<i>N</i>-Glucosidation of amobarbital in the cat

Carro-Ciampi, Giovanna; Jurima, M; Kadar, D.; Tang, Boyu; Kalow, W.

doi:10.1139/y85-209

Cited by 8 publications

(2 citation statements)

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“…UDP-glucose acts as a cofactor by transferring D-glucose to the substrate, forming b-D-glucosides (Testa & Kramer, 2008). Glucosidation is an understudied metabolic pathway for drugs that occurs in species other than humans and was notably described in the cat by Carro-Ciampi et al, 1985, when evaluating barbiturate metabolism.…”

Section: Introductionmentioning

confidence: 99%

Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes

Slovak

Mealey

Court

2016

Vet Pharm & Therapeutics

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Use of the immunosuppressant mycophenolic acid (MPA) in cats is limited because MPA elimination depends on glucuronidation, which is deficient in cats. We evaluated formation of major (phenol glucuronide) and minor (acyl glucuronide, phenol glucoside, and acyl glucoside) MPA metabolites using liver microsomes from 16 cats, 26 dogs, and 48 humans. All MPA metabolites were formed by human liver microsomes, while dog and cat liver microsomes formed both MPA glucuronides, but only one MPA glucoside (phenol glucoside). Intrinsic clearance (CLint) of MPA for phenol glucuronidation by cat liver microsomes was only 15–17% that of dog and human liver microsomes. However CLint for acyl glucuronide and phenol glucoside formation in cat liver microsomes was similar to or greater than that for dog and human liver microsomes. While total MPA conjugation CLint was generally similar for cat liver microsomes compared with dog and human liver microsomes, relative contributions of each pathway varied between species with phenol glucuronidation predominating in dog and human liver microsomes and phenol glucosidation predominating in cat liver microsomes. MPA conjugation variation between cat liver microsomes was 3-fold for total conjugation and for phenol glucosidation, 6-fold for phenol glucuronidation, and 11-fold for acyl glucuronidation. Our results indicate that total MPA conjugation is quantitatively similar between liver microsomes from cats, dogs, and humans despite large differences in the conjugation pathways that are utilized by these species.

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Section: Introductionmentioning

confidence: 99%

Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes

Slovak

Mealey

Court

2016

Vet Pharm & Therapeutics

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“…Furthermore, N-glucosidation of xenobiotics could also be classified into aliphatic and aromatic conjugations. Aliphatic N-glucosidation in mammals has been documented for a limited number of drugs such as phenobarbital, amobarbital, pentobarbital, bromfenac, and sulfon- dmd.aspetjournals.org amides (Paulson et al, 1981;Carro-Ciampi et al, 1985;Ahmad and Powell, 1988;Soine et al, 1990Soine et al, , 1994Kirkman et al, 1998;Paibir et al, 2004). However, aromatic N-glucosidation is not common.…”

Section: Nakazawa Et Almentioning

confidence: 99%

Metabolic Profile of FYX-051 (4-(5-Pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the Rat, Dog, Monkey, and Human: Identification of N-Glucuronides and N-Glucosides

