The pharmacokinetics and pharmacological effect of ethyl 2-[4, 5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate (KBT-3022), were studied after administration of KBT-3022 to guinea pigs.
1. The unchanged KBT-3022 was detected in plasma at only early phase after intravenous or oral administration of KBT-3022. KBT-3022 was readily metabolized to desethyl KBT-3022, 2-[4, 5-bis(4-methoxyphenyl)thiazol-2-yl]-pyrrol-1-ylacetic acid.
2. Both C_max and AUC0_0-∞ of desethyl KBT-3022 increased approximately in proportion to the administerd dose over the dose range 5-20 mg/kg.
3. The levels of radioactivity in the pla telets were 9-44 times higher than those in plasma after oral administration of ¹⁴C-KBT-3022, and the level of desethyl KBT-3022 in the platelets was estimated to be about 75 times higher than that in plasma.
4. TXB₂ production was almost completely inhibited by 48h after oral administration of KBT-3022 both at a dose of 1 and 5 mg/kg, but duration of this inhibitory effect at a dose of 5 mg/kg was longer than that at a dose of 1 mg/kg. IC₅₀ value of desethyl KBT-3022 in plasma was estimated to be 1-2 ng/ml.

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The pharmacokinetics of levofloxacin (LVFX) was investigated after a single or repeated topical application of 0.5% ¹⁴C-LVFX ophthalmic solution to pigmented rats. In the case of repeated application, the ophthalmic solution was instilled 3 times a day for 14 days (total 40 times).
1. The radioactivity in the plasma reached a maximum at 10 minutes after single administration and then decreased with half-life of 0.9 hours. The radioactivity distributed rapidly into various tissues. Radioactivity levels in the peripheral tissues were the highest in the kidney, following by the harderian gland, duodenum, liver and lung. Radioactivity disappeared rapidly from almost all tissues within 24 hours after administration.
2. The radioactivity distributed rapidly to anterior segment, cornea and aqueous humor after a single administration. The decrease of radioactivity was rapid in the absence of melanin, but it was slow in the melanin containing ocular tissues.
3. The radioactivity in the melanin containing ocular tissues gradually increased during repeated administration. However, judging from the increase of radioactive concentration after repeated instillation for 40 days, further repeated instillation would not cause a rapid increase of radioactive concentration in these tissues.
4. Ten minutes after a single administration, the radioactivity in the plasma contained mainly the unchanged form.
5. The excretions of radioactivity in the urine and feces amounted to 44.4 and 55.5% of the dose, respectively, within 96 hours after a single administration.

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S-1, a new oral anti-cancer drug, is composed of tegafur(FT), gimestat(CDHP) and potassium otastat(Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5 fluorouracil (5-FU) plays a role as an effector. Both CDHP and Oxo which do not have anti-tumor activity themselves play roles as modulators.
The absorption and excretion of the components of S-1 after administration of [14C-FT]-S-1, [14C-CDHP]-S-1 or [14C-Oxo]-S-1 to rats were investigated in the present study.
1. After administration of [14C-FT]-S-1 to male rats under fasting condition, the blood levels of the radioactivity reached the Cmax value of 6215 ng eq./ml at 1 hr post-dose, and decreased thereafter biphasically. The main route of elimination was the urinary excretion. During a period up to 72 hr after administration, 74.7%, 1.6% and 15.5% of the dose administered were excreted in the urine, feces and expired air, respectively. In the bile, collected up to 48 hr after administration, 4.3% of the dose was excreted.
2. In female rats administered with [14C-FT]-S-1 under fasting condition, the blood levels of the radioactivity and the excretion ratios did not differ much from those in fasted male rats.
3. In male rats administered with [14C-FT]-S-1 under non-fasting condition, the food ingestion was demonstrated to show no effects on the absorption and excretion.
4. The absorption ratios determined at 30 min after injection of [14C-FT]-S-1 to the loops of digestive tract were 96.0% in the duodenum, 96.2% in the jejunum, 91.4% in the ileum and 67.8% in the colon.
5. After administration of [14C-CDHP]-S-1 to male rats under fasting condition, the blood leve ls of the radioactivity reached the Cmax value of 569 ng eq./ml at 1 hr post-dose, and decreased thereafter monophasically. The main route of elimination was the urinary excretion. During a period up to 72 hr after administration, 74.8%, and 22.5% of the dose administered were excreted in the urine and feces, respectively. In the bile, collected up to 48 hr after administration, 1.3% of the dose was excreted.
6. Female rats administered with [14C-CDHP]-S-1 under fasting condition showed 1.3 times higher Cmax value and 1.4 times greater AUC value than those values in male rats, while the ratio of urinary excretion in female rats was lower than that in fasted male rats by 9.8%.
7. In male rats administered with [14C-CDHP]-S-1 under non-fasting condition, the food ingestion was demonstrated to decrease the absorption ratio.
8. The absorption ratios determined at 30 min after injection of [14C-CDHP]-S-1 to the loops of digestive tract were 18.2% in the duodenum, 20.2% in the jejunum, 12.1% in the ileum and 4.0% in the colon.
9. After administration of [14C-Oxo]-S-1 to male rats under fasting condition, the blood levels of the radioactivity reached the Cmax value of 947 ng eq./ml at 1.3 hr post-dose, and decreased thereafter biphasically. The main route of elimination was the urinary excretion. During a period up to 72 hr after administration, 70.7%, 27.0% and 3.0% of the dose administered were excreted in the urine, feces and expired air, respectively. In the bile, collected up to 48 hr after administration, 1.0% of the dose was excreted.
10. Female rats administered with [14C-Oxo]-S-1 under fasting condition showed 1.3 times higher Cmax value and 1.5 times greater AUC value than those values in male rats, while the ratio of urinary excretion in female rats was lower than that in fasted male rats by 16.6%.
11. In male rats administered with [14C-Oxo]-S-1 under non-fasting condition, the food ingestion was demonstrated to cause the decrease in the absorption ratio and the marked change in the time course of the blood radioactivity.
12. The absorption ratios determined at 30 min after injection of [14C-Oxo]-S-1 to the loops of digestive tract were 20.4% in the duodenum, 37.6% in the jejunum, 18.6% in the ileum and 6.8% in the colon.

