Identification of Human P450 Isoforms Involved in the Metabolism of the Antiallergic Drug, Oxatomide, and Its Inhibitory Effect on Enzyme Activity

Abstract

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...

Identification of Human P450 Isoforms Involved in the Metabolism of the Antiallergic Drug, Oxatomide, and Its Kinetic Parameters and Inhibition Constants

“…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.…”

“…The result of quinidine was unexpected, considering that our previous result showed that bufuralol metabolism was inhibited by oxatomide. 9) From these results, oxatomide might be metabolized by CYP2D6 at a different site from the quinidine binding site. In addition, the K m value of the microsomes for oxatomide metabolism was 26.1 mM.…”

“…9) These results suggested that more detailed examinations should be investigated using human liver microsmes to evaluate the metabolic activity and K i value of oxatomide regarding CYP2D6 and CYP3A4.…”

Development and Validation of an In Silico P450 Profiler Based on Pharmacophore Models

“…To test the ability of this pharmacophore collection to predict the in vitro pharmacokinetic profile of new compounds, 17 substances with known P450-mediated metabolism (Table 22) [77,115,125,137,138] were submitted to database search by all general inhibitors and substrates models as well as the general model for promiscuous P450 Using the Best Flexible Search algorithm of Catalyst, a database consisting of these 17 compounds was searched. For the identification of P450 inhibitors, the qualitative general inhibitors models were used.…”

Inflammation and neurological adverse drugs reactions: a case of long lasting impaired consciousness after oxatomide administration in a patient with gastroenteritis

“…Studies in neutrophils have also shown that it inhibits arachidonic acid mobilization, and the synthesis of leukotriene B4 and platelet-activating factor, possibly by reducing the activities of cytosolic phospholipase A2 [1]. Studies in human liver microsomes [2] have shown that oxatomide is mainly metabolized by cytochromes 3A4 (CYP3A4) and 2D6 (CYP2D6), two enzymes encoded by highly polymorphic genes [3,4]…”