Disposition of the opioid antagonist, nalmefene, in rat and dog

Murthy, Satya S.; Mathur, C; Kvalo, L T; Lessor, Ralph A.; Wilhelm, Jeffrey A.

doi:10.3109/00498259609046748

Cited by 16 publications

(11 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Quite interestingly, however, another type of glucuronide, referred here as a diglucuronide, has been reported in the case of nalmefene, a narcotic antagonist excreted mainly as nalmefene 3-O-diglucuronide in the urine after administration to dogs, where glucuronidation occurred in duplicate at a single functional group of aglycone. 6,7) This novel diglucuronide has a chemical structure where the second glucuronosyl group is connected directly to the 2?-hydroxyl group of theˆrst glucuronic acid moiety that is conjugated to the 3-hydroxyl group of nalmefene. After publication of the diglucuronide of nalmefene formed in vivo, weˆrst reported that 4-hydroxybiphenyl Odiglucuronide is produced in vitro from 4-hydrox- ybiphenyl by dog liver microsomes but not by rat, monkey or human liver microsomes, and showed that the monoglucuronide serves as the next substrate for further glucuronidation.…”

Section: Introductionmentioning

confidence: 99%

Repeated Glucuronidation at One Hydroxyl Group Leads to Structurally Novel Diglucuronides of Steroid Sex Hormones

Murai

Iwabuchi

Ikeda

2005

Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

Androgens (androsterone, dihydrotestosterone and testosterone) and estrogens (estradiol, estriol and estrone) were incubated with liver microsomes from rats, dogs, monkeys and humans in the presence of uridine diphosphoglucuronic acid (UDPGA), and the glucuronides produced were structurally characterized by liquid chromatography-tandem mass spectrometry. After 2-h incubation with dog liver microsomes, all substrates tested were converted (approximately 2-10%) to structurally novel diglucuronides, where two glucuronosyl groups are bound to a single hydroxyl group in tandem. Two-dimensional nuclear magnetic resonance spectroscopy unambiguously elucidated the chemical structures of the 3-O-diglucuronide of estrone and the 17-O-diglucuronide of testosterone isolated from the incubation mixture. Monkey and human liver microsomes were also found to have the activity to form this type of diglucuronide, albeit more slowly than the dog liver microsomes, but rat liver microsomes produced no detectable diglucuronides. The rate of formation of estrone 3-O-diglucuronide from the corresponding monoglucuronide in dog liver microsomes followed classical Michaelis-Menten kinetics at substrate concentrations from 50 to 1000 microM, with a K(m) value of 127.1 microM and a V(max) value of 47.0 pmol/min/mg protein.

show abstract

“…Glucuronidation reaction could proceed on another functional group of monoglucuronide leading to bisglucuronides (BGs) or diglucuronides . In the first type, two separated functional groups on the same molecule are conjugated with glucuronic acid, whereas in the other, glucuronidation occurred two times at a single functional group of the aglycone …”

Section: Introductionmentioning

confidence: 99%

Ionization and collision induced dissociation of steroid bisglucuronides

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

Disposition of the opioid antagonist, nalmefene, in rat and dog

Cited by 16 publications

References 10 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

Repeated Glucuronidation at One Hydroxyl Group Leads to Structurally Novel Diglucuronides of Steroid Sex Hormones

Ionization and collision induced dissociation of steroid bisglucuronides

Contact Info

Product

Resources

About