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S-1, a new oral anti-cancer drug, is composed of tegafur(FT), gimestat(CDHP) and potassium otastat(Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5-fluorouracil (5-FU) plays a role as an effector. Both CDHP and Oxo which do not have anti-tumor activity themselves play roles as modulators.
After a single oral administration of [¹⁴C-FT]-S-1, [¹⁴C-CDHP]-S-1 or [¹⁴C-Oxo]-S-1 to rats, the tissue distribution of the radioactivity and the serum protein binding of FT, 5-FU, CDHP and Oxo were investigated in the present study.
1. In the experime nt on the tissue distribution of the radioactivity by direct counting method after administration of [¹⁴C-FT]-S-1 to male rats, the kidneys showed the highest while the white fat showed a low levels of radioactivity. According to whole body autoradiograms, the nasal cavity and eye ball (cornea and sclera) were found to show the high present of radioactivity.
2. In the experiment on the tissue distribution of the radioactivity by direct counting method after administration of [¹⁴C-FT]-S-1 to female rats, the distribution pattern of radioactivity in tissues except the genital organ was similar to that in male rats.
3. In the experiment on the tissue dist ribution of the radioactivity by direct counting method after administration of [¹⁴C-CDHP]-S-1 to male rats, the kidneys and digestive tract showed the highest radioactivity at early collection time points after administration. The elimination of the radioactivity from each tissues was rapid, and the levels of the radioactivity in the tissues and organs other than the large intestine decreased to the levels not more than 7% of the maximum concentrations at 24 hr after administration.
4. In the experiment on the tissue distribution of the radioactivity by direct counting method after administration of [¹⁴C-Oxo]-S-1 to male rats, the kidneys, liver, mesenteric lymph node and digestive tract showed the highest radioactivity at early data points after administration. A slow elimination of the radioactivity was observed in the white fat and brown fat, which showed originally low levels, but even at 72 hr after administration, showed the concentrations of about 50% of the maximum levels. The levels of the radioactivity in other tissues and organs decreased to the levels of 23% of the maximum levels, while at 72 hr after administration the levels in about half of tissues were below the detection limit. In the whole body autoradiograms prepared up to 24 hr after administration, a high radioactivity was observed in the periosteum and nasal cavity.
5. The ratios of serum protein binding of FT were 55.7-48.9% in human, 52.1-50.2% in dog and 42.9-40.7% in rat, and were higher than those ratios of other compounds in either animal species. The serum protein binding ratios of 5-FU, CDHP and Oxo were highest in human.

