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DMD #44271 in Vitro Evaluation of the Interaction Potential Of DMD Fast Forward. Published on March 26, 2012 as DOI: 10.1124/dmd.111.044271 DMD FastThis article Forward. has not beenPublished copyedited on and March formatted. 26, The 2012 final version as doi:10.1124/dmd.111.044271 may differ from this version. DMD #44271 In Vitro Evaluation of the Interaction Potential of Irosustat with Drug Metabolizing Enzymes. Verònica Ventura, Josep Solà, Concepción Peraire, Françoise Brée and Rosendo Obach. Ipsen Pharma, S.A. Pharmacokinetics and Drug Metabolism Department. Sant Feliu de Llobregat, Barcelona, Spain. (V.V., J.S., C.P., R.O.) Downloaded from Xenoblis. Parc d’Affaires de la Bretèche. Saint Grégoire, France (F.B.) dmd.aspetjournals.org at ASPET Journals on October 1, 2021 1 Copyright 2012 by the American Society for Pharmacology and Experimental Therapeutics. DMD Fast Forward. Published on March 26, 2012 as DOI: 10.1124/dmd.111.044271 This article has not been copyedited and formatted. The final version may differ from this version. DMD #44271 Running Title: Metabolic drug-drug interactions of Irosustat Corresponding Author: Josep Solà (e-mail: [email protected]) Ipsen Pharma S.A. Crta. Laureà Miró, 395. 08980 Sant Feliu del Llobregat. Barcelona. Spain Telephone: +34 93 685 81 00 / Fax: +34 93 685 10 53 Downloaded from Number of text pages: 46 (including references and tables) Tables: 7 dmd.aspetjournals.org Figures: 3 References: 37 at ASPET Journals on October 1, 2021 Abstract: 250 Introduction: 746 Discussion: 1490 Nonstandard abbreviations used are: AI, aromatase inhibitor; Cmax,ss, maximum plasma concentration at steady state; CT, threshold cycle; DDI, drug-drug interaction; HLM, human liver microsomes; HPLC, high performance liquid chromatography; P450, cytochrome P450; PCR, polymerase chain reaction; RT, reverse transcription; STS, steroid sulfatase; TDI, time-dependent inhibition; UGT, UDP glucuronosyltransferase; 2 DMD Fast Forward. Published on March 26, 2012 as DOI: 10.1124/dmd.111.044271 This article has not been copyedited and formatted. The final version may differ from this version. DMD #44271 Abstract Irosustat is a first-generation irreversible steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitant medications, the inhibition/induction potential of irosustat on the main drug metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors on the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in Downloaded from human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive showing a Ki of 0.77 µM, a concentration exceeding only by 5-fold the highest steady state maximum dmd.aspetjournals.org concentration of 667-coumarin in human plasma at the irosustat recommended dose. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Consequently, further clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. at ASPET Journals on October 1, 2021 667-coumarin also appeared as a competitive inhibitor of CYP2C19 (Ki = 5.8 µM) in human liver microsomes, and this inhibition increased when assessed in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 and UGTs 1A1, 1A4 and 2B7 activities, nor induced CYP1A2, 2C9, 2C19 or 3A4/5 at clinically relevant concentrations. Finally, results in human liver microsomes indicate that no changes in irosustat pharmacokinetics are expected in vivo resulting from inhibition of irosustat metabolism in case of concomitant medication or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole or exemestane. 3 DMD Fast Forward. Published on March 26, 2012 as DOI: 10.1124/dmd.111.044271 This article has not been copyedited and formatted. The final version may differ from this version. DMD #44271 Introduction Irosustat, (BN83495, 667 COUMATE, STX64), is a first-generation irreversible steroid sulfatase (STS) inhibitor for hormone-dependent cancer therapy. STS catalyzes the formation of estrone and dehydroepiandrosterone from their sulfate conjugates. Both compounds are further converted by 17β-hydroxysteroid dehydrogenase type 1 to estradiol and androstenediol, respectively, which are described to promote tumour growth (Reed et al., 2005; Foster, 2008). Downloaded from STS and aromatase are considered as the key enzymes in the two main pathways of estrogen synthesis in peripheral tissues of postmenopausal women, where estrogens are formed exclusively, and in whom breast cancer most frequently occurs. While the aromatase pathway is dmd.aspetjournals.org already targeted in breast cancer treatment by widely prescribed aromatase inhibitors (AIs) such as letrozole, anastrozole, and exemestane (Mouridsen et al., 2003; Nabholtz et al., 2003; Paridaens et al., 2003), increasing amounts of evidence support the role of STS as an important at ASPET Journals on October 1, 2021 source of estrogens. STS activity is higher than aromatase activity in normal and malignant breast tissue (James et al., 1987), and the origin of estradiol in breast cancer tissue has been described to be predominantly estrone sulfate (Santner et al,. 