Nakazawa¹,

Miyata²,

Omura³

et al. 2006

Drug Metab Dispos

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ABSTRACT:FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile, is a novel xanthine oxidoreductase inhibitor that can be used for the treatment of gout and hyperuricemia. We examined the metabolism of FYX-051 in rats, dogs, monkeys, and human volunteers after the p.o. administration of this inhibitor. The main metabolites in urine were pyridine N-oxide in rats, triazole Nglucoside in dogs, and triazole N-glucuronide in monkeys and humans, respectively. Furthermore, N-glucuronidation and N-glucosidation were characterized by two types of conjugation: triazole N 1 -and N 2 -glucuronidation and N 1 -and N 2 -glucosidation, respectively. N 1 -and N 2 -glucuronidation was observed in each species, whereas N 1 -and N 2 -glucosidation was mainly observed in dogs. With regard to the position of conjugation, N 1 -conjugation was predominant; this resulted in a considerably higher amount of N 1 -conjugate in each species than N 2 -conjugate. The present results indicate that the conjugation reaction observed in FYX-051 metabolism is unique, i.e., N-glucuronidation and N-glucosidation occur at the same position of the triazole ring, resulting in the generation of four different conjugates in mammals. In addition, a urinary profile of FYX-051 metabolites in monkeys and humans was relatively similar; triazole N-glucuronides were mainly excreted in urine.FYX-051 (4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) is a new xanthine oxidoreductase (XOR) inhibitor that is synthesized by Fuji Yakuhin Co., Ltd (Saitama, Japan). It is expected that this inhibitor has potential applications in the treatment of gout and hyperuricemia. This compound has more potent inhibitory effect on bovine milk XOR in vitro than allopurinol. With regard to hypouricemic effects in potassium oxonate-induced hyperuricemic rodent models, FYX-051 caused a dose-dependent reduction in serum urate concentrations. In rats, these effects of FYX-051 were approximately 30-fold more potent than those of allopurinol. In yeast RNAinduced hyperuricemic chimpanzees, FYX-051 was shown to continuously reduce the serum urate level; this implies that FYX-051 is more effective than allopurinol. Very recently, Okamoto et al. (2004) determined the X-ray crystal structure of the XOR-FYX-051 complex. They showed that FYX-051 binds to the active-site molybdenum by a covalent linkage, similar to allopurinol. In contrast to the purine ring structure of allopurinol, FYX-051 has a unique pyridine-triazolecyanopyridine structure that excludes an oxygen atom.Preliminary in vitro metabolic studies on FYX-051 were carried out using animal and human liver microsomes. In these studies, the oxidative metabolites and conjugates of FYX-051 were observed; however, their structures remained to be elucidated. Therefore, we attempted to identify these metabolites. Authentic samples were synthesized for determining the oxidative metabolites, and conjugates were purified from the urine of mammals after dosing of FYX-051.In the present study, we characterized ...

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Genetically determined polymorphisms in drug oxidation

1986

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It is well recognized that wide interindividual variation in the efficiency of elimination can be anticipated for drugs which are predominantly eliminated by metabolism. The capacity of an individual to metabolize such a drug is dependent upon genetic and environmental factors. Numerous studies have investigated the impact of environmental factors [for reviews see (1-3)] but less information is available concerning genetic regulation. An important role for genetic factors was initially suggested by twin and family studies. Interindividual differences in drug metabolism in sibling pairs are less in identical (monozygotic) twins than in fraternal (dizygotic) twins (3). The first reports of the extent to which genetic variations contribute to interindividual variations were related to N-acetylation reactions in 1954 (4). However, it was not until 1975 that genetic polymorphisms of oxidative metabolism were reported, with the simultaneous publication of two genetic defects associated with sparteine oxidation in a German population (5) and debrisoquine hydroxylation in an English population (6). These defects were subsequently shown to be two expressions of the same gene defect. A number of other drugs have also been shown to exhibit polymorphic distribution in the efficiency of their oxidation. In some instances, defects in oxidation have been linked with debrisoquine and sparteine metabolism, in other instances, the defects in oxidation have been independent. These differences probably reflect the fact that cytochrome P-450 exists as a family of isozymes with selective but overlapping substrate and product specificity. A number of previous reviews have discussed this topic (7-10). The objective of the present review is to develop the evidence for, and pharmacokinetic and clinical consequences of, polymorphic distribution of oxidative drug metabolism. Recent advances in our understanding of the molecular basis that determines drug metabolism and its genetic regulation are presented. Finally, we have evaluated methods used in the identification of drugs that cosegregate in their metabolism.

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N-Glucosidation of amobarbital in the cat

Cited by 8 publications

References 0 publications

Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes

Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes

Metabolic Profile of FYX-051 (4-(5-Pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the Rat, Dog, Monkey, and Human: Identification of N-Glucuronides and N-Glucosides

Genetically determined polymorphisms in drug oxidation

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