β-Cyclodextrin (β-CyD), heptakis (2, 6-di-O-methyl)-β-CyD (DM-β-CyD) and 2-hydroxypropyl-β-CyD (HP-β-CyD, substitution degree 4.3) were found to alleviate the phototoxic contact dermatitis induced by chlorpromazine hydrochloride (CPZ), a typical antipsychotic agent, in dorsal skin of guinea pigs. The inhibitory effect of CyDs was in the following order DM-β-CyD>β-CyD>HP-β-CyD, depending on the magnitude of the stability constants of CPZ-CyD complexes. The percutaneous absorption of CPZ was inhibited particularly by DM-β-CyD. The photoreaction pathway of CPZ in the skin was changed by CyDs, i.e. less toxic promazine was predominantly produced in the presence of CyDs (DM-β-CyD≥β-CyD>HP-β-CyD).
The results indicate that the alleviative effects of CyDs may be attributable to the reduction of percutaneous absorption of CPZ and the alternation in phototoxic reaction pathway of CPZ through inclusion complexation.

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The studies on the mechanism of pharmacokinetic interaction of aluminum hydroxide with new quinolones, ofloxacin, enoxacin and norfloxacin, were performed in rats. New quinolones (20 mg/kg) were administered orally with or without aluminum hydroxide or aluminum chloride (50 mg/kg). Co-administration of aluminum hydroxide induced a significant decrease in C_max of enoxacin and norfloxacin, and in the AUC values of the three drugs. This effect was enhanced by co-administration of aluminum chloride. The combination of aluminum hydroxide caused a significant increase in the intestinal contents and decrease in urinary excretion of new quinolones. The formation of the stable chelate of new quinolones with Al³⁺ ions formed from aluminum hydroxide in the same acidic solution as gastric juice was observed. Thus, it is concluded that the co-administration of aluminum hydroxide affects the pharmacokinetics of new quinolones, probably, by the inhibition of the intestinal absorption of new quinolones by the chelate formation of these compounds with Al³⁺ ions released from aluminum hydroxide in the gastric juice.

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Mexazolam, a benzodiazepinooxazole-anxiolytic, was first N-dealkylated to M₁ and then hydroxylated to lorazepam in rat liver microsomes. The production of M₁ in vitro was inhibited by SKF-525 A, carbon monoxide and in the atmosphere of nitrogen. The heat-treated microsomes, the omission of an NADPH-generating system and the substitution of NADPH with NADH showed practically no activity. The microsomes obtained from the phenobarbital treated rats showed increased activity toward both the production of M₁ and lorazepam from mexazolam, but the clofibrate and 3-methylcholanthrene treatments failed to induce this activity. Cimetidine inhibited non-competitively both steps in the metabolism of mexazolam: mexazolam to M₁ (K_i: 375 μM) and M₁ to lorazepam (K_i: 390 μM). Ranitidine did not inhibit in vitro metabolism of mexazolam at the concentrations so far investigated ( ?? 400 μM). The pretreatment of rats with cimetidine (200 mg/kg, i.p.) 30 min prior to the administration of mexazolam (50 mg/kg, i.p.), increased AUC and the plasma half-life of mexazolam 8.8-fold and 7.7-fold, respectively. On the other hand, the co-administration of ranitidine did not change the pharmacokinetic parameters of mexazolam.

