Fast hepatic biotransformation of p-synephrine and p-octopamine and implications for their oral intake

Silva-Pereira, Juliany Fontoura da; Bubna, Gisele Adriana; Gonçalves, Geferson de Almeida; Bracht, Fabrício; Peralta, Rosane Marina; Bracht, Adelar

doi:10.1039/c6fo00014b

Cited by 15 publications

(9 citation statements)

References 27 publications

(45 reference statements)

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“…Stereoselective membrane transport, especially by peripherally expressed OCTs, might be highly relevant for the elimination of racemic synephrine from the body. Synephrine is rapidly removed from the bloodstream by hepatic uptake [ 62 ]. Thus, OCT1 is likely to be involved, and here we show a higher clearance for the active (R) -enantiomer.…”

Section: Discussionmentioning

confidence: 99%

Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

2022

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Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters.

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Section: Discussionmentioning

confidence: 99%

Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

2022

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“…p‐ Synephrine has been shown to be rapidly extracted from the blood by the liver. The single pass extraction of p ‐synephrine was shown to be higher than 90% at a portal concentration of 10 μM (de Silva‐Pereira et al ., ), indicating rapid removal and metabolism. The half‐life of p ‐synephrine has been estimated to be in the range of 2–3 h (Hengtmann and Aulepp, ; Haller et al ., , ), agreeing with the blood levels observed by Shara et al .…”

Section: Discussionmentioning

confidence: 99%

Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p‐Synephrine

Stohs

2017

Phytotherapy Research

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Citrus aurantium L. (bitter orange) extracts that contain p‐synephrine as the primary protoalkaloid are widely used for weight loss/weight management, sports performance, appetite control, energy, and mental focus and cognition. Questions have been raised about the safety of p‐synephrine because it has some structural similarity to ephedrine. This review focuses on current human, animal, in vitro, and mechanistic studies that address the safety, efficacy, and mechanisms of action of bitter orange extracts and p‐synephrine. Numerous studies have been conducted with respect to p‐synephrine and bitter orange extract because ephedra and ephedrine were banned from use in dietary supplements in 2004. Approximately 30 human studies indicate that p‐synephrine and bitter orange extracts do not result in cardiovascular effects and do not act as stimulants at commonly used doses. Mechanistic studies suggest that p‐synephrine exerts its effects through multiple actions, which are discussed. Because p‐synephrine exhibits greater adrenergic receptor binding in rodents than humans, data from animals cannot be directly extrapolated to humans. This review, as well as several other assessments published in recent years, has concluded that bitter orange extract and p‐synephrine are safe for use in dietary supplements and foods at the commonly used doses. Copyright © 2017 The Authors Phytotherapy Research Published by John Wiley & Sons Ltd.

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“…Several mandelic acids have sometimes been considered as gut microbiota catabolites, but it is now recognised that 4-hydroxymandelic acid is a metabolite of p-sympatol (p-synephrine) and / or p-octopamine, which in dietary terms are known only from citrus fruit [65,153]. However, the rapid appearance of 4 -hydroxymandelic acid in plasma (C max ≈ 1 h) indicates that the gut microbiota are not necessarily involved [65,154].…”

Section: Controls Used In Model Fermentations Have Clearly Demonstratmentioning

confidence: 99%

Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols

Williamson

Clifford

2017

Biochemical Pharmacology

257

172

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Please cite this article as: G. Williamson, M.N. Clifford, Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols, Biochemical Pharmacology (2017), doi: http://dx.doi.org/10.1016/ j. bcp.2017.03.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1Role of the small intestine, colon and microbiota in determining the metabolic fate of in the small intestine, or reaches the colon and is subject to extensive catabolism by colonic microbiota. Untransformed substrates may be absorbed, appearing in plasma primarily as methylated, sulfated and glucuronidated derivatives, with in some cases the unchanged substrate. Many of the catabolites are well absorbed from the colon and appear in the plasma either similarly conjugated, or as glycine conjugates, or in some cases unchanged.Although many (poly)phenol catabolites have been identified in human plasma and / or urine, the pathways from substrate to final catabolite, and the species of bacteria and enzymes involved, are still scarcely reported. While it is clear that the composition of the human gut microbiota can be modulated in vivo by supplementation with some (poly)phenol-rich commodities, such modulation is definitely not an inevitable consequence of supplementation, it depends on the treatment, length of time and on the individual metabotype, and it is not clear whether the modulation is sustained when supplementation ceases. Some catabolites have been recorded in plasma of volunteers at concentrations similar to those shown to be effective in in vitro studies suggesting that some benefit may be achieved in vivo by diets yielding such catabolites. and are also present at high levels in supplements [4], and form essential components of many Chinese medicines [5]. A study within the European Prospective Investigation intoCancer and Nutrition (EPIC) using the Phenol Explorer database reported that the cohort studied consumed 427 different polyphenols including 94 that were consumed at a rate of >1 g/day. The estimated total polyphenol consumption ranged from 584 mg/day by Greek women to 1786 mg/day for men in Aarhus-Denmark. The corresponding data for Greek men and for Aarhus women were 744 mg/day and 1626 mg/ day, respectively, with all data adjusted for age and weighted by season and weekday of dietary recall [6]. This study defined the major contributors to be the phenolic acids (predominantly the caffeoylquinic acids (27-53%), also called chlorogenic acids) and flavonoids (predominantly flavanols (16-29%), proanthocyanidins (5-9%) and theaflavins (14-25%)) [6]. Hydroxybenzoic acids (3.3-7.4%), alkyl-phenols (1.6...

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Fast hepatic biotransformation of p-synephrine and p-octopamine and implications for their oral intake

Cited by 15 publications

References 27 publications

Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

Safety, Efficacy, and Mechanistic Studies Regarding Citrus aurantium (Bitter Orange) Extract and p‐Synephrine

Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols

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