The results of in vitro studies indicated that ARIPIPRAZOLE, a newly developed antipsychotic, is mainly metabolized by the human cytochrome P450 isozymes CYP3A4 and CYP2D6. The objective of the present study was to investigate the influence of itraconazole (hereafter referred to as ITZ) co-administration (CYP3A4 inhibition) on the pharmacokinetics of ARIPIPRAZOLE administered to 24 healthy adult male volunteers in a fasting condition. The influence of CYP3A4 inhibition was also examined by CYP2D6 genotype. All subjects were administered a single oral dose of ARIPIPRAZOLE alone in Period I and a single oral dose of ARIPIPRAZOLE following administration of ITZ at 100 mg/day for 7 consecutive days in Period II. The pharmacokinetic parameters of ARIPIPRAZOLE and its main metabolite OPC-14857 were determined. Co-administration of ITZ increased the Cmax, AUC336 hr, and t1/2,z of ARIPIPRAZOLE and OPC-14857 by 19.4%, 48.0%, and 18.6% and by 18.6%, 38.8%, and 53.4%, respectively. By co-administration of ITZ, the CL/F of ARIPIPRAZOLE in extensive metabolizers was decreased by 26.6%, with an even greater decrease (47.3%) in intermediate metabolizers. For the co-administration period, the CL/F of ARIPIPRAZOLE in intermediate metabolizers was about half of that in extensive metabolizers. For Cmax, there was no significant difference between extensive metabolizers and intermediate metabolizers, and the percent change by co-administration of ITZ was less than 20% in both extensive metabolizers and intermediate metabolizers. For OPC-14857, the t(max) in intermediate metabolizers was longer than that in extensive metabolizers, with the difference being amplified by co-administration of ITZ. The AUC336 hr showed similar increases by co-administration of ITZ in all genotypes. The urinary 6beta-hydroxycortisol/cortisol concentration ratio following ITZ administration for 7 consecutive days was about half of that before the start of ITZ administration, indicating that CYP3A4 metabolic activity was inhibited by administration of ITZ. The influence of CYP3A4 inhibition on the pharmacokinetics of ARIPIPRAZOLE was not considered to be clinically significant. On the other hand, definite differences in pharmacokinetics were observed between CYP2D6 genotypes.
Aims To identify the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) isoforms responsible for the formation of the primary metabolite(s) of zaltoprofen, and to predict possible drug interactions by investigating the inhibition of CYP isoforms in vitro . Methods The metabolism of zaltoprofen was studied in vitro using recombinant CYP and UGT isoform cDNA-expression systems. The effects of selective isoform inhibitors on zaltoprofen metabolism were studied using human liver microsomes. The inhibitory effects of zaltoprofen on the metabolism of selective probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 were also determined in human liver microsomes. Results Zaltoprofen was extensively metabolized by CYP2C9 and UGT2B7. CYP2C9 catalysed sulphoxidation but not hydroxylation of zaltoprofen. In the human liver microsomal metabolism study, zaltoprofen metabolism was markedly inhibited by sulphaphenazole, a selective inhibitor of CYP2C9. In the drug interaction study, negligible inhibition ( < 15%) of the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 was apparent at 5 µ g ml − 1 , the maximum plasma concentration observed in humans after oral administration of an 80 mg zaltoprofen tablet. However, zaltoprofen inhibited CYP2C9 by 26% at 5 µ g ml − 1 . At higher concentrations, zaltoprofen produced some inhibition of CYP2C9 (I C 50 = 19.2 µ g ml − 1 ; 64.4 µ M ) and CYP3A4 (I C 50 = 53.9 µ g ml − 1 ; 181 µ M ). The free drug concentrations in plasma (0.02 µ g ml − 1 , 67.0 n M ) at the C max of the clinically effective doses are much lower than the I C 50 values corrected for the nonspecific binding ratio of zaltoprofen to microsomal protein (15.5 µ g ml − 1 for CYP3A4, 49.5 µ g ml − 1 for CYP3A4). Furthermore, the maximum free drug concentrations in the hepatic intracellular was calculated to be 0.068 µ g ml − 1 and the increase in the AUC in the presence of zaltoprofen was estimated to be only 0.4% for CYP2C9 substrates and 0.1% for CYP3A4 substrates, respectively. Conclusions Zaltoprofen is predominantly metabolized by CYP2C9 and UGT2B7, and is considered unlikely to cause significant drug interactions in vivo when coadministered with CYP substrates at clinically effective doses.Keywords: CYP2C9, human liver microsomes, in vitro metabolism, UGT2B7, zaltoprofen S. Furuta et al. 296
A new liquid chromatographic/mass spectrometric assay has been developed for the determination of DX-8951, a new anti-tumor drug, and its 4-hydroxymethyl metabolite (UM-1) in human plasma and urine. Solid-phase extractions were used for sample preparation. A gradient reverse-phase HPLC separation was developed with mobile phases consisting of trifluoroacetic acid and methanol. The detection was conducted using atmospheric pressure chemical ionization tandem mass spectrometry in the selected reaction monitoring mode. A structural analog, camptothecin (CPT), was used as the internal standard. The assay was validated for the determination of DX-8951 and UM-1 in human plasma and urine. The lower limits of quantitation of DX-8951 and UM-1 were 0.1 ng/mL in plasma and 1 ng/mL in urine. The method showed a satisfactory sensitivity, precision, accuracy, recovery and selectivity.
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...
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