Liquiritigenin pharmacokinetics in a rat model of diabetes mellitus induced by streptozotocin: greater formation of glucuronides in the liver, especially M2, due to increased hepatic uridine 5′-diphosphoglucuronic acid level

Kang, Hee Eun; Sohn, Se I.; Baek, Seung Ryel; Lee, Jee W.; Lee, Myung G.

doi:10.1016/j.metabol.2010.01.012

Cited by 10 publications

(14 citation statements)

References 21 publications

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“…It is possible that the CL ( CL NR ) of MPA remained unchanged in HL rats, despite its increased free fraction, due to changes in hepatic UDPGA levels. It has been reported that there is increased formation of glucuronide conjugates in diabetic rats without in vitro CL int changes, and that this is due to increases in vivo hepatic UDPGA levels resulting from alterations in carbohydrate metabolism . Because the reabsorption of MPA through enterohepatic recirculation could also influence the AUC of MPA and, thus, the CL and CL NR , the comparable CL and CL NR values of the control and HL rats in the present study could not be directly correlated with changes in the free fraction of MPA in the plasma.…”

Section: Discussioncontrasting

confidence: 67%

Effects of poloxamer 407‐induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats

Kwon

Yoon

Baek

et al. 2016

Biopharm & Drug Disp

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Hepatic multidrug resistance-associated protein 2 (Mrp2) is responsible for the majority of the biliary elimination of endogenous and exogenous substances, therefore it is important to evaluate possible functional changes in Mrp2 activity under conditions of hyperlipidemia (HL). Thus, the present study assessed the protein expression and transporting activity of hepatic Mrp2 based on the in vivo biliary excretion of phenolsulfonphthalein (PSP) as a model anionic substrate for Mrp2 in poloxamer 407-induced hyperlipidemic rats (HL rats) and compared these values with those for control rats. The pharmacokinetics of mycophenolic acid (MPA) and mycophenolic acid-7-O-glucuronide (MPAG) were evaluated after the intravenous (5 mg/kg) and oral (10 mg/kg) administration of MPA to control and HL rats. In HL rats, the protein expression of hepatic Mrp2 and its biliary transporting activity exhibited significant reductions (by 24.3% and 24.6%, respectively) in the absence of a change in bile flow rate. Unexpectedly, HL and control rats showed comparable biliary excretion rates of MPAG due to the counter effects of the reduced expression and activity of Mrp2 and a 484% increase in the free fraction of MPAG in HL rats. The estimated biliary clearance value of free MPAG in HL rats was considerably slower (by 77.1%) than that in control rats. Although significant pharmacokinetic changes in total MPA and MPAG levels were not observed in HL rats, there was a marked increase in free MPA and MPAG levels. Clinically relevant pharmacokinetic changes in subjects with HL that are related to MRP2 could not be ruled out. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussioncontrasting

confidence: 67%

Effects of poloxamer 407‐induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats

Kwon

Yoon

Baek

et al. 2016

Biopharm & Drug Disp

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“…The incubation contained microsomes (0.2 mg/ml protein), 50 mM Tris-HCl buffer (pH 7.4), 20 mg/ml alamethicin, 2 mM UDP-GLcA, 10 mM MgCl 2 , 5 mM Dsaccharic acid 1,4-lactone, and 50 mM BRB at 37°C for 1 hour. Similarly, the UDP-GLcA levels were determined in the incubation system according to methods previously described elsewhere (Bánhegyi et al, 1996;Yamamura et al, 2000;Kang et al, 2010) based on the formation of rNPG. All reactions were terminated by icecold acetonitrile (containing 10 ng/ml IS) at a ratio of 1:3 (v/v) and prepared for liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effects of Endogenous Linoleic Acid and Glutaric Acid on the Renal Glucuronidation of Berberrubine in Mice and on Recombinant Human UGT1A7, 1A8, and 1A9

