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Aldehyde Oxidase and Its Role As a Drug Metabolizing Enzyme

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Aldehyde Oxidase and Its Role As a Drug Metabolizing Enzyme Pharmacology & Therapeutics 201 (2019) 137–180 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Aldehyde oxidase and its role as a drug metabolizing enzyme Deepak Dalvie a,⁎,LiDib a Drug Metabolism and Pharmacokinetics, Celgene Corporation, 10300, Campus Point Drive, San Diego, CA 92121, USA b Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT 06340, UK article info abstract Available online 24 May 2019 Aldehyde oxidase (AO) is a cytosolic enzyme that belongs to the family of structurally related molybdoflavoproteins like xanthine oxidase (XO). The enzyme is characterized by broad substrate specificity and marked species differences. It catalyzes the oxidation of aromatic and aliphatic aldehydes and various heteroaromatic rings as well as reduction of several functional groups. The references to AO and its role in metab- olism date back to the 1950s, but the importance of this enzyme in the metabolism of drugs has emerged in the past fifteen years. Several reviews on the role of AO in drug metabolism have been published in the past decade indicative of the growing interest in the enzyme and its influence in drug metabolism. Here, we present a com- prehensive monograph of AO as a drug metabolizing enzyme with emphasis on marketed drugs as well as other xenobiotics, as substrates and inhibitors. Although the number of drugs that are primarily metabolized by AO are few, the impact of AO on drug development has been extensive. We also discuss the effect of AO on the systemic exposure and clearance these clinical candidates. The review provides a comprehensive analysis of drug discov- ery compounds involving AO with the focus on developmental candidates that were reported in the past five years with regards to pharmacokinetics and toxicity. While there is only one known report of AO-mediated clin- ically relevant drug-drug interaction (DDI), a detailed description of inhibitors and inducers of AO known to date has been presented here and the potential risks associated with DDI. The increasing recognition of the impor- tance of AO has led to significant progress in predicting the site of AO-mediated metabolism using computational methods. Additionally, marked species difference in expression of AO makes it is difficult to predict human clear- ance with high confidence. The progress made towards developing in vivo, in vitro and in silico approaches for predicting AO metabolism and estimating human clearance of compounds that are metabolized by AO have also been discussed. © 2019 Elsevier Inc. All rights reserved. Contents 1. Introduction............................................... 138 2. StructureandfunctionofAO....................................... 138 3. SubstratesofAO............................................. 142 4. AOmetabolismandtoxicity........................................ 157 5. InhibitionofAObyxenobiotics...................................... 160 6. RegulationandinductionofAO...................................... 164 7. Tissuedistribution............................................ 165 8. Speciesdifferences............................................ 165 9. FactorsaffectingAOexpressionandactivity................................ 168 10. PredictionofAOmetabolismandclearance................................ 169 Abbreviations: P450, cytochrome P450; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; MAO, monoamine oxidase; SAR, structure activity relationship; XO, xanthine oxidase; AO, aldehyde oxidase; PK, pharmacokinetics; DDI, drug-drug interactions; FAD, flavin adenine dinucleotide; Moco, molybdenum center; Mo, molybdenum; DFT, density func- + 1 1 tional theory; NAD , nicotinamide adenine dinucleotide; 2-PY, N -methyl-2-pyridone-5-carboxamide; 4-PY, N -methyl-4-pyridone-3-carboxamide; t1/2, half-life; 5-IPdR, 5-iodo-2- pyrimidinone-2’-deoxyribose; 5-EP, ethynylpyrimidinone; 5-FP, 5-fluoropyrimidinone; 5-EU, 5-ethynyluracil, 5-FU, 5-fluorouracil; TDI, time-dependent inhibitor; DACA, N-[2- (dimethylamino)ethyl]acridone-4-carboxamide; h-chimeric mice, human-chimeric mice; NHE-1, sodium/hydrogen exchanger; AUC, area under the curve; Cmax, maximum concentrations. ⁎ Corresponding author. E-mail address: [email protected] (D. Dalvie). https://doi.org/10.1016/j.pharmthera.2019.05.011 0163-7258/© 2019 Elsevier Inc. All rights reserved. 138 D. Dalvie, L. Di / Pharmacology & Therapeutics 201 (2019) 137–180 11. Conclusion.............................................. 172 Declaration of conflictofinterest....................................... 173 References................................................. 