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S-1, a new oral anti-cancer drug, is composed of tegafur (FT), gimestat (CDHP) and potassium otastat (Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5-fluorouracil (5-FU) plays a role as an effector. Both CDHP and Oxo which do not have anti-tumor activity themselves play roles as modulators.
Repeated oral administration of [¹⁴C-FT]-S-1, [¹⁴C-CDHP]-S-1 or [¹⁴C-Oxo]-S-1 to male rats once daily for a period of 21 days was conducted, and the absorption and excretion of the radioactivity were investigated. Effects of repeated administration on the hepatic drug-metabolizing enzyme system were also investigated after repeated oral administration of S-1 to rats once daily for a period of 7 days.
1. In the animal group administered with [¹⁴C-FT]-S-1 repeatedly, the blood le vels of the radioactivity at 24 hr after each dosing increased along with the number of dose, and showed a 8.2 times higher concentration after 18th dosing than that after the first dosing, almost reaching the steady state. The blood levels of the radioactivity after the final dosing showed a slow elimination compared to that in the animal group received single dosing. The ratios of the radioactivity excreted in the urine, feces and respiratory air to the cumulative dose administered during a period up to 24 hr after each dosing did not show the change associated with the number of administered doses. The ratios of excretion of the radioactivity in the urine, feces and respiratory air during a period up to 168 hr after the 21st dosing were 76.4%, 2.6% and 16.8% of the cumulative dose, respectively.
2. In the animal group administered with [¹⁴C-CDHP]-S-1 repeatedly, the blood levels of the radioactivity at 24 hr after each dosing reached the steady state after the 4th dosing and thereafter, being 7-35 ng eq./ml up to the 21st dosing. The C_max value after the 21st dosing was 1.3 times higher than that after the single dosing, whereas there was no marked difference in the elimination of the radioactivity between the 21st dosing and single dosing. The ratios of excretion of the radioactivity in the urine and feces to the cumulative dose administered during a period up to 24 hr after each dosing showed no marked change associated with the number of doses after the second dosing and thereafter. During a period up to 168 hr after the 21st dosing, the radioactivity was excreted in the urine at a ratio of 54.8% of the cumulative dose and in the feces at a ratio of 41.6% of the cumulative dose.
3. In the animal group administ ered with [¹⁴C-Oxo]-S-1 repeatedly, the blood levels of the radioactivity at 24 hr after each dosing increased along with the number of doses, showed 2.5 times higher concentration after the 14th dosing than that after the first dosing, reaching almost the steady state thereafter. The blood levels of the radioactivity after the 21st dosing showed a slow elimination compared to that in the animal group received the single dosing. The ratios of excretion of the radioactivity in the urine, feces and respiratory air to the cumulative dose administered during a period up to 24 hr after each dosing showed no marked change associated with the increase of the number of repeated dosing after the third dosing and thereafter. During a period up to 168 hr after the 21st dosing, the radioactivity was excreted in the urine at a ratio of 31.5% of the cumulative dose, in the feces at a ratio of 58.5% of the cumulative dose and in the respiratory air at a ratio of 5.6% of the cumulative dose.
4. Repeated dosing of S-1 (5 mg/kg as FT) for a period of 7 days did not cause a marked change in the drug-metabolizing enzyme system in hepatic microsomes.

