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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ラットに³H-CU-83(S)を25μg/kgで静脈内あるいは経口投与し，血液中濃度および尿糞中排泄を検討した．
静脈内投与後の血液中濃度推移は投与後5分より上昇し，投与後45分に25.74ng eq./mlのC_maxを示し，それ以後t_1/2 3.05時間とt_1/2 33.09時間の二相で減少した．投与後72時間までのAUCは135.42ng eq.·hr/mlであった．
経口投与では，投与後3時間でC_max 4.10ng eq./mlに達し，以後t_1/2α 4.46時間とt_1/2β 26.83時間の二相で減少した．投与後72時間までのAUCは48.62ng eq.·hr/mlであった．
静脈内投与と経口投与のいずれの場合も，尿および糞中への放射能の排泄は，投与後48時間でほぼ終了した．静脈内投与では，投与後72時間までに投与量の30.52%が尿中に，60.42%が糞中に排泄された．経口投与では，同じく72時間までに40.34%が尿中に，69.24%が糞中に排泄された．

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妊娠ラットと授乳中の母獣に³H-CU-83を25μg/kg経口投与し，胎盤通過性および乳汁中への移行性を検討した．また，雄ラットに³H-CU-83を25μg/kgで1日1回で7日間あるいは14日間連続経口投与した際の体内動態を単回投与の結果と比較検討した．
妊娠19日の雌ラットに経口投与した時の母獣の組織内放射能濃度で高い値を示したのは肝臓と腎臓であったが，それぞれ血漿中濃度の約2.4倍と約1.9倍であった．胎仔の組織内濃度は投与後6時間に最高値を示したが，いずれも母獣に比べ極めて低い値であり，CU-83およびその代謝物は胎盤を極めて通過しにくいことが示された．
分娩後の授乳ラットに経口投与した場合，乳汁中放射能濃度は投与後2時間に最高値を示し減少した．しかし，血液中濃度と比較して，その濃度比は0.23～0.72と低く，乳汁中への移行は小さいことが明らかとなった．
²H-CU-83を25μg/kgで1日1回，単回投与と7日間あるいは14日間連続経口投与した時の血液中濃度推移，組織分布および尿，糞中排泄を検討した．7日あるいは14日間連続投与の最終投与後の血液中濃度推移は単回投与の結果と差がなかった．毎回投与後24時間の血液中濃度は投与後5日まで上昇し，その後は一定となる傾向を示した．組織内濃度は，単回投与に比べ7日間投与では増加が見られたが，7日間と14日間投与ではほぽ同じ濃度であった．また，尿および糞中への放射能の排泄は，最終投与後24時間までにほぼ終了した．以上より，本化合物の生体への蓄積性は極めて低く，連続投与しても体内に残留しないと考えられる．

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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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