Evaluation of the in vitro/in vivo drug interaction potential of BST204, a purified dry extract of ginseng, and its four bioactive ginsenosides through cytochrome P450 inhibition/induction and UDP-glucuronosyltransferase inhibition

Zheng, Yin; Bae, Soo Hyeon; Choi, Eu Jin; Park, Jung Bae; Kim, Sun Ok; Jang, Min Jung; Park, Gyu Hwan; Shin, Wonjae; Oh, Euichaul

doi:10.1016/j.fct.2014.03.004

Cited by 25 publications

(24 citation statements)

References 52 publications

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“…These studies suggest that LCA can reduce the elimination of many therapeutic drugs that are substrates of CYPs and P-gp, which may cause subsequent HDIs. It is also possible that HDIs can result from herbal-associated inhibition against major phase II metabolizing enzymes (Na et al, 2011;Choi et al, 2011;Li et al, 2012;Zheng et al, 2014;Wang et al, 2015 ). Unlike the extensive investigations on LCA interactions with CYPs, there is currently no reported evidence on the inhibitory effects of LCA and other major constituents of licorice against common phase II metabolizing enzymes.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Hong

et al. 2016

Food and Chemical Toxicology

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Licochalcone A (LCA) is a major bioactive compound in Licorice, a widely used herbal medicine. In this study, the inhibitory effects of LCA against human UDP-glucuronosyltransferases (UGTs) and LCA associated herb-drug interactions were systematically investigated. Our results demonstrated that LCA displayed broad-spectrum inhibition against human UGTs. LCA exhibited strong inhibitory effects against UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A9, and 2B7 (both IC50 and Ki values lower than 5 μM), while showing moderate inhibitory effects against UGT1A8, 1A10, 2B4, 2B15, and 2B17. The inhibitory effects of LCA against two major UGTs, including UGT1A1 and 1A9, were further investigated in human liver microsomes (HLMs), where the potential risks of LCA via inhibition of UGT1A1 and 1A9 were predicted by combining the in vitro inhibitory data and physiological data. The results from this study also showed that several LCA-containing products were able to increase the area under the curve (AUC) of the substrates that were predominantly metabolized by UGT1A1 or 1A9. These findings together demonstrate that LCA has a potent and broad-spectrum inhibitory effect against most human UGTs and thus suggest that much caution should be exercised when high-dose LCA is co-administered with UGT substrates.

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Section: Introductionmentioning

confidence: 99%

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Hong

et al. 2016

Food and Chemical Toxicology

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“…The authors described inhibition of UGT2B7 by valproic acid as the cause of increased concentrations of lamotrigine when the two drugs are coadministered. Another study compared purified dry extract of ginseng to well‐documented UGT inhibitors and demonstrated a significant inhibition of UGT1A1 and a weak inhibition of both UGT1A9 and UGT2B7 by ginseng . Thus it is likely that ginseng can exhibit this same mechanism of interaction.…”

Section: Discussionmentioning

confidence: 99%

“…Another study compared purified dry extract of ginseng to well-documented UGT inhibitors and demonstrated a significant inhibition of UGT1A1 and a weak inhibition of both UGT1A9 and UGT2B7 by ginseng. 19 Thus it is likely that ginseng can exhibit this same mechanism of interaction. We postulate that the inhibition of UGT2B7 by ginseng predisposed our patient to a drug hypersensitivity reaction.…”

Section: Discussionmentioning

confidence: 99%

Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome Probably Induced by a Lamotrigine-Ginseng Drug Interaction

