Identification of a suitable and selective inhibitor towards aldehyde oxidase catalyzed reactions

Nirogi, Ramakrishna; Kandikere, Vishwottam; Palacharla, Veera Raghava Chowdary; Bhyrapuneni, Gopinadh; Kanamarlapudi, Vijaya Bhargava; Ponnamaneni, Ranjith Kumar; Manoharan, Arun Kumar

doi:10.3109/00498254.2013.819594

Cited by 23 publications

(11 citation statements)

References 18 publications

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“…In principle, coadministration of a perpetrator drug could result in observed elevations in metabolite plasma levels as a consequence of several possible mechanisms: 1) decreased metabolite clearance due to inhibition of secondary metabolism, 2) metabolic activation (stimulation of enzyme activity), 3) enzyme induction, or 4) metabolic shunting toward the uninhibited pathway (e.g., AO) when another pathway is inhibited (e.g., P450). It is unlikely that the elevated M1 levels were due to a decrease in M1 clearance in rats pretreated with ABT, as the major M1 clearance pathway in vitro was previously determined to be XO-mediated metabolism to M2 (Morrison et al, 2012); and although the activation of AO has been previously suggested (Nirogi et al, 2014), the present increased M1 formation observed in hepatic S9 fractions absent NADPH relative to NADPH-containing reactions indicate there is no contribution from an ABT-mediated cooperativity on AO. Furthermore, data from our laboratory outlining incubations of 1 with hepatocytes revealed no increase in M1 formation when ABT was present (data not shown).…”

Section: Discussionmentioning

confidence: 42%

Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity

Crouch

Morrison

Byers

et al. 2016

Drug Metabolism and Disposition

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Marketed drugs cleared by aldehyde oxidase (AO) are few, with no known clinically relevant pharmacokinetic drug interactions associated with AO inhibition, whereas cytochrome P450 (P450) inhibition or induction mediates a number of clinical drug interactions. Little attention has been given to the consequences of coadministering a P450 inhibitor with a compound metabolized by both AO and P450. Upon discovering that VU0409106 (1) was metabolized by AO (to M1) and P450 enzymes (to M4-M6), we sought to evaluate the in vivo disposition of 1 and its metabolites in rats with attenuated P450 activity. Male rats were orally pretreated with the pan-P450 inactivator, 1-aminobenzotriazole (ABT), before an i.p. dose of 1. Interestingly, the plasma area under the curve (AUC) of M1 was increased 15-fold in ABT-treated rats, indicating a metabolic shunt toward AO resulted from the drug interaction condition. The AUC of 1 also increased 7.8-fold. Accordingly, plasma clearance of 1 decreased from 53.5 to 15.3 ml/min per kilogram in ABT-pretreated rats receiving an i.v. dose of 1. Consistent with these data, M1 formation in hepatic S9 increased with NADPH-exclusion to eliminate P450 activity (50% over reactions containing NADPH). These studies reflect possible consequences of a drug interaction between P450 inhibitors and compounds cleared by both AO and P450 enzymes. Notably, increased exposure to an AO metabolite may hold clinical relevance for active metabolites or those mediating toxicity at elevated concentrations. The recent rise in clinical drug candidates metabolized by AO underscores the importance of these findings and the need for clinical studies to fully understand these risks.

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Section: Discussionmentioning

confidence: 42%

Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity

Crouch

Morrison

Byers

et al. 2016

Drug Metabolism and Disposition

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“…A reported approach for estimating the contribution of AO compared to other routes of metabolism (fraction metabolized by AO, or f m,AO ) in hepatocytes is the use of the AO-selective inhibitor hydralazine (30 minute pre-incubation at 25 μM) (18). Employment of raloxifene or menadione as inhibitors of AO would be inappropriate in human hepatocytes due to their lack of inhibition specificity (19, 20). Alternatively, 1-aminobenzotriazole (ABT) may be used to effectively knock down CYP-mediated metabolism without inhibiting AO metabolism, or other non-CYP pathways such as UGT (30 minute pre-incubation at 1 mM).…”