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S-1, a new oral anti-cancer drug, is composed of tegafur (FT), gimestat (CDHP) and potassium otastat (Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5-fluorouracil (5-FU) plays a role as an effector. Both CDHP and Oxo which do not have anti-tumor activity themselves play roles as modutators.
Repeated oral administration of [¹⁴C-FT]-S-1, [¹⁴C-CDHP]-S-1 or [¹⁴C-Oxo]-S-1 to male rats once daily for maximum 21 days was conducted, and the distribution of the radioactivity in the tissues and organs was investigated in the present study.
1. In the animal group admini stered with [¹⁴C-FT]-S-1 repeatedly, the tissue levels of the radioactivity at 24 hr after dosing increased with the number of administered doses, and showed a tendency to reach almost the steady state in all tissues and organs until the 21st dosing. The fat and brown fat showed the greatest increase in the levels, which were 15 times and 11 times higher, respectively, after the 21st dosing than after a single dosing. The increases of the levels in other tissues and organs after the 21st dosing did not exceed 7.4 times compared to the tissue levels after the single dosing. The tissue levels of the radioactivity after the 21st dosing declined slowly when compared to those in the animal group received the single administration (fasted male rats), and the levels of the radioactivity in the fat and femur were 46% and 27% of the maximum levels, respectively, at 504 hr after the 21st dosing. The levels in other tissues were not higher than 17% of the maximum levels.
2. In the animal group ad ministered with [¹⁴C-CDHP]-S-1 repeatedly, the tissue levels of the radioactivity at 24 hr after dosing did not show the increase associated with the number of doses. There was no difference in the tissue levels of the radioactivity at 1 hr post-dose between the animal group received the repeated (21 times) and the animal group received the single administration. The tissue levels in the animal group received repeated administration for 21 times decreased to the levels not exceeding 5% of the maximum levels at 168 hr after the final dosing, although the elimination of the radioactivity from the tissues was slightly slower than that in the animal group received the single dosing.
3. In the animal group administered with [¹⁴C-Oxo]-S-1 repeatedly, almost all of the tissue levels of the radioactivity at 24 hr after dosing increased along with the number of dose, and showed a tendency to further increase after the 21st dosing. The extents of the increase in the tissue levels were large after the first-7th dosing and small after the 14th-21st dosing. The fat and brown fat showed great increase in the levels, which were 16 times and 9.3 times higher, respectively, after the 21st dosing than after the single dosing.
The increases of the level in other tissues and organs after the 21st dosing were not more than 5.3 times compared to the tissue levels after the single dosing. The tissue levels of the radioactivity after the 21st dosing showed a slow elimination compared to those in the animal group received the single dosing, and the level of the radioactivity in the fat was 51% of the maximum level at 336 hr after the 21st dosing. The levels in other tissues were not more than 33% of the maximum levels.

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S-1, a new oral anti-cancer drug, is composed of tegafur (FT), gimestat (CDHP) and potassium otastat (Oxo) in a molar ratio of 1 : 0.4 : 1. FT which is masked compound of 5-fluorouracil (5-FU) plays a role as an effector. Both CDHP and Oxo which do not have anti-tumor activity themselves play roles as modulators.
The feto-placental transfer of the radioactivity and the excretion in the milk were investigated in the present study after administration of [¹⁴C-FT]-S-1, [¹⁴C-CDHP]-S-1 or [14C-Oxo]-S-1 to rats.
1. After administration of [¹⁴C-FT]-S-1 to the pregnant rats on day 12 of gestation, the f etus showed the maximum level of the radioactivity at 1 hr post-dose, accounting for 60% of the level of the radioactivity in maternal plasma. At 24 hr post-dose and thereafter, the levels of the radioactivity in the fetus were slightly higher than the levels in the maternal plasma but were not higher than 12% of the maximum levels. After administration of [¹⁴C-FT]-S-1 to pregnant rats on day 18 of gestation, the levels of the radioactivity in the whole fetus and each fetal tissues showed the maximum levels at 1 hr post-dose, which were 56-49% of the level of the radioactivity in the maternal plasma. At 48 hr post-dose, the levels of the radioactivity in the fetus and fetal tissues were almost same as or 3 times higher than maternal plasma levels but were equal or lower than 14% of the maximum levels. After administration of [¹⁴C-FT]-S-1 to lactating rats, the levels of the radioactivity in the milk showed the maximum level at 15 min post-dose, and decreased thereafter biphasically. At all data points, the levels in the milk were almost same as or lower than the plasma levels determined simultaneously.
2. After administration of [¹⁴C-CDHP]-S-1 to the pregnant rats on day 12 of gestation, the fetus showed the maximum level of the radioactivity at 1 hr post-dose, which was very low and corresponded to 5%of the level of the radioactivity found in maternal plasma. At 48 hr after administration, the level of the radioactivity in the fetus decreased to the level below the detection limit. After administration of [¹⁴C-CDHP]-S-1 to pregnant rats on day 18 of gestation, the levels of the radioactivity in the whole fetus and most of the fetal tissues showed the maximum levels at 1 hr post-dose, however, were very low and corresponded to 10-2 % of the levels of the radioactivity in the maternal plasma. At 48 hr after administration, the levels of the radioactivity in the fetus and fetal tissues decreased to the levels not more than 15% of the maximum levels. After administration of [¹⁴C-CDHP]-S-1 to lactating rats, the level of the radioactivity in the milk showed the maximum level at 1 hr post-dose, continued to stay at almost the same level during a period up to 4 hr post-dose, and decreased thereafter monophasically, reaching the level of the detection limit at 48 hr post-dose. At 4 hr after administration and thereafter, the levels in the milk were higher than the plasma levels determined simultaneously.
3. After administration of [¹⁴C-Oxo]-S-1 to the pregnant rats on day 12 of gestation, the fetus showed the maximum level of the radioactivity at 6 hr post-dose, and, thereafter, the concentrations were similar to the levels of the radioactivity in the maternal plasma during a period up to 48 hr after administration. After administration of [¹⁴C-Oxo]-S-1 to pregnant rats on day 18 of gestation, the levels of the radioactivity in all fetal tissues showed the levels similar to the levels of the radioactivity in the maternal plasma during a period from 6 hr to 24 hr post-dose.......................

