Oxatomide is an antiallergic drug used to treat diseases mainly mediated by type I allergic reaction. The drug is widely applied to skin diseases including chronic urticaria, 1) skin itching 2) and atopic dermatitis, 3) allergic rhinitis 4) and bronchial asthma 5) in the clinical field. Pharmacological studies have demonstrated that oxatomide acts as an antagonist for various chemical mediators such as histamine, leukotriene and platelet-activating factor, as well as inhibits the release of these substances, and that all these actions contribute to the therapeutic effects of the drug. [6][7][8] It has been reported that terfenadine and astemizole, which have antiallergic effects similar to those of oxatomide, have side effects on the cardiovascular system, such as QT prolongation, ventricular arrhythmia and cardiac arrest. [9][10][11][12][13][14] It is well known that drugs taken into organisms are transformed to metabolites, and that the major organ responsible for degrading such drugs is the liver, where there are a large number of enzymes involved in drug metabolism.15) Among them are a family of cytochrome P450 (CYP), which greatly contribute to drug metabolism, showing variable isoform expression in the liver microsomes. Terfenadine 16,17) and astemizole 18) have been demonstrated to be metabolized mainly by two P450 isoforms, CYP2D6 and CYP3A4, the latter of which is known to be responsible for the metabolism of various drugs, including steroids (testosterone, estradiol, etc.), antibiotics (erythromycin, cyclosporin, etc.), plant alkaloids (lovastatin, benzphetamine, etc.) and quinidine, 19) and to be markedly inhibited by azole antifungal agents such as itraconazole and ketoconazole. 20) When itraconazole or ketoconazole is orally administered together with terfenadine or astemizole, drug interaction occurs, and the blood concentration of terfenadine or astemizole is increased, resulting in severe side effects. [21][22][23][24] Although oxatomide is also antiallergic and shares a common partial chemical structure with terfenadine and astemizole, as shown in Fig. 1, there has been no report of the side effects of the drug on the cardiovascular system. However, it has been reported that extrapyramidal disorder is rarely induced by oxatomide, 25) suggesting the possibility of side effects relating to extrapyramidal symptoms, if oxatomide undergoes a drug interaction. Nevertheless, there has been no available information on drug interaction of oxatomide, which leads to side effects, or on isoforms Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd.; 1188 Shimotogari, Nagaizumicho, Suntogun, Shizuoka 411-8731, Japan: b ADME and TOX Research Institute, Daiichi Pure Chemicals Co., Ltd.; 2117 Muramatsu, Tokiai, Ibaraki 319-1182, Japan: and c Department of Pharmacy, Kyorin University Hospital; 6-30-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan. Received October 16, 2003; accepted January 19, 2004 Oxatomide is an antiallergic drug used for the treatment of diseases mediated by type I allergy. Recent...
Oxatomide is an antiallergic drug used for the treatment of diseases mainly mediated by a type I allergic reaction. Pharmacological studies have demonstrated that oxatomide acts as an antagonist for various chemical mediators such as histamine, leukotriene and platelet-activating factor, as well as inhibits the release of these substances, and that all these actions contribute to therapeutic effects of the drug.1-3) Oxatomide is widely applied to skin diseases, including chronic urticaria, 4) skin itching, 5) atopic dermatitis, 6) allergic rhinitis 7) and bronchial asthma 8) in the clinical field. In a previous article, we showed that the P450 isoforms responsible for the metabolism of oxatomide were cytochrome P450 2D6 (CYP2D6) and CYP3A4, using microsome preparations of the in vitro expression systems derived from a human lymphoblastoid cell line. 9) We also demonstrated that oxatomide inhibited the enzyme activity of CPY2D6-Val and CYP3A4 in a dose-dependent manner, using model substrates for these isoforms. A similar action has been reported for the antiallergic drugs, terfenadine and astemizole, which inhibit both CYP2D6-Val and CYP3A4. [10][11][12] It has been shown that terfenadine and astemizole have side effects on the cardiovascular system, such as QT prolongation, ventricular arrhythmia and cardiac arrest. [13][14][15][16][17][18] Since the principal metabolic pathway for the two drugs is mediated by CYP3A4, the blood concentration of the drugs is increased when CYP3A4 is strongly inhibited by concomitant drugs such as itraconazole and ketoconazole. [19][20][21][22] On the other hand, there has been no report of side effects of oxatomide on the cardiovascular system, such as QT prolongation, but the drug has been shown to induce catalepsy at high doses in experimental animals, 23) and infrequently to cause extrapyramidal disorder by clinical usage. 24) Our results in the former article raised the possibility that oxatomide might inhibit the same enzymes as those inhibited by terfenadine and astemizole, which suggests we should investigate the mode of action of oxatomide in greater detail. Therefore, to clarify whether oxatomide brings about any drug interaction or is affected by the interaction, we examined kinetic parameters (K m and V max ) for the oxatomide metabolism and inhibition constants (K i ) of oxatomide in metabolism of the model substrates for CYP2D6 and CYP3A4, and possible drug interaction is discussed. MATERIALS AND METHODS ReagentsOxatomide and 3Ј-ethyloxatomide were synthesized at Kyowa Hakko Kogyo Co., Ltd. b-NAD ϩ , b-NADP ϩ , glucose-6-phosphate, and glucose-6-phosphate dehydrogenase were purchased from Oriental Yeast Co., Ltd.; MgCl 2 , from Wako Pure Chemicals Industries, Ltd.; a-naphthoflavone, sulfaphenazole, tranylcypromine hydrochloride, quinidine and alprenolol hydrochloride, from Sigma Chemical Co.; 6b-hydroxytestosterone, from Ultrafine Chemicals; (Ϯ)-bufuralol hydrochloride and 1Ј-hydroxybufuralol maleate, from Gentest; testosterone and phenacetin, from Nacalai Tesque, I...
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