Cytochrome P450-mediated alterations in clinical pharmacokinetic parameters of conventional drugs coadministered with piperine: a systematic review and meta-analysis

Pradeepa, B. R.; Vijayakumar, T.; Krishnan, Manikandan; Kammala, Ananth Kumar

doi:10.1016/j.hermed.2023.100713

Cited by 2 publications

(2 citation statements)

References 17 publications

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“…We have a long-standing interest in the chemistry [19] and molecular interactions [20] of the biologically active natural product, piperine. Piperine is a potent inhibitor of cytochrome CYP4A6 and related familial isoforms [21][22] but to the best of our knowledge the exact biological mechanism by which piperine is metabolised remains unknown. [23] There is, however, a body of evidence of typical piperine metabolites to enable confirmation by comparison.…”

Section: Introductionmentioning

confidence: 99%

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

Asra,

P.R. Povinelli,

Zazeri

et al. 2024

Preprint

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In this article we introduce a proof of concept strategy: Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) to expedite the discovery of drug metabolites. The use of a bioactive natural product, piperine, that has a well curated metabolite profile but has an unpredictable computational metabolism (Biotransformer v3.0) was selected. We developed an electrochemical reaction to oxidise piperine into a range of metabolites, which were detected by LC-MS. In turn, a series of chemically plausible metabolites were predicted based on ion-fragmentation patterns. These metabolites were docked into the active site of CYP3A4 using Autodock4.2 From the clustered low-energy profile of piperine in the active site it can be inferred that the most likely metabolic position of piperine (based on intermolecular distances to the Fe-oxo active site) is the benzo[d][1,3]dioxole motif. The metabolic profile was confirmed by literature comparison and the electrochemical reaction delivered plausible metabolites vide infra. Thus, demonstrating the power of the hyphenated technique of tandem electrochemical detection and computational evaluation of binding poses. Taken together, we outline a novel approach where diverse data sources are combined to predict and confirm a metabolic outcome for a bioactive structure.

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Section: Introductionmentioning

confidence: 99%

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

Asra,

P.R. Povinelli,

Zazeri

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…In vivo studies in rats [22] revealed that after oral administration, piperine reached its highest concentration (C max ) in serum and various organs within 6 h. Piprerine's presence remained detectable for up to 96 h post-administration, being metabolized before excretion from the organism. Piperine is a potent inhibitor of cytochrome CYP3A4 and related familial isoforms [23,24], but to the best of our knowledge, the full biological mechanism by which piperine is metabolized remains unknown [25]. There is, however, a body of evidence of typical piperine metabolites to enable confirmation by comparison vida infra [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

Asra,

Povinelli,

Zazeri

et al. 2024

Molecules

View full text Add to dashboard Cite

In this article, we introduce a proof-of-concept strategy, Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM), to expedite the discovery of drug metabolites. The use of a bioactive natural product, piperine, that has a well-curated metabolite profile but an unpredictable computational metabolism (Biotransformer v3.0) was selected. We developed an electrochemical reaction to oxidize piperine into a range of metabolites, which were detected by LC-MS. A series of chemically plausible metabolites were predicted based on ion fragmentation patterns. These metabolites were docked into the active site of CYP3A4 using Autodock4.2. From the clustered low-energy profile of piperine in the active site, it can be inferred that the most likely metabolic position of piperine (based on intermolecular distances to the Fe-oxo active site) is the benzo[d][1,3]dioxole motif. The metabolic profile was confirmed by comparison with the literature, and the electrochemical reaction delivered plausible metabolites, vide infra, thus, demonstrating the power of the hyphenated technique of tandem electrochemical detection and computational evaluation of binding poses. Taken together, we outline a novel approach where diverse data sources are combined to predict and confirm a metabolic outcome for a bioactive structure.

show abstract

Cytochrome P450-mediated alterations in clinical pharmacokinetic parameters of conventional drugs coadministered with piperine: a systematic review and meta-analysis

Cited by 2 publications

References 17 publications

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine

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