2015

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The likelihood of a drug reaction with lamotrigine is increased by dose escalation that is too rapid or drug interactions that increase the concentration of lamotrigine. There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lymphocytes and has a mortality rate of 10-40%. We describe the first case, to our knowledge, of DRESS syndrome that was probably induced by a drug interaction between lamotrigine and ginseng. A 44-year-old white man presented to the emergency department after experiencing a possible seizure. His medical history included two other lifetime events concerning for seizures at ages 14 and 29 years old. After referral to the neurology clinic, he was diagnosed with generalized tonic-clonic seizure disorder, and lamotrigine was started with up-titration according to the drug's package insert to a goal dosage of 150 mg twice/day. The patient had also been taking deer antler velvet and ginseng that he continued during his lamotrigine therapy. On day 43 of therapy, the patient presented to the emergency department with a pruritic rash that had started on his extremities and spread to his torso. He was thought to have experienced a drug reaction to lamotrigine, and the drug was discontinued. Thirteen days later, the patient was admitted from the acute care clinic for inpatient observation due to laboratory abnormalities in the setting of continued rash, headache, and myalgias. His admission laboratory results on that day were remarkable for leukocytosis, with a white blood cell count up to 17.6 × 10(3) /mm(3) , with a prominent eosinophilia of 3.04 × 10(3) /mm(3) ; his liver enzyme levels were also elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl. Use of the Drug Interaction Probability Scale indicated that a drug interaction between lamotrigine and ginseng was the probable cause (score of 5). The proposed mechanism of the interaction is ginseng inhibition of the uridine diphosphate glucuronosyltransferase 2B7 enzyme, similar to the mechanism of the interaction with valproic acid. Clinicians should be aware of this probable drug interaction and avoid coadministration of ginseng and lamotrigine or use a more conservative dose titration of lamotrigine for patients who are also taking ginseng.

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“…The inhibitory effects of SPN on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 were evaluated in pooled human liver microsomes through the use of specific CYP probe substrates (cocktail assay), as previously described [17,18] with a slight modification. Concentrations of each CYP probe in Table 1 were used close to their reported K m values [17,18].…”

Section: Reversible Inhibition Of (-)-Sophoranone Towards the Nine Cymentioning

confidence: 99%

Lack of Correlation between In Vitro and In Vivo Studies on the Inhibitory Effects of (‒)-Sophoranone on CYP2C9 Is Attributable to Low Oral Absorption and Extensive Plasma Protein Binding of (‒)-Sophoranone

et al. 2020

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(‒)-Sophoranone (SPN) is a bioactive component of Sophora tonkinensis with various pharmacological activities. This study aims to evaluate its in vitro and in vivo inhibitory potential against the nine major CYP enzymes. Of the nine tested CYPs, it exerted the strongest inhibitory effect on CYP2C9-mediated tolbutamide 4-hydroxylation with the lowest IC50 (Ki) value of 0.966 ± 0.149 μM (0.503 ± 0.0383 μM), in a competitive manner. Additionally, it strongly inhibited other CYP2C9-catalyzed diclofenac 4′-hydroxylation and losartan oxidation activities. Upon 30 min pre-incubation of human liver microsomes with SPN in the presence of NADPH, no obvious shift in IC50 was observed, suggesting that SPN is not a time-dependent inactivator of the nine CYPs. However, oral co-administration of SPN had no significant effect on the pharmacokinetics of diclofenac and 4′-hydroxydiclofenac in rats. Overall, SPN is a potent inhibitor of CYP2C9 in vitro but not in vivo. The very low permeability of SPN in Caco-2 cells (Papp value of 0.115 × 10−6 cm/s), which suggests poor absorption in vivo, and its high degree of plasma protein binding (>99.9%) may lead to the lack of in vitro–in vivo correlation. These findings will be helpful for the safe and effective clinical use of SPN.

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Evaluation of the in vitro/in vivo drug interaction potential of BST204, a purified dry extract of ginseng, and its four bioactive ginsenosides through cytochrome P450 inhibition/induction and UDP-glucuronosyltransferase inhibition

Cited by 25 publications

References 52 publications

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases

Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome Probably Induced by a Lamotrigine-Ginseng Drug Interaction

Lack of Correlation between In Vitro and In Vivo Studies on the Inhibitory Effects of (‒)-Sophoranone on CYP2C9 Is Attributable to Low Oral Absorption and Extensive Plasma Protein Binding of (‒)-Sophoranone

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