Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

Ma, Haiying; Sun, Dongxue; Cao, Yun‐Feng; Ai, Chun-Zhi; Qu, Yanqing; Hu, Cui-Min; Jiang, Changtao; Dong, Peipei; Sun, Xiaoyu; Hong, Mo; Tanaka, Naoki; Gonzalez, Frank J.; Ma, Xiaochi; Fang, Zhong‐Ze

doi:10.1016/j.taap.2014.02.021

Cited by 25 publications

(16 citation statements)

References 24 publications

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“…27) Many compounds have been reported to inhibit UGT2B7, such as arbidol and herbal andrographolide derivatives. 28,29) In vitro data tend to underestimate inhibition of drug glucuronidation in vivo. 21) Thus, HET and NGR might be more potent than data here suggest and individuals with greater systemic concentrations of HET and NGR may have increased the risk for herb-drug interactions, so IV-IVE should be done with care.…”

Section: Discussionmentioning

confidence: 99%

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Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Liú

Xie

et al. 2016

Biological & Pharmaceutical Bulletin

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Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) andAurantii Fructus Immaturus. The present study aims to investigate the inhibition potential of HET and NGR derivatives towards one of the most important phase II drug-metabolizing enzymes-uridine diphosphate (UDP)-glucuronosyltransferases (UGTs). We used trifluoperazine as a probe substrate to test UGT1A4 activity, and recombinant UGT-catalyzed 4-methylumbelliferone glucuronidation was used as a probe reaction for other UGT isoforms. Data show that HET and NGR displayed broad-spectrum inhibition against human UGTs. Besides, HET exhibited strong inhibitory effects on UGT1A1, 1A3 and 1A9 (both IC 50 and K i values lower than 10 µM), and the inhibitory effects of NGR against three major UGTs, including UGT1A1, 1A3 and 2B7. In a combination of inhibition parameters (K i ) and in vivo concentration of HET and NGR, the potential in vivo inhibition magnitude was predicted. Based on the reported maximum plasma concentration of HET and NGR in vivo, these findings indicate the potential herb-drug interactions (HDI) between HET or NGR and the drugs mainly undergoing UGT1A3 or UGT2B7 catalyzed metabolic elimination. Considering the variety of citrus that contains HET and NGR, so caution should be applied when taking drugs that utilize UGTs for metabolism and clearance with citrus fruits. Key words herb-drug interaction; hesperetin; naringenin; uridine diphosphate (UDP)-glucuronosyltransferaseHesperetin (HET; 4′-methoxy-3′,5,7-trihydroxyflavanone) and naringenin (NGR; 4,5,7-trihydroxyflavanone), aglycones of the flavanone glycoside hesperidin (chiefly in oranges) and naringin (grapefruits) are also used as dietary flavonoids. 1)Moreover, flavanones are bioactive components of Aurantii Fructus Immaturus, which is reported to be used in traditional Chinese medicine.2) Several animal studies have been performed to document pharmacokinetics of HET and NGR. 3,4) The role of HET and NGR in the treatment of disease has received considerable attention, and it is reported to have antioxidant, anti-inflammatory, anti-hypertensive, anti-atherogenic, anti-diabetic, antiviral, and neuroprotective activities. 5-8)Thus, HET and NGR have multiple uses and pharmacokinetic studies of both compounds may elucidate information about efficacy and safety. Chemical structures of HET and NGR appear in Fig. 1.Herb-drug interaction (HDI) strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons.9) CYP450 and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) are two enzymes responsible for oxidative phase I and conjugative phase II reactions, respectively. 10) In the past decades, the CYP450 inhibition by HET and NGR has been widely studied, the effects of HET and NGR on UGTs activity have not been fully characterized. Moreover, a large number of different UGTs that exhibit a wide range of substrates are...

