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Dixon, R.; Hsiao, Jane; Hsu, Hon-Bin; Smulkowski, M.; Tze-Ming-Chan,; Pramanik, Birendra; Morton, J B

doi:10.1023/a:1015818316854

Cited by 11 publications

(1 citation statement)

References 4 publications

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“…A few cases were previously reported. Diglucuronides were identified as the metabolites of morphinan and nalmefene,13, 14 and diglucuronide and bisglucuronide conjugates were identified as estradiol and estriol metabolites in dog liver microsomes 15. More recently, diglucuronides of some endogenous steroids were isolated and identified as in vivo metabolites in dogs 16…”

Section: Resultsmentioning

confidence: 99%

In vitro metabolism of β‐lapachone (ARQ 501) in mammalian hepatocytes and cultured human cells

Miao¹,

Zhong²,

Wang³

et al. 2008

Rapid Comm Mass Spectrometry

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ARQ 501 (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione, beta-lapachone) is an anticancer agent, currently in multiple phase II clinical trials as monotherapy and in combination with other cytotoxic drugs. This study focuses on in vitro metabolism in cryopreserved hepatocytes from mice, rats, dogs and humans using [(14)C]-labeled ARQ 501. Metabolite profiles were characterized using liquid chromatography/mass spectrometry combined with an accurate radioactivity counter. Ion trap mass spectrometry was employed for further structural elucidation. A total of twelve metabolites were detected in the mammalian hepatocytes studied; all of which but one were generated from phase II conjugation reactions. Ten of the observed metabolites were produced by conjugations occurring at the reduced ortho-quinone carbonyl groups of ARQ 501. The metabolite profiles revealed that glucuronidation was the major biotransformation pathway in mouse and human hepatocytes. Monosulfation was the major pathway in dog, while, in rat, it appears glucuronidation and sulfation pathways contributed equally. Three major metabolites were found in rats: monoglucuronide M1, monosulfate M6, and glucuronide-sulfate M9. Two types of diconjugation metabolites were formed by attachment of the second glycone to an adjacent hydroxyl or to an existing glycone. Of the diconjugation metabolites, glucosylsulfate M10, diglucuronide M5, and glucuronide-glucoside M11 represent rarely observed phase II metabolites in mammals. The only unconjugated metabolite was generated through hydrolysis and was observed in rat, dog and human hepatocytes. ARQ 501 appeared less stable in human hepatocytes than in those of other species. To further elucidate the metabolism of ARQ 501 in extrahepatic sites, its metabolism in human kidney, lung and intestine cells was also studied, and only monoglucuronide M1 was observed in all the cell types examined.

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Section: Resultsmentioning

confidence: 99%

In vitro metabolism of β‐lapachone (ARQ 501) in mammalian hepatocytes and cultured human cells

Miao¹,

Zhong²,

Wang³

et al. 2008

Rapid Comm Mass Spectrometry

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Ionization and collision induced dissociation of steroid bisglucuronides

et al. 2017

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Studies on steroid metabolism are of utmost importance to improve the detection capabilities of anabolic androgenic steroids (AASs) misuse in sports drug testing. In humans, glucuronoconjugates are the most abundant phase II metabolites of AAS. Bisglucuronidation is a reaction where two separated functional groups on the same molecule are conjugated with glucuronic acid. These metabolites have not been studied in depth for steroids and could be interesting markers for doping control. The aim of the present work was to study the ionization and collision-induced dissociation of steroid bisglucuronides to be able to develop mass spectrometric analytical strategies for their detection in urine samples after AAS administration. Because steroid bisglucuronides are not commercially available, 19 of them were qualitatively synthesized to study their mass spectrometric behavior. Bisglucuronides ionized as [M+NH ] in positive mode, and as [M-H] and [M-2H] in negative mode. The most specific product ions of steroid bisglucuronides in positive mode resulted from the neutral losses of 387 and 405 Da (corresponding to [M+NH -NH -2gluc-H O] and [M+NH -NH -2gluc-2H O] , respectively, being "gluc" a dehydrated glucuronide moiety), and in negative mode, the fragmentation of [M-2H] showed ion losses of m/z 175 and 75 (gluc and HOCH CO , respectively). On the basis of the common behavior, a selected reaction monitoring method was developed to detect bisglucuronide metabolites in urine samples. As a proof of concept, urines obtained after administration of norandrostenediol were studied, and a bisglucuronide metabolite was detected in those urines. The results demonstrate the usefulness of the analytical strategy to detect bisglucuronide metabolites in urine samples, and the formation of these metabolites after administration of AAS.

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Pathways of Biotransformation — Phase II Reactions

Drug Metabolism

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Cited by 11 publications

References 4 publications

In vitro metabolism of β‐lapachone (ARQ 501) in mammalian hepatocytes and cultured human cells

In vitro metabolism of β‐lapachone (ARQ 501) in mammalian hepatocytes and cultured human cells

Ionization and collision induced dissociation of steroid bisglucuronides

Pathways of Biotransformation — Phase II Reactions

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