Yang¹,

Li²,

Yan³

et al. 2018

Molecular Pharmacology

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Berberrubine (BRB) has a strong lipid-lowering effect and can be extensively metabolized into berberrubine-9---d-glucuronide (BRBG) in vivo. Recently, pharmacokinetics studies showed that the production of BRBG was significantly decreased in the urine of mice fed with a high-fat diet (HFD), indicating a decreased glucuronidation capacity. Based on the UDP-glucuronosyltransferase (UGT) isoform identification, hepatic and renal microsomal incubation, glucuronidation was examined to suggest the metabolism of BRB in liver and kidneys. The results showed that the renal UGT activity for metabolizing BRB markedly decreased, which may be highly related to the decreased expression and activity of renal Ugt1a7c. Surprisingly, in vitro studies revealed neither BRB nor BRBG inhibited the renal UGT activity. By employing an integrated strategy of metabolomics and pharmacokinetics, we identified and confirmed for the first time the inhibitory effect of some potential endogenous molecules on the renal glucuronidation of C57BL/6J mice, such as glutaric acid (GA) and linoleic acid (LA). By employing recombinant human UGTs, we found that GA and LA efficiently affect the activity of recombinant human UGT1A7, 1A9, and 1A8 at their normal or abnormal physiologic levels in vivo. GA (2 mM) markedly inhibited the activity of UGT1A7 by 89.4% and UGT1A9 by 32.8%. The inhibition rates reached 99.3% for UGT1A9, 48.3% for UGT1A7, and 46.8% for UGT1A8 with LA at 200 M. It has been suggested that the endogenous molecules have the potential to affect the efficiency of glucuronidation, which might be a key factor contributing to individual differences in drug metabolism.

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“…The achiral pharmacokinetics of liquiritigenin, and its corresponding glycosides have been reported in the literature (17). Differences in the disposition of an individual enantiomer may result in significant differences in their health benefits or toxic effects in humans (18192021222324252627). The chiral pharmacokinetics of liquiritigenin have only been preliminarily evaluated by our laboratory and one other group.…”

Section: Introductionmentioning

confidence: 99%

Stereospecific pharmacokinetic characterization of liquiritigenin in the rat

et al. 2017

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Liquiritigenin is a chiral flavonoid present in licorice and other medicinal plants. The nature of its biological fate with respect to the individual enantiomers has not been examined. In this study, we characterize, for the first time, the stereoselective pharmacokinetics of liquiritigenin. Liquiritigenin was intravenously (20 mg/kg) and orally (50 mg/kg) administered to male Sprague-Dawley rats (n = 4 per route of administration). Concentrations in serum and urine were characterized via stereospecific reversed-phase, isocratic HPLC method with UV detection. Serum concentrations were quantified but rapidly fell to undetectable levels. S-liquiritigenin showed a short half-life (0.25-0.54 h), while a better estimation of half-life (26-77 h) and other pharmacokinetic parameters was observed using urinary data. The flavonoid is predominantly excreted via non-renal routes (fe values of 0.16-3.46 %), and undergoes rapid and extensive phase II metabolism. Chiral differences in the chemical structure of the compound result in some pharmacokinetic differences. Serum concentrations rapidly declined, making modeling difficult. S-liquiritigenin showed an increased urinary half-life.

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Liquiritigenin pharmacokinetics in a rat model of diabetes mellitus induced by streptozotocin: greater formation of glucuronides in the liver, especially M2, due to increased hepatic uridine 5′-diphosphoglucuronic acid level

Cited by 10 publications

References 21 publications

Effects of poloxamer 407‐induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats

Effects of poloxamer 407‐induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats

Inhibitory Effects of Endogenous Linoleic Acid and Glutaric Acid on the Renal Glucuronidation of Berberrubine in Mice and on Recombinant Human UGT1A7, 1A8, and 1A9

Stereospecific pharmacokinetic characterization of liquiritigenin in the rat

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