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Section: Discussionmentioning

confidence: 99%

“…9) CYP450 and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) are two enzymes responsible for oxidative phase I and conjugative phase II reactions, respectively. 10) In the past decades, the CYP450 inhibition by HET and NGR has been widely studied, the effects of HET and NGR on UGTs activity have not been fully characterized.…”

Section: )mentioning

confidence: 99%

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Liú

Xie

et al. 2016

Biological & Pharmaceutical Bulletin

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“…The same trend was observed for BSA's influence towards the maximum reaction velocity of the metabolism of (R)‐fenoprofen and (S)‐fenorpofen. To evaluate whether the addition of BSA can affect metabolism‐mediated DDI, andrographolide was selected due to its strong inhibition towards UGTs . The results showed a stronger difference for the influence of BSA towards the inhibition capability of andrographolide towards the metabolism of fenoprofen enantiomers.…”

Section: Discussionmentioning

confidence: 99%

Albumin Supplement Affects the Metabolism and Metabolism‐Related Drug–Drug Interaction of Fenoprofen Enantiomers

Wang

Meng

et al. 2015

Chirality

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The influence of albumin towards the metabolism behavior of fenoprofen enantiomers and relevant drug-drug interaction was investigated in the present study. The metabolic behavior of fenoprofen enantiomers was compared in a phase II metabolic incubation system with and without bovine serum albumin (BSA). BSA supplement increased the binding affinity parameter (Km) of (R)-fenoprofen towards human liver microsomes (HLMs) from 148.3 to 214.4 μM. In contrast, BSA supplement decreased the Km of (S)-fenoprofen towards HLMs from 218.2 to 123.5 μM. For maximum reaction velocity (Vmax), the addition of BSA increased the Vmax of (R)-fenoprofen from 1.3 to 1.6 nmol/min/mg protein. In the contrast, BSA supplement decreased the Vmax value from 3.3 to 1.5 nmol/min/mg protein. Andrographolide-fenoprofen interaction was used as an example to investigate the influence of BSA supplement towards fenoprofen-relevant drug-drug interaction. The addition of 0.2% BSA in the incubation system significantly decreased the inhibition potential of andrographolide towards (R)-fenoprofen metabolism (P < 0.001). Different from (R)-fenoprofen, the addition of BSA significantly increased the inhibition potential of andrographolide towards the metabolism of (S)-fenoprofen. BSA supplement also changed the inhibition kinetic type and parameter of andrographolide towards the metabolism of (S)-fenoprofen. In conclusion, albumin supplement changes the metabolic behavior of fenoprofen enantiomers and the fenoprofen-andrographolide interaction.

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“…Additionally, the activity of UGT1A8 has high correlation with the occurrence of cancers . UGT2B7 is regarded as one of the most important UGT isoforms involved in drug metabolism, such as the glucuronidation process of zidovudine . Therefore, compared with (S)‐zaltoprofen, (R)‐zaltoprofen exhibited higher risk when coadministered with the drugs mainly undergoing UGT1A8 and UGT2B7‐catalyzed metabolism.…”

Section: Discussionmentioning

confidence: 99%

Chirality Influence of Zaltoprofen Towards UDP‐Glucuronosyltransferases (UGTs) Inhibition Potential

Jia

Wang

et al. 2015

Chirality

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Zaltoprofen (ZLT) is a nonsteroidal antiinflammation drug, and has been clinically employed to treat rheumatoid arthritis, osteoarthritis, and other chronic inflammatory pain conditions. The present study aims to investigate the chirality influence of zaltoprofen towards the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation system was employed to investigate the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT isoforms. The inhibition difference capability was observed for the inhibition of (R)-zaltoprofen and (S)-zaltoprofen towards UGT1A8 and UGT2B7, but not for other tested UGT isoforms. (R)-zaltoprofen exhibited noncompetitive inhibition towards UGT1A8 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters were calculated to be 35.3 μM and 19.2 μM for UGT1A8 and UGT2B7. (R)-zaltoprofen and (S)-zaltoprofen exhibited a different inhibition type towards UGT1A7. Based on the reported maximum plasma concentration of (R)-zaltoprofen in vivo, a high drug-drug interaction between (R)-zaltoprofen and the drugs mainly undergoing UGT1A7, UGT1A8, and UGT2B7-catalyzed glucuronidation was indicated.

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Herb–drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7

Cited by 25 publications

References 24 publications

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Albumin Supplement Affects the Metabolism and Metabolism‐Related Drug–Drug Interaction of Fenoprofen Enantiomers

Chirality Influence of Zaltoprofen Towards UDP‐Glucuronosyltransferases (UGTs) Inhibition Potential

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