Saturation of an α,β-unsaturated ketone: A novel xenobiotic biotransformation in mammals

Lindstrom, Terry D.; Whitaker, G. W.

doi:10.3109/00498258409151438

Cited by 9 publications

(5 citation statements)

References 16 publications

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“…Reduction of the double bond of ,-unsaturated carbonyls by an oxidoreductase is one of several pathways by which the organism can abolish the reactivity of these molecules (Dick et al 2001). Drugs containing this ,-unsaturated ketone motif have also been shown to undergo such reductive metabolism (Lindstrom & Whitaker 1984;Taskinen et al 1991). M7 was a major metabolite in bile, urine and faeces and could also be detected in plasma suggesting that furan cleavage is a major metabolic pathway of prazosin metabolism in the rat.…”

Section: Discussionmentioning

confidence: 97%

Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS)

Erve¹,

Vashishtha²,

Ojewoye

et al. 2008

Xenobiotica

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1. Prazosin, 2-[4-(2-furanoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, is an antihypertensive agent that has been used safely since 1976 and is currently being investigated for the treatment of post-traumatic stress disorder. The in vivo metabolism of prazosin in rat was first reported in 1977, although at the time analytical techniques were not as sophisticated, nor were the mass spectrometers as sensitive, as today. Recently, the in vitro metabolism of prazosin in rat liver microsomes and cryopreserved hepatocytes was investigated using liquid chromatography/mass spectrometry (LC/MS), which revealed new metabolic pathways. 2. In the present work, rat in vivo metabolism was reinvestigated using a quadrupole time-of-flight mass spectrometer coupled with ultra-performance liquid chromatography, or chip-based nanoflow electrospray ionization, with the aim of identifying metabolites revealed by the in vitro studies and any new metabolites. 3. It is reported that prazosin was metabolized in rats to produce the metabolites observed in vitro. In addition, new phase I metabolites, M18, M20 and M21, were formed and conjugation with glucose or taurine formed the new phase II metabolites, M16 and M19, respectively. 4. Evidence for bioactivation of prazosin included detection of ring-opened metabolites (M4 and M7) and a cysteinyl-glycine conjugate (M17). Further support to the structure of the ring-opened metabolite M7 was obtained by nuclear magnetic resonance (NMR) experiments on M7 isolated from urine.

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Section: Discussionmentioning

confidence: 97%

Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS)

Erve¹,

Vashishtha²,

Ojewoye

et al. 2008

Xenobiotica

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“…Double bond reduction by hepatic NAD(P)H oxidoreductase also abolishes reactivity of ␣,␤-unsaturated carbonyls (Dick et al, 2001). Carbon-carbon double bond reductive metabolism has been reported for drugs containing this ␣,␤-unsaturated carbonyl structure (Lindstrom and Whitaker, 1984;Taskinen et al, 1991), and it is possible that NAD(P)H oxidoreductase is also involved in the metabolism of prazosin.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Prazosin in Rat, Dog, and Human Liver Microsomes and Cryopreserved Rat and Human Hepatocytes and Characterization of Metabolites by Liquid Chromatography/Tandem Mass Spectrometry

Erve¹,

Vashishtha²,

DeMaio³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Prazosin (2-[4-(2-furanoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline) is an antihypertensive agent that was introduced to the market in 1976. It has since established an excellent safety record. However, in vitro metabolism of prazosin has not been investigated. This study describes the in vitro biotransformation of prazosin in liver microsomes from rats, dogs, and humans, as well as rat and human cryopreserved hepatocytes and characterization of metabolites using liquid chromatography/tandem mass spectrometry. The major in vivo biotransformation pathways reported previously in rats and dogs include demethylation, amide hydrolysis, and O-glucuronidation. These metabolic pathways were also confirmed in our study. In addition, several new metabolites were characterized, including a stable carbinolamine, an iminium species, and an enamine-all formed via oxidation of the piperazine ring. Two ring-opened metabolites generated following oxidative cleavage of the furan ring were also identified. Using semicarbazide hydrochloride as a trapping agent, an intermediate arising from opening of the furan ring was captured as a pyridazine product. In the presence of glutathione, three glutathione conjugates were detected in microsomal incubations, although they were not detected in cryopreserved hepatocytes. These data support ring opening of the furan via a reactive ␥-keto-␣,␤-unsaturated aldehyde intermediate. In the presence of UDP-glucuronic acid, prazosin underwent conjugation to form an N-glucuronide not reported previously. Our in vitro investigations have revealed additional metabolic transformations of prazosin and have shown the potential of prazosin to undergo bioactivation through metabolism of the furan ring to a reactive intermediate.Prazosin (Fig. 1), a short-acting vasodilator discovered in the mid1970s, has been widely used in treating hypertension and congestive heart failure (Constantine, 1974;Althuis and Hess, 1977;Stanaszek et al., 1983). It was the first of a new class of direct-acting vasodilators acting by ␣-adrenoreceptor blockade. Prazosin was introduced to the U.S. market as MINIPRESS by Pfizer (New York, NY) in 1976. Prazosin is well tolerated, with the most common side effect associated with treatment being postural hypotension. Although no longer a major drug among the antihypertensive agents, based on prazosin's ability to antagonize centrally located ␣ 1 -adrenergic receptors, a new indication for treatment of post-traumatic stress disorders (PTSD) encountered during civilian life is being explored in clinical studies (Taylor and Raskind, 2002). In addition, prazosin is also being investigated in treating combat-related nightmares characteristic of PTSD among soldiers recently returned from Operation Iraqi Freedom (Daly et al., 2005).In vitro metabolism of prazosin in animals or humans has not been reported. Early metabolism studies with 14 C-labeled prazosin (label in quinazoline ring) in rats and dogs revealed that it undergoes extensive hepatic metabolism with biliary excret...