Section: Aldehyde Oxidasementioning

confidence: 99%

Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance

Argikar

Potter

Hutzler

et al. 2016

AAPS J

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Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High throughput metabolic stability screening has enabled advancement of compounds with little to no oxidative metabolism. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for non CYP-mediated metabolism. UGTs, esterases and aldehyde oxidase are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such pathways including elucidation of major metabolites. To predict human PK parameters for P450-mediated metabolism, in vitro–in vivo extrapolation using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, such methods have not been sufficiently evaluated for non-P450 enzymes. In addition to the involvement of liver, extra-hepatic enzymes (intestine, kidney, lung) are also likely to contribute to these pathways. While there has been considerable progress in predicting metabolic pathways and clearance primarily mediated by the liver, progress in characterizing extra-hepatic metabolism and prediction of clearance has been slow. Well-characterized in vitro systems or in vivo animal models to assess drug-drug interaction potential and inter-subject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non CYP-mediated metabolism; understand the enzymes involved followed by pharmacokinetic studies in the appropriately characterized surrogate species. The review will highlight progress made in establishing in vitro-in vivo correlation; predicting human clearance and avoid costly clinical failures when non-CYP mediated metabolic pathways are predominant.

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“…The AOX activity in rat livers was determined by measuring AOX-mediated metabolites from probe substrates MTX [ 1 , 21 , 22 ], SGX523 [ 4 ], JNJ-38877605 [ 5 ], and phthalazine [ 6 – 8 ] in the RLCs prepared from different groups of rats. The incubation mixtures contained RLC (1.0 mg/mL), AOX substrates (50 μM MTX or phthalazine, 10 μM SGX523 or JNJ-38877605), and PBS at a final volume of 100 μL.…”

Section: Methodsmentioning

confidence: 99%

“…It plays an important role in the oxidation of aromatic azaheterocycles. The common substrates for this reaction type include methotrexate (MTX) [ 1 – 3 ], SGX523 [ 4 ], JNJ-38877605 [ 5 ], and phthalazine [ 6 – 8 ] (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Nimesulide increases the aldehyde oxidase activity of humans and rats

et al. 2020

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An increasing number of drugs are metabolized by aldehyde oxidase (AOX), but AOX-mediated drug interactions are seldom reported due to the lack of appropriate inhibitors and inducers. A recent study reported that nimesulide (NIM) could increase the liver injury risk of methotrexate. The latter was mainly metabolized by AOX to form hepatotoxic 7-hydroxymethotrexate (7-OH MTX). Thus, we speculated that NIM could induce AOX. In this study, we investigated the potential induction of AOX activity by NIM using methotrexate as the probe substrate. Treatment of primary human and rat hepatocytes with NIM (20 μM) for 24 h caused a 2.0- and 3.1-fold, respectively, increase in 7-OH MTX formation. Oral administration of NIM (100 mg·kg −1 ·d −1 , for 5 days) to rats significantly increased the systematic exposure (6.5-fold), liver distribution (2.5-fold), and excretion (5.2-fold for urinary excretion and 2.1-fold for fecal excretion) of 7-OH MTX. The 7-OH MTX formation in liver cytosol from rats pretreated with 20, 50, and 100 mg·kg −1 ·d −1 NIM for 5 days increased by 1.9-, 3.2-, and 3.7-fold, respectively, compared with that of rats pretreated with the vehicle. We revealed that the elevation of AOX activity was accompanied by an increase in AOX1 protein levels but not the corresponding mRNA levels. Collectively, our results demonstrate for the first time that NIM can increase the AOX activity of humans and rats, and may raise concerns regarding the risk of drug interactions between NIM and AOX substrates in clinical practice.

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Identification of a suitable and selective inhibitor towards aldehyde oxidase catalyzed reactions

Cited by 23 publications

References 18 publications

Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity

Evaluating the Disposition of a Mixed Aldehyde Oxidase/Cytochrome P450 Substrate in Rats with Attenuated P450 Activity

Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance

Nimesulide increases the aldehyde oxidase activity of humans and rats

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