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Nabumetone, a new anti-inflammatory drug, was studied in six healthy male volunteers to evaluate its steady-state pharmacokinetics after oral dosing. The subjects were given a single dose of 800 mg, followed by 800 mg once a day for seven days after a washout period of two weeks.
The plasma (or serum) and urinary concentrations of nabumetone, and its metabolites BRL 10720 or BRL 18725 were determined by high performance liquid chromatography.
Nabumetone was extensively metabolized mainly to its active form BRL 10720 after oral dosing. The pharmacokinetics of BRL 10720 were well described by one-compartment model with first-order input. The plasma concentrations of BRL 10720 reached steady state by the fourth day of multiple dosing with 1.52 times accumulation of trough concentration and declined with a half-life of 19.2 hours after the last dose. The mean plasma concentration at steady state was 34.9 μg/ml. The AUC from time zero to 24 hours at the steady state was 26.6 % lower than the AUC from time zero to infinity after single dosing. BRL 10720 was extensively bound to serum proteins with range from 99.75 to 99.91 % in a concentration-dependent manner.
The plasma concentrations of nabumetone and BRL 18725 were very low and were about 1/1500 times or less than that of BRL 10720.
Urinary excretion of BRL 10720 was very small and 2.32 % of the dose was recovered in 72 hours after single dosing, while 25.6 % of the dose as the total amount of BRL 10720 and its conjugated form. Only negligible amounts of nabumetone were excreted in the urine.
Nabumetone was well tolerated by all subjects. Clinically significant adverse effects were not observed.

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The effect of phenylbutazone on the serum protein binding and disposition of sulfadimethoxine (SDM) was investigated in the human and rabbit.
1. When SDM and phenylbutazone were co-administered, phenylbutazone considerably reduced the in vivo binding of SDM to rabbit serum. However, the co-administration of phenylbutazone had little effect on the in vivo binding of SDM to human serum.
2. N⁴-Acetylsulfadimethoxine (N⁴-AcSDM), a major metabolite of SDM, reduced the in vitro binding of SDM to rabbit serum, but did not affect the in vitro binding of SDM to human serum. In the rabbit, the serum concentration of N⁴-AcSDM was clearly enhanced by the co-administration of phenylbutazone. Furthermore, phenylbutazone did not cause the reduction in both the in vitro bindings of SDM to human and rabbit serum. These findings indicated that in the case of rabbit, phenylbutazone indirectly reduced the in vivo binding of SDM to serum through the displacing effect of N⁴-AcSDM.
3. The co-administration of phenylbutazone, as expected, significantly increased the total body clearance and steady-state volume of distribution of SDM in the rabbit, but did not in the human.

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The metabolites of nabumetone, a new nonsteroidal anti-inflammatory agent, were identified in rats. Urine from rats dosed orally with nabumetone was hydrolysed with a mixture of β-glucuronidase and arylsulfatase and extracted with ethyl acetate. Sixteen metabolites were isolated by HPLC and TLC from urine extracts and then structual analysis was carried out using IR, NMR and mass spectrometry. The results showed that nabumetone was metabolized by various reactions involving demethylation of the methoxy group, reduction of the ketone group, hydroxylation of the alkyl side chain and cleavage of the C-C bond. A major urinary metabolite was 6-hydroxy-2-naphthylacetic acid (M-I), and minor metabolites were 2, 3-dihydroxy-4-(6-hydroxy-2-naphthyl)butan-4-one (M-XII), 6-hydroxy-2-naphthoic acid (M-XIII) and 3-(6-hydroxy-2-naphthyl)propionic acid (M-XV), accounted for 32.4, 7.4, 5.9, and 2.9 % of the administered dose, respectively, which were predominantly excreted as conjugates. Identified metabolites accounted for about 55 % of the dose.

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15(R)-15-Methylprostaglandin E₂ (CU-83) is converted to its epimer (CU-83(S)) in gastric acid after oral administration. In this study, the blood level and excretion of radioactivity were investigated in rats after intravenous and oral administration of ³H-CU-83(S) at a dose of 25 μg/kg.
After intravenous dosing, the peak blood concentration of radioactivity, of 25.74 ng eq./ml, was observed at 45 min. Thereafter, the concentrations of radioactivity area under the blood concentration-time curve (AUC) during 72 hr period after the dosing was 135.42 ng eq.·hr/ml. After oral dosing, the maximum concentration of radioactivity in blood was 4.10 ng eq./ml at 3 hr and then declined bi-exponentially with the following half-lives of 4.46 and 26.83 hr. AUC was 48.62 ng eq.·hr/ml for 72 hr.
After intravenous dosing, excretion of radioactivity was 30.52 % of the dose in urine and 60.42 % in feces during 72 hr. After oral dosing, excretion of radioactivity was 40.34 % in urine and 69.24 % in feces within 72 hr.