1984). Besides, STS expression is an important prognostic factor in human breast carcinoma (Suzuki et al,. 2003). Irosustat inhibits STS activity in vitro and in vivo in tumour bearing rodents (Woo et al., 2000; Foster et al., 2006), in which regression of mammary tumours has been also demonstrated (Purohit et al., 2000). Also, irosustat is the first STS inhibitor tested in phase I clinical trials in postmenopausal women with advanced metastatic hormone-dependent breast cancer (Stanway et al., 2006). Irosustat structure is a tricyclic coumarin-based sulfamate, and the presence of the sulfamoyl-ester group is indispensable for its STS inhibitory activity (Figure 1). Irosustat 4 DMD Fast Forward. Published on March 26, 2012 as DOI: 10.1124/dmd.111.044271 This article has not been copyedited and formatted. The final version may differ from this version. DMD #44271 undergoes spontaneous desulfamoylation at physiologic pH (Ireson et al., 2003) and also as a result of its mechanism of inhibition of STS (Woo et al., 2000), leading to the formation of its main degradation product and metabolite, 667-coumarin. Data from clinical trials indicate that the mean steady state maximum plasma concentrations (Cmax, ss) of irosustat and 667-coumarin are around 0.23 µM (range 0.05-0.41 µM) and 0.08 µM (range 0.02-0.15 µM), respectively, following 40 mg daily irosustat oral doses (recommended dose). Both compounds are highly bound to plasma proteins. Irosustat and 667-coumarin plasma free fractions are 1.3 and 1.1%, Downloaded from respectively (unpublished data). Previous metabolism studies (Ventura et al., 2011) revealed that irosustat and 667- dmd.aspetjournals.org coumarin are primarily metabolized towards different hydroxylated derivatives in liver microsomes from preclinical species and humans. These metabolites and also 667-coumarin are further conjugated with sulfate and/or glucuronic acid (Figure 1). The human enzymes at ASPET Journals on October 1, 2021 responsible of the primary transformation of irosustat are the cytochrome P450 enzymes (P450s): CYP2C8, CYP2C9, CYP3A4/5, and to a lesser extent, CYP2E1. A minor contribution of CYP1A2 and CYP2C19 may not be fully excluded. The formation of most of the primary metabolites can be catalyzed by two or more P450 enzymes, meaning that compensatory mechanisms in irosustat metabolism are likely to occur in vivo, minimizing the risk of interactions due to P450 inhibition by co-administered drugs or dietary constituents. The aim of the present work was to investigate the inhibition/induction potential of irosustat on drug metabolizing enzymes in order to predict drug-drug interactions (DDIs) between irosustat and possible concomitant medications in the clinical setting (Pelkonen et al., 1998; Weaver, 2001). The inhibition experiments were performed on the nine major human drug metabolizing P450s: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, 5 DMD Fast Forward. Published on March 26, 2012 as DOI: 10.1124/dmd.111.044271 This article has not been copyedited and formatted. The final version may differ from this version. DMD #44271 CYP2E1, and CYP3A4/5, using human liver microsomes (HLM) and P450 probe substrates. The potential inhibitory effect of irosustat on the three main UDP glucuronosyltransferase (UGT) enzymes involved in drug metabolism: UGT1A1, UGT1A4, and UGT2B7 (Williams et al., 2004) was also studied using recombinant enzymes. Finally, the induction potential of irosustat on the four major inducible human P450s: CYP1A2, CYP2C9, CYP2C19, and CYP3A4/5, was assessed in human hepatocytes. Because AIs are potential medications for combined therapy with irosustat (Woo et al., Downloaded from 2011), the prediction of possible interactions between AIs and irosustat was assessed specifically for letrozole, anastrozole, and exemestane. From published data, letrozole inhibits CYP2C19 dmd.aspetjournals.org activity (Ki = 42.2 µM) in HLM (Jeong et al., 2009), and anastrozole inhibits CYP2C9, CYP3A
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