The purpose of the study was to elucidate human intestinal cytochrome P450 isoform(s) involved in the metabolism of an antihistamine, ebastine, having two major pathways of hydroxylation and N-dealkylation. The ebastine dealkylase in human intestinal microsomes was CYP3A4, based on the inhibition studies with antibodies against CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, and CYP3A isoforms and their selective inhibitors. However, ebastine hydroxylase could not be identified. We then examined the inhibitory effects of anti-CYP4F antibody and 17-octadecynoic acid, an inhibitor of the CYP4 family, on ebastine hydroxylation in intestinal microsomes, since CYP4F was recently found to be the predominant ebastine hydroxylase in monkey intestine; and a novel CYP4F isoform (CYP4F12), also capable of hydroxylating ebastine, was found to exist in human intestine. However, the inhibitory effects were only partial (about 20%) and thus it was thought that, although human CYP4F was involved in ebastine hydroxylation, another predominant enzyme exists. Further screening showed that the hydroxylation was inhibited by arachidonic acid. CYP2J2 was selected as a candidate expressed in the intestine and closely related to arachidonic acid metabolism. The catalytic activity of recombinant CYP2J2 was much higher than that of CYP4F12. Anti-CYP2J antibody inhibited the hydroxylation to about 70% in human intestinal microsomes. These results demonstrate that CYP2J2 is the predominant ebastine hydroxylase in human intestinal microsomes. Thus, the present paper for the first time indicates that, in human intestinal microsomes, both CYP2J and CYP4F subfamilies not only metabolize endogenous substrates but also are involved in the drug metabolism. Ebastine is a potent nonsedative H 1 -receptor antagonist (Fig. 1), and after oral administration to experimental animals and humans, the agent is almost completely metabolized to the pharmacologically active principle, the carboxylated metabolite (carebastine), and other inactive metabolites Matsuda et al., 1994;Yamaguchi et al., 1994). Carebastine alone was the major metabolite detectable in the blood. Our previous in situ studies using rats indicated that the small intestine extensively converted the orally given ebastine to carebastine via hydroxylated ebastine and the dealkylated metabolite (Fujii et al., 1997). Therefore, it seemed that small intestine plays an important role in the first-pass metabolism of this drug, and the enzymes responsible for its metabolism exist there.We reported that ebastine was primarily metabolized by human liver microsomes to two metabolites, hydroxy-and desalkyl-ebastine (Hashizume et al., 1998). N-Dealkylation to desalkyl-ebastine was mediated by CYP3A4, whereas hydroxylation to hydroxy-ebastine, the most important intermediate metabolite yielding carebastine, was mediated by unidentified P450(s) other than CYP3A4. Our recent studies revealed that two novel CYP4F isoforms (P450 MI-2 and CYP4F12) obtained from monkey and human small intestine, respectively, were ...

Polycrystalline BiFeO 3 ͑BFO͒, Ti-doped BFO, Mn-doped BFO, and ͑Mn, Ti͒-codoped BFO ͑BFMT͒ thin films were fabricated on Pt/ SrTiO 3 ͑100͒ substrate by pulsed laser deposition. Observed leakage current behavior in those ion-doped BFO films indicated the dominance of space-charge-limited current in the high electric field region. The leakage current of the BFMT film was much reduced in relation to the other films due to the formation of deep traps. In the BFMT film, well saturated P-E hysteresis curves were observed. Remanent polarization and coercive field for maximum electric field of 2100 kV/cm were 75 C / cm 2 and 310 kV/cm, respectively. © 2009 American Institute of Physics. ͓DOI: 10.1063/1.3098408͔ Excellent ferro-/piezoelectric properties have been reported in the BiFeO 3 ͑BFO͒ thin films comparable to those of Pb͑Zr x Ti 1−x ͒O 3 , 1-3 and thus the BFO is expected as an alternative Pb-free ferro-/piezoelectric material. However, the large leakage current of BFO thin films at room temperature ͑RT͒ is known to be a serious problem, which could limit the various applications of this material.In the past several years, site-engineering technique by substitution of small amount of impurities was proposed to solve this problem, and reduced leakage current properties were reported. [4][5][6][7][8][9][10][11]15 The site-engineering technique is quite important from industrial aspects because this technique can be applied to most deposition methods. However, it is not easy to reduce the leakage current of BFO films by a single ion-doping method since the excess substitution causes an increase in leakage current in the films. 6,7 Besides, modification of electrical properties of BFO films by ion doping at Bi site is quite difficult because of the degradations in ferroelectric properties, although rare-earth elements doped at Bi site is effective to reduce the impurity phases due to bismuth and oxygen vacancies. 5,8,9 Therefore, we propose a new combination of Mn and Ti as codoping elements for Fe site of BFO thin films. In this work, we report the synthesis and characterization of ͑Mn, Ti͒-codoped BFO ͑BFMT͒ thin films by comparing with those of pure BFO, Ti-doped BFO ͑BFT͒, and Mn-doped BFO ͑BFM͒ thin films. Moreover, it is required to reduce the leakage current of BFO films in the high electric field region ͑at least more than 400 kV/cm͒ since coercive electric fields of BFO film capacitors are generally 300-500 kV/cm. Hence, we also discuss the change in conduction mechanism in the high electric field region by ion doping in the BFO thin films.BFO, BFT, BFM, and BFMT thin films were deposited on Pt-coated ͑100͒ SrTiO 3 ͑STO͒ substrates with thicknesses ranging from 220 to 240 nm, using a conventional pulsed laser deposition ͑PLD͒ system. The ceramic targets with metal compositions of Bi 1.1 FeO 3 , Bi͑Fe 0.98 Ti 0.02 ͒O 3 , Bi 1.1 ͑Fe 0.97 Mn 0.03 ͒O 3 , and Bi͑Fe 0.95 Mn 0.03 Ti 0.02 ͒O 3 were used for deposition of BFO, BFT, BFM, and BNFM films, respectively. The details of thin film fabrication were described...

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Our results indicate that more than 10% of the dogs studied were CYP1A2-null. Because CYP1A2-null phenotype in dogs affects the results of pharmacokinetic, toxicological and pharmacological studies of drug candidates, these findings are important in the pharmaceutical and the veterinary fields.

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