Pharmacokinetics, safety, and tolerability of single and multiple-doses of pinocembrin injection administered intravenously in healthy subjects

Cao, Guoying; Ying, Pengyue; Yan, Bin; Xue, Wei; Li, Kexin; Ai, Shi; Sun, Tao; Yan, Jin; Hu, Xin

doi:10.1016/j.jep.2015.03.041

Cited by 38 publications

(29 citation statements)

References 13 publications

(11 reference statements)

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“…This flavanone protects endothelial cells from oxidized LDL-induced injury, and has neuroprotective effects on ischemia/reperfusion-induced brain injury by inhibiting autophagy [ 36 , 37 ]. Although pharmacokinetic of pinocembrin was studied, no CYP3A4 inhibition was reported [ 38 ]. In this study, pinocembrin decreased enzyme activity by 50% ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

The Inhibitory Effect of Flavonoid Aglycones on the Metabolic Activity of CYP3A4 Enzyme

et al. 2018

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Flavonoids are natural compounds that have been extensively studied due to their positive effects on human health. There are over 4000 flavonoids found in higher plants and their beneficial effects have been shown in vitro as well as in vivo. However, data on their pharmacokinetics and influence on metabolic enzymes is scarce. The aim of this study was to focus on possible interactions between the 30 most commonly encountered flavonoid aglycones on the metabolic activity of CYP3A4 enzyme. 6β-hydroxylation of testosterone was used as marker reaction of CYP3A4 activity. Generated product was determined by HPLC coupled with diode array detector. Metabolism and time dependence, as well as direct inhibition, were tested to determine if inhibition was reversible and/or irreversible. Out of the 30 flavonoids tested, 7 significantly inhibited CYP3A4, most prominent being acacetin that inhibited 95% of enzyme activity at 1 µM concentration. Apigenin showed reversible inhibition, acacetin, and chrysin showed combined irreversible and reversible inhibition while chrysin dimethylether, isorhamnetin, pinocembrin, and tangeretin showed pure irreversible inhibition. These results alert on possible flavonoid–drug interactions on the level of CYP3A4.

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Section: Resultsmentioning

confidence: 99%

The Inhibitory Effect of Flavonoid Aglycones on the Metabolic Activity of CYP3A4 Enzyme

et al. 2018

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“…The achiral pharmacokinetics of pinocembrin and pinostrobin, and their corresponding glycosides have been reported (9)(10)(11)(12). Differences in the disposition of an individual enantiomer can cause significant or toxic effects in humans.The chiral pharmacokinetics of these compounds have only been preliminarily evaluated by our laboratory (13,14).…”

Section: Introductionmentioning

confidence: 99%

Pre-Clinical Pharmacokinetic and Pharmacodynamic Characterization of Selected Chiral Flavonoids: Pinocembrin and Pinostrobin

et al. 2015

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Purpose: Delineate the stereospecific pharmacokinetics and pharmacodynamics of the chiral flavonoids pinocembrin and pinostrobin. Objective: Characterize for the first time the stereoselective pharmacokinetics of two flavonoids, pinocembrin and pinostrobin and their bioactivity in several in vitro assays with relevant roles in heart disease, colon cancer, and diabetes etiology and pathophysiology. Methods: Chiral flavonoids were intravenously and orally administered to male Sprague-Dawley rats. Concentrations in serum and urine were characterized via stereospecific HPLC or LC/MS. Pure enantiomeric forms of each flavonoid were tested, where possible, to identify the stereospecific contribution to bioactivity in comparision to their racemates. Results: Short half-lives (0.2-6 h) in serum were observed, while a better estimation of half-life (3-26 h) and other pharmacokinetic parameters were observed using urinary data. The flavonoids are predominantly excreted via non-renal routes (fe values of 0.3-4.6 %), and undergo rapid and extensive phase II metabolism. Chiral differences in the chemical structure of these compounds result in significant pharmacodynamic differences. Conclusion: The importance of understanding the stereospecific pharmacokinetics and pharmacodynamics of two chiral flavonoids were delineated.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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“…The analyses were performed on an Agilent Zorbax SB-C18 chromatographic column (5 μ m, 4.6 × 250 mm) at 35°C with an Agilent Zorbax SB-C18 precolumn. The chromatographic conditions and sample preparation were in accordance with a previous report [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Pinocembrin Protects Blood-Brain Barrier Function and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in a Rat Thromboembolic Stroke Model

Kong

et al. 2018

BioMed Research International

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Tissue-type plasminogen activator (t-PA) remains the only approved therapy for acute ischemic stroke but has a restrictive treatment time window of 4.5 hr. Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of hemorrhagic transformation (HT) secondary to reperfusion. In this study, we sought to determine the effect of pinocembrin (PCB; a pleiotropic neuroprotective agent) on t-PA administration-induced BBB damage in a novel rat thromboembolic stroke model. By assessing the leakage of Evans blue into the ischemic hemisphere, we demonstrated that PCB pretreatment 5 min before t-PA administration significantly reduced BBB damage following 2 hr, 4 hr, 6 hr, and even 8 hr ischemia. Consistently, PCB pretreatment significantly decreased t-PA infusion-resulting brain edema and infarction volume and improved the behavioral outcomes following 6 hr ischemia. Mechanistically, PCB pretreatment inhibited the activation of MMP-2 and MMP-9 and degradation of tight junction proteins (TJPs) occludin and claudin-5 in the ischemic hemisphere. Moreover, PCB pretreatment significantly reduced phosphorylation of platelet-derived growth factor receptor α (PDGFRα) as compared with t-PA alone. In an in vitro BBB model, PCB decreased transendothelial permeability upon hypoxia/aglycemia through inhibiting PDGF-CC secretion. In conclusion, we demonstrated that PCB pretreatment shortly before t-PA infusion significantly protects BBB function and improves neurological outcomes following prolonged ischemia beyond the regular 4.5 hr t-PA time window. PCB pretreatment may represent a novel means of increasing the safety and the therapeutic time window of t-PA following ischemic stroke.

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Pharmacokinetics, safety, and tolerability of single and multiple-doses of pinocembrin injection administered intravenously in healthy subjects

Cited by 38 publications

References 13 publications

The Inhibitory Effect of Flavonoid Aglycones on the Metabolic Activity of CYP3A4 Enzyme

The Inhibitory Effect of Flavonoid Aglycones on the Metabolic Activity of CYP3A4 Enzyme

Pre-Clinical Pharmacokinetic and Pharmacodynamic Characterization of Selected Chiral Flavonoids: Pinocembrin and Pinostrobin

Pinocembrin Protects Blood-Brain Barrier Function and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in a Rat Thromboembolic Stroke Model

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