Characterization of brimonidine metabolism with rat, rabbit, dog, monkey and human liver fractions and rabbit liver aldehyde oxidase

Acheampong, Akwasi A.; Chien, D-S.; Lam, S.; Vekich, S.; Breau, A.; Usansky, J.; Harcourt, D.; Munk, S. A.; Nguyen, H.; Garst, M.; Tang-Liu, Diane

doi:10.3109/00498259609062804

Cited by 17 publications

(12 citation statements)

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“…Aldehyde oxidase is a cytosolic molybdo-flavoenzyme that is expressed predominantly in the liver, lung, and kidney and plays a major role in the oxidation of aldehydes and nitrogen-containing heterocyclic compounds (Kitamura et al, 2006). Some heteroaromatic compounds of pharmacological and toxicological importance that are metabolized by aldehyde oxidase include carbazeran (Kaye et al, 1985), famciclovir (Rashidi et al, 1997), methotrexate (Jordan et al, 1999), zaleplon , brimonidine (Acheampong et al, 1996), and N- [(2Ј-diethylamino)ethyl]acridine-4-carboximide (Schofield et al, 2000). Thus, it is not surprising that zoniporide was a substrate of aldehyde oxidase.…”

Section: Discussionmentioning

confidence: 99%

Cross-Species Comparison of the Metabolism and Excretion of Zoniporide: Contribution of Aldehyde Oxidase to Interspecies Differences

Dalvie

Zhang²,

Chen³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Excretion and metabolism of zoniporide were investigated in humans after intravenous infusion of [ 14 C]zoniporide at an 80-mg dose. Bile was the primary route of excretion because 57% of dose was recovered in the feces after intravenous infusion. Zoniporide was primarily cleared via metabolism in humans. 2-Oxozoniporide (M1) was the major excretory and circulating metabolite in humans and was catalyzed by aldehyde oxidase (K m of 3.4 M and V max of 74 pmol/min/mg protein). Metabolites M2 (17% of the dose) and M3 (6.4% of circulating radioactivity), in which the guanidine moiety was hydrolyzed to a carboxylic acid, were also detected in human feces and plasma, respectively, suggesting that hydrolysis was another route of metabolism of zoniporide in humans. The metabolism and excretion of [ 14 C]zoniporide in rats and dogs were also evaluated. As in humans, bile was the primary route of excretion of the radiolabeled material in both species, and metabolism was the primary route of clearance. A comparison of plasma metabolites showed that for M3, rats had a higher concentration than human or dog. M1 was absent in dog and present in human and rat plasma at comparable levels, whereas comparison of excreta showed that the total body burden of M1 was greater in rat than that in human. No further evaluation of M2 was considered because it was detected only in the human fecal extracts. Hence, no further toxicological evaluation of the three human metabolites was undertaken.Zoniporide [1-(quinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl guanidine] (Fig. 1) was designed and synthesized as a highly selective inhibitor of the sodium/hydrogen exchanger (NHE-1) Knight et al., 2001;Marala et al., 2002;Tracey et al., 2003) and was being developed to reduce the perioperative myocardial ischemic injury in high-risk surgery patients. It inhibited 22 Na ϩ uptake in fibroblasts expressing human NHE-1 in a concentrationdependent manner with an IC 50 of 14 nM and had Ͼ150-fold selectivity over other NHE isoforms (Marala et al., 2002). Zoniporide also produced a reduction in infarct size and decreased the incidence and duration of potentially lethal arrhythmias after intravenous administration to animal models of ischemic-reperfusion injury Tracey et al., 2003). Preclinical pharmacokinetic studies of zoniporide in mice, rats, rabbits, dogs, and monkeys demonstrated that its clearance (Cl p ) was moderate to high in all species. The volume of distribution (V d ) was moderate, and the plasma t 1/2 was 1.5 h or shorter in all species evaluated. There was a linear increase in systemic exposure of zoniporide in healthy male human volunteers, after a 1-h infusion of doses ranging from 0.003 to 1.0 mg/kg, as assessed by C max and the area under plasma concentration versus time curve (AUC 0 -tlast ). The C max and AUC 0 -tlast ranged from 2 to 622 ng/ml and from 2 to 930 ng-h/ml, respectively, at these doses. The Cl p and V d were independent of dose, and the mean t 1/2 was approximately 3 h. The most common adverse events reported...

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Section: Discussionmentioning

confidence: 99%

Cross-Species Comparison of the Metabolism and Excretion of Zoniporide: Contribution of Aldehyde Oxidase to Interspecies Differences

Dalvie

Zhang²,

Chen³

et al. 2009

Drug Metab Dispos

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“…Of consequence is the AO-catalyzed oxidation of heteroaromatic rings because these rings are commonly incorporated into new drug entities and form the backbone of several marketed drugs and drug candidates. Some drugs that are AO substrates are famciclovir (Rashidi et al, 1997), zaleplon (Kawashima et al, 1999), brimonidine (Acheampong et al, 1996), and N- [(2-diethylamino)ethyl] acridine-4-carboximide (Schofield et al, 2000) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Dalvie