173 1. Introduction conjugative) enzymes such as glucuronosyltransferase (UGT) (Rowland, Miners, & Mackenzie, 2013), sulfotransferase (ST) (Gamage Biotransformation remains a major route of elimination for most et al., 2006; Hempel, Gamage, Martin, & McManus, 2007), N- drugs with approximately 75% of the top most prescribed drugs in the acetyltransferase (NAT) (Sim, Abuhammad, & Ryan, 2014) and glutathi- United States being cleared by metabolism (Cerny, 2016; Kola & one transferase (GT) (Chasseaud, 1979; Hayes, Flanagan, & Jowsey, Landis, 2004; Rendic & Guengerich, 2015; van De Waterbeemd, Smith, 2005). One redox enzyme that has emerged as a common drug metab- Beaumont, & Walker, 2001; Wienkers & Heath, 2005; Williams et al., olizing enzyme in the past decade is AO. Several reviews on the role of 2004; Zhong, 2013; Zhong, Mashinson, Woolman, & Zha, 2013). Thus, AO in drug metabolism have been published in the past decade. This is identification of the metabolic pathways of a new drug candidate and indicative of the growing interest in this enzyme and its influence in characterization of the enzymes responsible for catalyzing them are drug metabolism (Garattini & Terao, 2011, 2013; Hutzler, Obach, major facets that are generally explored during drug discovery and de- Dalvie, & Zientek, 2013; Mota et al., 2018; Pryde et al., 2010; Rashidi & velopment (Di et al., 2013; Lin & Lu, 1997). Soltani, 2017; Sanoh, Tayama, Sugihara, Kitamura, & Ohta, 2015). Here Metabolism of drugs is generally categorized into phase I we present a comprehensive treatise describing drugs that are AO sub- (i.e., functionalization reactions involving oxidation, reduction, and hy- strates and inhibitors with the focus on the clinical relevance with re- drolysis) and phase II (i.e., conjugation) reactions (R. T. Williams, 1969). spect to clearance, pharmacokinetic (PK) variability, drug-drug Functionalization reactions are commonly catalyzed by cytochrome interactions (DDI) and toxicity. An attempt has been made to capture P450s (P450s). These are a superfamily of membrane bound heme- the latest developments in understanding AO and its impact in drug dis- containing versatile enzymes that catalyze the oxidation or reduction covery and development. of over 60% of drugs and xenobiotics (Guengerich, 2017; Rendic & Guengerich, 2015). Although about fifty-seven isoforms make up the 2. Structure and function of AO P450 family in humans (Zanger & Schwab, 2013), approximately 90% of drug metabolism is attributed to CYP1A1, 1A2, 2B6, 2C8, 2C9, 2C19, AO (EC1.2.3.1) is a cytosolic molybdoflavoprotein that belongs to a 2D6, 2E1, 3A4, and 3A5 (Rendic & Guengerich, 2015; Walsky & Obach, family of structurally related molybdenum containing enzymes like 2004; Wienkers & Heath, 2005). Given their role in drug metabolism, XO (EC 1.17.3.2), and utilizes molybdenum (Mo) and flavin adenine di- high P450-mediated turnover of a drug can result in suboptimal phar- nucleotide (FAD) for its catalytic activity in oxidizing and/or reducing macokinetics due to extensive intestinal and liver first-pass metabolism substrates (Romao et al., 2017). Structurally, AO and XO are very similar (Riley, 2001). in their overall topology and share up to 50% of their amino acid se- Metabolism by P450s is partly attributed to the lipophilic nature of quence (Terao et al., 2016). Like XO, the AO family exists as a homodi- drug molecules. The predominant interaction of these enzymes with mer in its catalytically active form with two identical subunits of substrates arises from hydrophobic forces as demonstrated from struc- about 145 to 150 kDa and approximately 1330 to 1340 amino acid res- ture activity relationship (SAR) studies with the major constitutively idues. Each monomeric subunit consists of three conserved domains expressed human P450 isoform, CYP3A4 (Stepan, Vincent, Beaumont, that are connected by two linking regions. The small 25-kDa N- & Kalgutkar, 2013). Moreover, the presence of electron rich aromatic terminal domain contains two non-equivalent and spectroscopically rings (phenyl and substituted phenyl rings) makes these hydrophobic distinct iron-sulfur (2Fe-2S) centers, a 45-kDa central domain accom- compounds even more prone to P450-mediated oxidation. Hence, the modates a FAD binding site and a 85-kDa carboxyl-terminal domain basic strategy in fixing P450 liability involves modulation of physico- harbors the molybdenum cofactor (Moco) (Garattini, Fratelli, & Terao, chemical properties like molecular weight and LogP (Yang, Engkvist, 2008; Garattini, Mendel, Romao, Wright, & Terao, 2003; Garattini & Llinas, & Chen, 2012). One strategy involves introducing azaheterocyclic Terao, 2012, 2013). The Moco complex is made up of Mo that is rings into new molecules. Simply replacing a carbon in aromatic and non-aromatic carbocycles with heteroatoms has been increasingly suc- cessful
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