The Metabolic Fate of Prazosin

Taylor, James; Twomey, Thomas M.; Wittenau, M. Schach von

doi:10.3109/00498257709035794

Cited by 84 publications

(35 citation statements)

References 2 publications

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“…The former drug had to be given at very high doses (16-32 mg/kg) in order to pass the blood-brain barrier in these animals. (The low doses of prazosin generally used in behavioral research (0.5-2.0 mg/ kg) did not significantly reduce ex vivo a 1 -binding in the cerebral cortex of our mice (male Swiss Webster) in support of similar findings by others for the mouse (Lindroos et al, 1984) and dog (Taylor et al, 1977).) A similar and nearperfect correlation was obtained again between loss of a 1 -binding sites and loss of active behavior, which made it virtually certain that these receptors controlled behavioral activity in this species.…”

Section: Role Of a 1 -Adrenoceptors In Behavioral Activitysupporting

confidence: 90%

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

Stone

Yang

Rosengarten

et al. 2003

Neuropsychopharmacol

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Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain a 1B -adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression. The present review covers the evidence for this system and includes findings that brain a 1 -adrenoceptors are instrumental in behavioral activation, are located near the major monoamine cell groups or target areas, receive EPI as their neurotransmitter, are impaired or inhibited in depressed patients or after stress in animal models, and are restored by a number of antidepressants. This 'EPI-a 1 system' may therefore represent a new target system for this disorder.

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Section: Role Of a 1 -Adrenoceptors In Behavioral Activitysupporting

confidence: 90%

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

Stone

Yang

Rosengarten

et al. 2003

Neuropsychopharmacol

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“…Product ions at m/z 233 and 190 were 14 Da less than the corresponding ions at m/z 247 and 204 for prazosin, supporting a single demethylation event on the amino-dimethoxyquinazoline group. Previously it was reported that the major demethylated metabolite in vivo was 6-desmethyl prazosin (Taylor et al, 1977), and we observed that the abundance of M3 was larger than M6. Therefore, M3 and M6 were tentatively identified as 6-desmethyl and 7-desmethyl prazosin, respectively.…”

Section: Metabolism Of Prazosin In Nadph-and Udpga-fortifiedmentioning

confidence: 49%

“…One objective of this work was to use current in vitro methodology and analytical tools to study the metabolism of prazosin and to determine the correlation with in vivo data (Taylor et al, 1977;Piotrovskii et al, 1984). Further understanding prazosin metabolism remains relevant because of renewed interest in prazosin for PTSD.…”

Section: Discussionmentioning

confidence: 99%

“…In humans, prazosin is highly bound to plasma protein and readily absorbed from the gastrointestinal tract with oral bioavailability ranging from 44 to 77% and a half-life from 2.2 to 3.7 h (Bateman et al, 1979). In vivo, the primary metabolic route of prazosin consists of 6-Oand 7-O-demethylation followed by glucuronidation (Taylor et al, 1977), with 6-hydroxy-prazosin glucuronide the major metabolite. Other routes of metabolism include hydrolysis of the amide linkage to yield 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline (N-desfuranoyl prazosin) and to a lesser extent, piperazine ring opening and N-dealkylation to give dimethoxyquinazoline-2,4-diamine (DQ).…”

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confidence: 99%

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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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“…Since the ratio of adipose to lean tissue increases with age (Bender, 1964) it would not be unexpected to find lipophilic drugs demonstrating a greater VdSS in the elderly. Prazosin has, in fact, only modest lipophilic properties (Taylor et al, 1977) and its 40% greater Vdss in the elderly is presumably a reflection of this fact when viewed against the 200-300% changes seen with the far more lipophilic drug diazepam.…”

Section: Discussionmentioning

confidence: 99%

Prazosin disposition in young and elderly subjects.

Rubin¹,

Scott²,

Reid³

1981

Brit J Clinical Pharma

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1 The disposition of prazosin following oral and intravenous administration has been studied in seven young and seven elderly men, all of whom were in good health and living independently in the community. 2 The elimination half-life (min) of prazosin was 123 + 19.4 (s.d.) in the young and 194 + 36 in the elderly (P < 0.01). 3 Clearance (ml min-m kg-') was 3.94 + 0.73 in the young and 3.53 + 1 in the elderly (P > 0.1). Volume of distribution at steady state (1 kg-') was 0.63 + 0.14 in the young and 0.89 + 0.26 in the elderly (P < 0.05). 4 The absolute bioavailability of orally administered prazosin was 0.68 -+ 0.17 in the young and 0.48 + 0.16 in the elderly (P < 0.05). 5 The significant increase in prazosin half-life in the elderly results from an increased volume of distribution, not from decreased clearance. 6 Gastrointestinal absorption of prazosin decreases in old age.

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The Metabolic Fate of Prazosin

Cited by 84 publications

References 2 publications

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

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

Prazosin disposition in young and elderly subjects.

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