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Identification and characterization of polymorphic genes of drug metabolizing enzymes leads the increased understanding of the metabolism to the basis of idiosyncratic adverse reactions and drug resistance. Polymorphisms of N-acetyltransferese (NAT), cytochrome P450 (CYP) 1A2, CYP2D6 and CYP2A6 were investigated in this study. NAT and CYP1A2 were phenotyped by the urinary metabolites of caffeine in Japanese. The genotype of NAT determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method correlated well with the phenotype. CYP1A2 phenotype and a genetic polymorphism in the CYP1A2 gene were comparably investigated. Although some differences of nucleotide sequence were observed in 5'-flanking regions and intron 1, these did not distinguish poor metabolizer (PM) and extensive metabolizer (EM). We analyzed the CYP2D6 gene of a Japanese sparteine PM. We found that the PM possessed a new 9-base insertion in exon 9. This insertion caused a large increase in the apparent Km value for bufuralol 1'-hydroxylation as examined by expression of the enzyme protein in yeast. Six of 556 Japanese carried a heterozygous allele (0.54%) as determined by a PCR analysis. We found that (+)-cis-3, 5-deimethyl-2-(3-pyridyl) thiazolidin-4-one hydrochloride (SM-12502) was a new specific substrate for CYP2A6. From the studies of Sac I-RFLP, cloning and sequencing of CYP2A6gene, the deficiency of in vivo metabolism of SM-12502 was clarified due to the whole gene deletion of CYP2A6. Six of 132 Japanese carried a heterozygous allele of whole deletion type (4.5%) as determined by a PCR analysis.

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It is well known that the oral bioavailability of peptide and protein drugs is generally poor because they are extensively degraded by proteases in the gastrointestinal tract and impermeable through the intestinal mucosa. Consequently, although the clinical administration of peptides is presently limited to administration by injection, such frequent administration subjects the patients to considerable pain, and there is also the possibility of the manifestation of serious side effects. Therefore, various approaches have been examined to overcome the delivery problems of these peptides. These approaches include (1) to use additives such as absorption enhancers and protease inhibitors, (2) to develop an administration method for peptides that can serve as an alternative to oral and injection administration, (3) to modify the molecules of peptide and protein drugs to produce prodrugs and analogues, and (4) to use the dosage forms to these peptide drugs. Of all these approaches, we examined the approaches (1)-(3) and demonstrated that transmucosal absorption of various peptides such as insulin, calcitonin, tetragastrin and thyrotropin releasing hormone (TRH) could be improved by using these approaches. Therefore, these approaches may give us basic information to improve the transmucosal absorption of peptide and protein drugs.

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The population pharmacokinetic analysis is a relatively new approach, which can be used to obtain the pharmacokinetic and/or pharmacodynamic information required to make rational decision about the magnitude of an initial dose for a given patient, and of a subsequent dose if adjustment is needed. The present article reviews our recent effort for population pharmacokinetics, focusing on the analysis of phenytoin disposition. A simulation study was conducted to compare the performance of various models for population analysis of the steady-state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. It was indicated that the usual Michaelis-Menten model generally gives poor estimates of the maximal elimination rate and the Michaelis-Menten constant, and that the one-compartment model with dose-dependent clearance should be considered for estimating population pharmacokinetic parameters. The population pharmacokinetic parameters of phenytoin were estimated using 531 routine therapeutic drug monitoring data from 116 epileptic patients. In addition, we showed that the genetic polymorphism of CYP2C isoenzymes plays an important role in the pharmacokinetic variability of phenytoin. The population pharmacokinetic parameters of phenytoin and the genetic test for CYP2C isoenzymes will be useful in designing dosage regimens and/or in detecting patients at risk for the drug intoxication.

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