The Role of Aldehyde Oxidase and Xanthine Oxidase in the Biotransformation of a Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5

Morrison, Ryan D.; Blobaum, Anna L.; Byers, Frank W.; Santomango, Tammy S.; Bridges, Thomas M.; Stec, Donald F.; Brewer, Kimberly; Sanchez-Ponce, Raymundo; Corlew, Melany M.; Rush, Roger; Felts, Andrew S.; Manka, Jason; Bates, Brittney S.; Venable, Daryl F.; Rodriguez, Alice L.; Jones, Carrie K.; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle A.; Daniels, J. Scott

doi:10.1124/dmd.112.046136

Cited by 37 publications

(51 citation statements)

References 30 publications

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“…We previously reported the disposition of a novel mGlu 5-negative allosteric modulator, VU0409106 (1), which was discovered to be predominantly metabolized by AO (Scheme 1), to the primary metabolite, M1 (Morrison et al, 2012). Notably, we demonstrated that the in vitro scaled hepatic clearance (CL HEP ) of 1 was in general agreement with the in vivo plasma clearance (CL p ) observed in Sprague-Dawley (SD) rats and cynomolgus monkey.…”

Section: Introductionsupporting

confidence: 72%

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: Introductionsupporting

confidence: 72%

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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“…To determine the enzymes responsible for the formation of metabolites related to the MRX-I DHPO ring opening, various specific phenotypic inhibitors were added to the S9 fraction incubation system: ABT [1000 mM final concentration, cytochrome P450 (P450) inhibitor], methimazole (100 mM final concentration, P450 and FMO inhibitor, except FMO5), menadione [1-100 mM final concentration, aldehyde oxidase (AO) and short-chain dehydrogenase reductase (SDR) inhibitor] (Rosemond and Walsh, 2004;Morrison et al, 2012), raloxifene (0.001-100 mM final concentration, AO inhibitor), methotrexate [50 mM final concentration, xanthine oxidase (XO) inhibitor], allopurinol (100 mM final concentration, XO inhibitor) (Morrison et al, 2012) (Stagos et al, 2010). After these inhibitors were incubated with human liver S9 fractions in the presence of NADPH for 15 minutes, the MRX-I in methanol stock solution was added to the incubation system.…”

Section: Metabolism Of Mrx-i In Vitromentioning

confidence: 99%

Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes

Zhong

et al. 2015

Drug Metab Dispos

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MRX-I is an analog of linezolid containing a 2,3-dihydropyridin-4-one (DHPO) ring rather than a morpholine ring. Our objectives were to characterize the major metabolic pathways of MRX-I in humans and clarify the mechanism underlying the oxidative ring opening of DHPO. After an oral dose of MRX-I (600 mg), nine metabolites were identified in humans. The principal metabolic pathway proposed involved the DHPO ring opening, generating the main metabolites in the plasma and urine: the hydroxyethyl amino propionic acid metabolite MRX445-1 and the carboxymethyl amino propionic acid metabolite MRX459. An in vitro phenotyping study demonstrated that multiple non-cytochrome P450 enzymes are involved in the formation of MRX445-1 and MRX459, including flavin-containing monooxygenase 5, short-chain dehydrogenase/reductase, aldehyde ketone reductase, and aldehyde dehydrogenase (ALDH). H 2 18O experiments revealed that two 18 O atoms are incorporated into MRX445-1, one in the carboxyethyl group and the other in the hydroxyl group, and three 18O atoms are incorporated into MRX459, two in the carboxymethyl group and one in the hydroxyl group. Based on these results, the mechanism proposed for the DHPO ring opening involves the metabolism of MRX-I via FMO5-mediated Baeyer-Villiger oxidation to an enol lactone, hydrolysis to an enol, and enol-aldehyde tautomerism to an aldehyde. The aldehyde is reduced by short-chain dehydrogenase/reductase, aldehyde ketone reductase, ALDH to MRX445-1, or oxidized by ALDH to MRX459. Our study suggests that few clinical adverse drug-drug interactions should be anticipated between MRX-I and cytochrome P450 inhibitors or inducers.

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“…This is because, in the liver, both of these animals are thought to synthesize a sole active AOX1 which is an ortholog of human and mouse AOX1 (Garattini and Terao, 2013). Although there are a few studies that support the monkey (rhesus and cynomologous) as a potential surrogate for human AOX metabolism in vivo (Dittrich et al, 2002;Morrison et al, 2012), there is no evidence in support of the guinea pig.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Rhesus Monkey and Guinea Pig Hepatic Cytosol Fractions as Models for Human Aldehyde Oxidase

2013

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Aldehyde oxidase (AOX) is a cytosolic enzyme expressed across a wide range of species, including guinea pig and rhesus monkey. These species are believed to be the best preclinical models for studying human AOX-mediated metabolism. We compared AOX activity in rhesus monkeys, guinea pigs, and humans using phthalazine and N-[2-(dimethylamino)ethyl]acridone-4-carboxamide (DACA) as substrates and raloxifene as an inhibitor. Michaelis-Menten kinetics was observed for phthalazine oxidation in rhesus monkey, guinea pig, and human liver cytosol, whereas substrate inhibition was seen with DACA oxidase activity in all three livers. Raloxifene inhibited phthalazine and DACA oxidase activity uncompetitively in guinea pig, whereas mixed-mode inhibition was seen in rhesus monkey.Our analysis of the primary sequence alignment of rhesus monkey, guinea pig, and human aldehyde oxidase isoform 1 (AOX1) along with homology modeling has led to the identification of several amino acid residue differences within the active site and substrate entrance channel of AOX1. We speculate that some of these residues might be responsible for the differences observed in activity. Overall, our data indicate that rhesus monkeys and guinea pigs would overestimate intrinsic clearance in humans and would be unsuitable to use as animal models. Our study also showed that AOX metabolism in species is substrate-dependent and no single animal model can be reliably used to predict every drug response in humans.

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The Role of Aldehyde Oxidase and Xanthine Oxidase in the Biotransformation of a Novel Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 5

Cited by 37 publications

References 30 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

Metabolism of MRX-I, a Novel Antibacterial Oxazolidinone, in Humans: The Oxidative Ring Opening of 2,3-Dihydropyridin-4-One Catalyzed by Non-P450 Enzymes

Evaluation of Rhesus Monkey and Guinea Pig Hepatic Cytosol Fractions as Models for Human Aldehyde Oxidase

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