Interspecies variation in the metabolism of zoniporide by aldehyde oxidase

Dalvie, Deepak; Xiang, Cathie; Kang, Ping; Zhou, Sue

doi:10.3109/00498254.2012.727499

Cited by 39 publications

(35 citation statements)

References 56 publications

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“…Beedham et al (1987) showed monkey hepatic cytosol to have the highest AOX activity with N-heterocyclic compounds. However, recent results by Dalvie et al (2013) indicate that zoniporide intrinsic clearance by rhesus monkey S9 is low when compared with humans and guinea pigs. The molecular basis for these species and substrate differences are not known.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

2013

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“…Rhesus monkey would require more compound for dosing (the rhesus monkey typically weighs 6 to 10 kg, whereas the cynomolgus monkey weighs 3 to 5 kg), is more expensive, and is a less often used species for conducting routine pharmacokinetic and toxicokinetic studies. Dalvie et al, 2013 …”

Section: Discussionmentioning

confidence: 99%

Cynomolgus Monkey as a Surrogate for Human Aldehyde Oxidase Metabolism of the EGFR Inhibitor BIBX1382

et al. 2014

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BIBX1382 was an epidermal growth factor receptor inhibitor under clinical investigation for treatment of cancer. This candidate possessed an attractive preclinical absorption, distribution, metabolism, and excretion profile, yet failed in clinical studies due in part to poor oral exposure, resulting from extensive metabolism by aldehyde oxidase (AO). In vitro metabolism studies were performed in liver cytosol and cryopreserved hepatocytes from multiple species. In addition, a pharmacokinetic study was performed in cynomolgus monkey for comparison with the reported human pharmacokinetics of BIBX1382. Estimated hepatic clearance of BIBX1382 in rhesus (42 ml/min per kg) and cynomolgus monkey (43 ml/min per kg) liver cytosol was comparable to human ( ‡93% of liver blood flow). Metabolite identification after incubation of BIBX1382 in liver cytosol fortified with the AO inhibitor raloxifene confirmed that AO is involved in the formation of the predominant metabolite (BIBU1476, M1) in cynomolgus monkey. After intravenous and oral administration of BIBX1382 to cynomolgus monkeys, high plasma clearance (118 ml/min per kg) and low oral exposure (C max = 12.7 nM and 6% oral bioavailability) was observed, with the exposure of M1 exceeding BIBX1382 after oral dosing. This pharmacokinetic profile compared favorably with the human clinical data of BIBX1382 (plasma clearance 25-55 ml/min per kg and 5% oral bioavailability). Thus, it appears that cynomolgus monkey represents a suitable surrogate for the observed human AO metabolism of BIBX1382. To circumvent clinical failures due to uncharacterized metabolism by AO, in vitro studies in the appropriate subcellular fraction, followed by pharmacokinetic and toxicokinetic studies in the appropriately characterized surrogate species should be conducted for substrates of AO.

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“…The second step was found to be mediated by both guinea pig AO and cow XO (Rashidi et al, 2007). Given that many studies have shown that animal models are poor predictor of molybdenum oxidase activity we decided to explore the in vitro metabolism with human XO and AO (Sahi et al, 2008;Choughule et al, 2013;Dalvie et al, 2013). We initially explored the time course of 6MP metabolism by monitoring the production of the intermediate 6TX and the final product 6TUA in pooled human liver cytosol.…”

Section: Resultsmentioning

confidence: 99%

“…One caveat to bear in mind is that all of these in vitro experiments were performed using AO/XO from nonhuman sources. Major species differences have already been reported for several compounds metabolized by AO and hence extrapolation of pharmacokinetic data from other mammalian species to humans is not advisable (Choughule et al, 2013;Dalvie et al, 2013). Moreover, mammalian xanthine oxidoreductase (XOR) exists in two interconvertible forms, xanthine oxidase (XO) and xanthine dehydrogenase (XDH).…”

mentioning

confidence: 99%

In Vitro Oxidative Metabolism of 6-Mercaptopurine in Human Liver: Insights into the Role of the Molybdoflavoenzymes Aldehyde Oxidase, Xanthine Oxidase, and Xanthine Dehydrogenase

et al. 2014

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Anticancer agent 6-mercaptopurine (6MP) has been in use since 1953 for the treatment of childhood acute lymphoblastic leukemia (ALL) and inflammatory bowel disease. Despite being available for 60 years, several aspects of 6MP drug metabolism and pharmacokinetics in humans are unknown. Molybdoflavoenzymes such as aldehyde oxidase (AO) and xanthine oxidase (XO) have previously been implicated in the metabolism of this drug. In this study, we investigated the in vitro metabolism of 6MP to 6-thiouric acid (6TUA) in pooled human liver cytosol. We discovered that 6MP is metabolized to 6TUA through sequential metabolism via the 6-thioxanthine (6TX) intermediate. The role of human AO and XO in the metabolism of 6MP was established using the specific inhibitors raloxifene and febuxostat.Both AO and XO were involved in the metabolism of the 6TX intermediate, whereas only XO was responsible for the conversion of 6TX to 6TUA. These findings were further confirmed using purified human AO and Escherichia coli lysate containing expressed recombinant human XO. Xanthine dehydrogenase (XDH), which belongs to the family of xanthine oxidoreductases and preferentially reduces nicotinamide adenine dinucleotide (NAD + ), was shown to contribute to the overall production of the 6TX intermediate as well as the final product 6TUA in the presence of NAD + in human liver cytosol. In conclusion, we present evidence that three enzymes, AO, XO, and XDH, contribute to the production of 6TX intermediate, whereas only XO and XDH are involved in the conversion of 6TX to 6TUA in pooled HLC.

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Interspecies variation in the metabolism of zoniporide by aldehyde oxidase

Cited by 39 publications

References 56 publications

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

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

Cynomolgus Monkey as a Surrogate for Human Aldehyde Oxidase Metabolism of the EGFR Inhibitor BIBX1382

In Vitro Oxidative Metabolism of 6-Mercaptopurine in Human Liver: Insights into the Role of the Molybdoflavoenzymes Aldehyde Oxidase, Xanthine Oxidase, and Xanthine Dehydrogenase

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