Metabolic interactions of rosmarinic acid with human cytochrome P450 monooxygenases and uridine diphosphate glucuronosyltransferases

Kim, Sang-Bum; Kim, Kyu-Sang; Kim, Dae‐Duk; Yoon, In‐Soo

doi:10.1016/j.biopha.2018.11.040

Cited by 26 publications

(14 citation statements)

References 29 publications

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“…Since CYP2C8- and CYP3A4-mediated metabolism are principally responsible for the elimination of RPG in humans [ 7 , 8 ], the results of the present in vitro microsomal metabolic interaction studies can be interpreted and discussed based on the principles and guidelines of CYP-mediated drug–drug interactions. The apparent K i values represent the dissociation constant for the interaction between the inhibitor and the enzyme [ 39 ]. As the concentration of the inhibitor (QCT) increased from 0 μM to 200 μM in the present K i estimation study, the V max of RPG metabolism tended to decrease (RLM: 2016 to 928 pmol/min/mg protein; HLM: 1507 to 818 pmol/min/mg protein) and the K m of RPG metabolism tended to increase (RLM: 53 to 81 μM; HLM: 23 to 111 μM).…”

Section: Discussionmentioning

confidence: 99%

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

et al. 2021

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Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

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Section: Discussionmentioning

confidence: 99%

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

et al. 2021

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“…This result might suggest that conjugation ability reached maximum. RA was reported to act as a weak or moderate inhibitor of drug-metabolizing enzymes, such as cytochrome P450 monooxygenase (CYP) uridine and diphosphate glucuronosyltransferase 22 . In the present study, we did not observe any apparent interactions between M. officinalis extract and concomitant medications.…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of Melissa officinalis extract containing rosmarinic acid in the prevention of Alzheimer’s disease progression

Noguchi‐Shinohara

Ono

Hamaguchi

et al. 2020

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We conducted a randomized placebo-controlled double-blind 24-week trial using Melissa officinalis (M. officinalis) extract richly containing rosmarinic acid (RA) on patients with mild dementia due to Alzheimer’s disease (AD) with the aim to examine the safety and tolerability (primary endpoint) of RA (500 mg daily) and its clinical effects and disease-related biomarker changes (secondary endpoints). Patients (n = 23) diagnosed with mild dementia due to probable AD were randomized to either the placebo or M. officinalis extract group. No differences in vital signs or physical and neurologic examination results were detected between the M. officinalis and placebo groups. No serious adverse events occurred. There were no significant differences in cognitive measures; however, the mean Neuropsychiatric Inventory Questionnaire (NPI-Q) score improved by 0.5 points in the M. officinalis group and worsened by 0.7 points in the placebo group between the baseline and 24-week visit, indicating a significant difference (P = 0.012). No significant differences were apparent in disease-related biomarkers between the groups. M. officinalis extract containing 500 mg of RA taken daily was safe and well-tolerated by patients with mild dementia due to AD. Our results suggest that RA may help prevent the worsening of AD-related neuropsychiatric symptoms. Trial registration: The registration number for this clinical trial is UMIN000007734 (16/04/2012).

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“…An in vitro microsomal metabolism study was conducted using Corning ® Gentest TM pooled male RLM (from Sprague-Dawley rats) and HLM (from more than 5 male donors) as previously described [29,30], with slight modifications and in accordance with the manufacturer’s protocol. To assess the possibility of metabolic interaction between REP and CEL, a microsomal reaction mixture was prepared as follows (total volume: 0.2 mL): RLM or HLM (0.5 mg/mL), 50 mM phosphate buffer, 1 mM NADPH, 10 mM MgCl 2 , 1 μM substrate, and various concentrations of inhibitor (1–100 μM).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection

et al. 2019

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Since diabetes mellitus and osteoarthritis are highly prevalent diseases, combinations of antidiabetic agents like repaglinide (REP) and non-steroidal anti-inflammatory drugs (NSAID) like celecoxib (CEL) could be commonly used in clinical practice. In this study, a simple and sensitive bioanalytical HPLC method combined with fluorescence detector (HPLC-FL) was developed and fully validated for simultaneous quantification of REP and CEL. A simple protein precipitation procedure and reversed C18 column with an isocratic mobile phase (mixture of ACN and pH 6.0 phosphate buffer) were employed for sample preparation and chromatographic separation. The fluorescence detector was set at a single excitation/emission wavelength pair of 240 nm/380 nm. The linearity (10–2000 ng/mL), accuracy, precision, extraction recovery, matrix effect, and stability for this method were validated as per the current FDA guidance. The bioanalytical method was applied to study pharmacokinetic interactions between REP and CEL in vivo, successfully showing that concurrent administration with oral REP significantly altered the pharmacokinetics of oral CEL. Furthermore, an in vitro metabolism and protein binding study using human materials highlighted the possibility of metabolism-based interactions between CEL and REP in clinical settings.

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Metabolic interactions of rosmarinic acid with human cytochrome P450 monooxygenases and uridine diphosphate glucuronosyltransferases

Cited by 26 publications

References 29 publications

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Safety and efficacy of Melissa officinalis extract containing rosmarinic acid in the prevention of Alzheimer’s disease progression

Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection

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