Sun²,

Xiang³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Current studies explored the effect of structural changes on the aldehyde oxidase (AO)-mediated metabolism of zoniporide (1). Zoniporide analogs with modifications of the acylguanidine moiety, the cyclopropyl group on the pyrazole ring, and the quinoline ring were studied for their AO-catalyzed metabolism using the human S9 fraction. Analysis of the half-lives suggested that subtle changes in the structure of 1 influenced its metabolism and that the guanidine and the quinoline moieties were prerequisites for AO-catalyzed oxidation to 2-oxozoniporide (M1). In contrast, replacement of the cyclopropyl group with other alkyl groups was tolerated. The effect of structural variation on AO properties was rationalized by docking 1 and its analogs into the human AO homology model. These studies indicated the importance of electrostatic, -stacking and hydrophobic interactions of the three motifs with residues in the active site. Differences in substrate properties were also rationalized by comparing their half-lives with cLogD, electrophilicity parameters [electrostatic potential (ESP) charges and energy of lowest unoccupied molecular orbitals (E LUMO )], and the energies of formation of tetrahedral intermediates (J Med Chem 50:4642-4647, 2007). Whereas the success of energetics in predicting the AO substrate properties of analogs was 87%, the predictive ability of other descriptors was none (cLogD) to 60% (ESP charges and E LUMO ). Overall, the structuremetabolism relationship could be rationalized using a combination of both the energy calculations and docking studies. This combination method can be incorporated into a strategy for mitigating AO liabilities observed in the lead candidate or studying structuremetabolism relationships of other AO substrates.

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“…Among those phenomena, species differences have been widely demonstrated in the metabolism of many drugs catalyzed by AO. They include an ocular hypotensive agent, brimonidine, 9) antiviral drugs, famciclovir and 6-deoxypenciclovir, 10) an antineoplastic drug, methotrexate, 11) an ultrashort acting hypnotic, zaleplon, 12) and an oral antitumor agent, zebularine. 13) Thus, it is now well established that the variations in AO activity may be dependent on not only animal species, but also on the chemical structure of the substrate.…”

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confidence: 99%

Functional Analysis of Aldehyde Oxidase Using Expressed Chimeric Enzyme between Monkey and Rat

Itoh

Asakawa

Hoshino

et al. 2009

Biological & Pharmaceutical Bulletin

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Aldehyde oxidase (AO, EC 1.2.3.1) and xanthine oxidase are major members of the molybdenum hydroxylase family. Both enzymes consist of a homodimer with a subunit molecular mass of about 150 kDa. Each subunit is made up of a 20 kDa domain containing two different 2Fe-2S clusters in which reducing equivalents necessary for catalysis are stored, a 40 kDa domain containing a flavine adenine dinucleotide (FAD), and an 80 kDa domain containing a molybdenum cofactor (MoCo) in which a substrate binding site is located. 1)AO catalyzes the oxidation of a wide range of endogenous and exogenous aldehydes and N-heterocyclic aromatic compounds. The representative N-heterocyclic-containing drugs that serve as substrates for AO are famciclovir, methotrexate, 6-mercaptopurine, and cinchona alkaloids. [1][2][3][4][5][6] In addition, the atypical antipsychotic drug, ziprasidone, is mainly metabolized by AO-catalyzed reductive ring cleavage in human. 7,8) AO has several pharmacokinetically interesting properties of remarkable species differences, large strain differences in rat, and individual differences in some kinds of rat strains. Among those phenomena, species differences have been widely demonstrated in the metabolism of many drugs catalyzed by AO. They include an ocular hypotensive agent, brimonidine, 9) antiviral drugs, famciclovir and 6-deoxypenciclovir, 10) an antineoplastic drug, methotrexate, 11) an ultrashort acting hypnotic, zaleplon, 12) and an oral antitumor agent, zebularine.13) Thus, it is now well established that the variations in AO activity may be dependent on not only animal species, but also on the chemical structure of the substrate. Roughly speaking, AO activity is high in monkeys and humans, moderate to low in rats and mice, and deficient in dogs. Similar to those reports, we observed remarkable species differences, rat strain differences, and polymorphism-based individual differences in Donryu strain rat in the AO-catalyzed 2-oxidation activity of the (S)-enantiomer of RS-8359,14-18) The compound is a reversible and selective monoamine oxidase (MAO)-A inhibitor 19,20) and has been developed as an anti-depressant. 21,22) As to species differences, monkeys showed the highest activity followed by humans. Furthermore, monkey and human liver cytosol preparations exhibited a biphasic pattern in the Eadie-Hofstee plots for the 2-oxidation activity of (S)-RS-8359, but not rat and mouse liver cytosols. The expression system of monkey AO full cDNA suggested that the biphasic Eadie-Hofstee profile might be produced by the existence of two active sites in a single AO enzyme rather than by the existence of two AO isoforms. 23)Molecular cloning of AO cDNA has been accomplished in mouse, 24,25) rat, 26) rabbit, 27) bovine, 28) and human. 29-31) The deduced primary structure of AO proteins have been characterized with regard to consensus sequences for two distinct 2Fe-2S clusters and five MoCo-binding sites. Wright et al. 26) indicated that the kinetic differences of AO activity between male and female rats are due...

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Characterization of brimonidine metabolism with rat, rabbit, dog, monkey and human liver fractions and rabbit liver aldehyde oxidase

Cited by 17 publications

References 0 publications

Cross-Species Comparison of the Metabolism and Excretion of Zoniporide: Contribution of Aldehyde Oxidase to Interspecies Differences

Cross-Species Comparison of the Metabolism and Excretion of Zoniporide: Contribution of Aldehyde Oxidase to Interspecies Differences

Effect of Structural Variation on Aldehyde Oxidase-Catalyzed Oxidation of Zoniporide

Functional Analysis of Aldehyde Oxidase Using Expressed Chimeric Enzyme between Monkey and Rat

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