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The distribution of radioactivity in the fetus and the excretion to the milk was studied following oral administration of ³H-15(R)-15-methylprostaglandin E₂ (³H-CU-83) at a dose of 25 μg/kg to pregnant or lactating rats. The blood concentration, tissue accumulation and excretion of radioactivity were also examined during and after repeated oral administration of the compound at the same dose to male rats for 7 and 14 days.
After oral administration to pregnant rats, very low radioactivity was detected in the tissues of fetus on day 19 of gestation. The blood level of radioactivity in the fetus was also lower than the maternal blood level and its ratio was about 0.08 times at 6 hr after administration.
The radioactivity in milk reached the maximum level 2 hr after oral administration to lactating rats but was 0.23-0.72 times in comparison to that in the maternal blood level.
The maximum blood concentration (Cmax) and the area under the blood concentration-time curve (AUC) for 24 hour period after single and final dosing of the 7 th and 14 th repeated administration were 3.17 ng eq./ml and 40.03 ng eq.·hr/ml, 3.41 ng eq./ml and 45.69 ng eq.·hr/ml and 2.97 ng eq./ml and 46.91 ng eq.·hr/ml, respectively. The concentrations of radioactivity in the plasma, blood and tissues after 7 th repeated administration of ³H-CU-83 were slightly higher than those after the single administration. The concentrations in the tissues after 14 th repeated administrations were similar to those after the 7 th repeated.
Excretion of radioactivity in urine and feces was almost constant during 14 th repeated administration and was almost completed within 24 hr after the final administration.

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Since chemical structures of peroxisome proliferators are so much versatile, it has been difficult to identify the essential chemical form required for the induction of peroxisome proliferation. From the fact that perfluorinated fatty acids (C 10, C 8 and C 4), the un-metabolizable derivatives of fatty acids, induced the peroxisome proliferation markedly in rat liver, the free fatty acids were considered as the true inducer. Perfluoroalkanes (C 12 and C 8) which possess no functional groups did not show any inducing activity, supporting this concept. Although the CoA form of fatty acids have been claimed as the intrinsic form for the peroxisome proliferator, this possibility should be negligible because perfluorooctane sulphonate, another unmetabolizable compound which is never converted into CoA form, induced the peroxisome proliferation. From these results, we have come to the conclution that the un-metabolizable lipophilic anion is the essential chemical structure common in the peroxisome proliferators. All of the known peroxisome proliferators are included into this category, as such or after receiving metabolism.

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Attempts to explore the structural basis for functions of cytochrome P-450 at the DNA level were outlined briefly and, as an example of such approaches, our studies on laurate (ω-1)-hydroxylase (P-450(ω-1)) were described. P-450(ω-1) exhibits 81 % similarity in the primary structure to testosterone 16 α-hydroxylase. Chimeras of the both P-450s were synthesized in yeast cells transformed with plasmids constructed for expression of chimeric P-450 cDNAs and their spectral and catalytic properties were examined. The region spanning about 50 residues is essential to the binding of substrates (laurate and caprate) for P-450(ω-1) was found. In addition to the sequence enough to bind the substrates, the segment of about 35 residues is necessery for the hydroxylase activity. Threonine-301 of P-450(ω-1), which is highly conserved in all P-450s and located at the distal heme surface trans to the thiolate ligand, was substituted by His, Val, Ser or Ala via site-directed mutagenesis. The addition of the fatty acids to ferric P-450(ω-1) induced spectral change ascribable to the bindig of substrates in the Val-or Ser-mutant as well as the wild-type P-450 but did not in the His-or Ala-mutant. These mutants were also devoid of the hydroxylase activity. On the other hand, substrate specificity of P-450(ω-1) was altered by substitution of Val or Ser for Thr-301. These findings indicate that residues (or atoms) at the γ-position of the amino acid-301 is important to the substrate interaction.

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