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“…Another observation following LC‐MS analysis of HepaRG cultures was the presence of [M‐H] + and [M + H 2 ‐H] + ions in incubations that contained the ketone compounds but not the esters. The ions were resolved chromatographically and are likely the results α,β‐unsaturated ketoalkene reductase that has been documented in the liver . Importantly, the saturated form of CAPE ( 2 ) was previously shown to be as effective for the inhibition of 5‐LO product biosynthesis, thus the reduction of the α,β‐unsaturated ketoalkene in the liver is unlikely to impact on the capacity of the ketone compounds to inhibit 5‐LO product biosynthesis.…”

Section: Discussionmentioning

confidence: 86%

“…The ions were resolved chromatographically and are likely the results α,β-unsaturated ketoalkene reductase that has been documented in the liver. [59][60][61] Importantly, the saturated form of CAPE (2) 29 was previously shown to be as effective for the inhibition of 5-LO product biosynthesis, thus the reduction of the α,β-unsaturated ketoalkene in the liver is unlikely to impact on the capacity of the ketone compounds to inhibit 5-LO product biosynthesis.…”

Section: F I G U R Ementioning

confidence: 99%

Phenolic acid phenethylesters and their corresponding ketones: Inhibition of 5‐lipoxygenase and stability in human blood and HepaRG cells

Mbarik

Poirier

Doiron

et al. 2019

Pharmacology Res & Perspec

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5‐lipoxygenase (5‐LO) catalyzes the biosynthesis of leukotrienes, potent lipid mediators involved in inflammatory diseases, and both 5‐LO and the leukotrienes are validated therapeutic targets. Caffeic acid phenethyl ester (CAPE) is an effective inhibitor of 5‐LO and leukotriene biosynthesis but is susceptible to hydrolysis by esterases. In this study a number of CAPE analogues were synthesized with modifications to the caffeoyl moiety and the replacement of the ester linkage with a ketone. Several new molecules showed better inhibition of leukotriene biosynthesis than CAPE in isolated human neutrophils and in whole blood with IC50 values in the nanomolar (290‐520 nmol/L) and low micromolar (1.0‐2.3 µmol/L) ranges, respectively. Sinapic acid and 2,5‐dihydroxy derivatives were more stable than CAPE in whole blood, and ketone analogues were degraded more slowly in HepaRG hepatocyte cultures than esters. All compounds underwent modification consistent with glucuronidation in HepaRG cultures as determined using LC‐MS/MS analysis, though the modified sinapoyl ketone (10) retained 50% of its inhibitory activity after up to one hour of incubation. This study has identified at least one CAPE analogue, compound 10, that shows favorable properties that warrant further in vivo investigation as an antiinflammatory compound.

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Saturation of an α,β-unsaturated ketone: A novel xenobiotic biotransformation in mammals

Cited by 9 publications

References 16 publications

Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS)

Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS)

Metabolism of Prazosin in Rat, Dog, and Human Liver Microsomes and Cryopreserved Rat and Human Hepatocytes and Characterization of Metabolites by Liquid Chromatography/Tandem Mass Spectrometry

Phenolic acid phenethylesters and their corresponding ketones: Inhibition of 5‐lipoxygenase and stability in human blood and HepaRG cells

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