioactivity, radioactivity in TCA precipitate, immunoreactive rt-PA, fibrinolytic activity, unchanged rt-PA and its metabolites were constant at 5 min after each dosing. After the repeated intravenous administration of ¹²⁵I-rt-PA for15 days, blood or plasma total radioactivity and radioactivity in TCA precipitate decreased slower than those after single administration, but decline of the immunoreactive rt-PA level and fibrinolytic activity were same as those after single administration.
2. During the repeated intravenous administration of ¹²⁵I-rt-PA, the radioactivity in organs at 24 hr after each dosing increased gradually till 5 th or 10 th days and remained almost constant till 15 th day. After repeated intravenous administration of ¹²⁵I-rt-PA for 15 days, the total radioactivity and radioactivity in TCA precipitate in each organ decreased slowly than those after single administration. At 5 min after each dosing, immunoreactive rt-PA levels in the liver and kidney were unchanged during the repeated administration. There was no clear indication of accumulation of rt-PA.
3. The excretion of radioactivity in the urine and feces was nearly the same throughout the period of repeated intravenous administration of ¹²⁵I-rt-PA. Within 120 hr after the last dosing, 90 % and 8 % of the administered radioactivity excreted into the urine and feces, respectively.

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This review has discussed the factors underlying the drug distribution into tissue in vivo. Free drug hypothesis could predict an unbound drug concentration in the intracellular fluid by means of the in vitro binding experiment . However, sometimes, the hypothesis would underestimate the unbound drug concentration in the cell, since plasma protein such as albumin and/or globulin could selectively deliver the drug to tissues depending on plasma-protein mediated transport. There appear to be five characteristic features for plasma protein-mediated transport: a) plasma protein specificity b) tissue specificity c) substrate specificity d) stereospecificity e) isoform specificity. An enhanced dissociation model is a valid biochemical mechanism for plasma protein-mediated transport, which is assuming that interactions between the plasma protein and the surface of the tissue microcirculatin cause a conformational change of the binding site and concomitantly, enhance the dissociation rate of drug. Physiological pharmacokinetics should be constructed by means of in vivo plasma protein binding experiment as well as traditional in vitro study. For the selective drug delivary to the target organ an application of protein-mediated transport process may be usful.

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The membrane permeability of rat intestine was estimated by using the transport equation in cylindrical coordinate.
?? +V_z ?? =D_r ?? r ?? −P_wC_w
Four fluid flow profiles were assumed. 1) Mixing tank model, 2) Complete radial mixing model, 3) Plug flow model, and 4) Laminar flow model. Laminar flow model that has a parabolic velocity profile (V_z=U_max{1-(r/R)²}) was found to be the best to correlate with the drug concentration change in the intestine. The differential equation was solved to obtaine the exit cup-mixing concentration profile at non-steady state after pulse input. The finite difference analysis and least squares method were used to estimate the permeability coefficient and the diffusion coefficient, and to simulate the concentration distribution in the intestine.

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