Physiologically Based Pharmacokinetic Modelling of Hyperforin to Predict Drug Interactions with St John’s Wort

Adiwidjaja, Jeffry; Boddy, Alan V.; McLachlan, Andrew J.

doi:10.1007/s40262-019-00736-6

Cited by 21 publications

(28 citation statements)

References 61 publications

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“…The pharmacokinetic drug interaction potential with St. John's wort is mainly attributed to the CYP3A induction activity upon prolonged usage, leading to reduced plasma concentration and thereby compromised efficacy of the co-administered CYP3A substrate drugs (Markowitz et al, 2003;Adiwidjaja et al, 2019). Our findings on CYP3A inhibition by St. John's wort is consistent with the reports by others that its major active constituent, hyperforin, has been reported to have both CYP3A inducing (Hellum et al, 2007) and inhibitory (Obach, 2000;Komoroski et al, 2004) effects.…”

Section: Discussionsupporting

confidence: 88%

Application of Cryopreserved Human Intestinal Mucosa and Cryopreserved Human Enterocytes in the Evaluation of Herb-Drug Interactions: Evaluation of CYP3A Inhibitory Potential of Grapefruit Juice and Commercial Formulations of Twenty-Nine Herbal Supplements

Loretz

Alam

et al. 2020

Drug Metab Dispos

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Commercial formulations of 29 commonly used herbal supplements (HS) and grapefruit juice were evaluated for drug interaction potential via quantification of their CYP3A inhibitory potential in two in vitro experimental models of human small intestine, cryopreserved human intestinal mucosa (CHIM) and cryopreserved human enterocytes (CHE). Two CYP3A substrates were used-in the studies with CHIM, CYP3A activity was quantified via LC/MS-MS quantification of midazolam 1'-hydroxylation while in CHE, luciferin IPA metabolism to luciferin was quantified by luminescence. Upon treatment of CHIM with the estimated lumen concentration of the HS upon each oral administration (manufacturers' recommended dosage dissolved in 200 mL of culture medium), >80% CYP3A inhibition was observed for green tea extract, St. John's wort, valerian root, horehound and grapefruit juice. Less than 50% inhibition was observed for fenugreek, aloe vera, guarana, soy isoflavone, maca, echinacea, spirulina, evening primrose, milk thistle, cranberry, red yeast rice, rhodiola, ginkgo biloba, turmeric, curcumin, white kidney bean,, garlic, cinnamon, saw palmetto berries, panax ginseng, black elderberry, wheat grass juice, flaxseed oil, black cohosh, and ginger root. The results were confirmed in a a dose-response study with HS obtained from three suppliers for the four inhibitory HS (green tea extract, horehound, St. John's wort, valerian root), and three representative non-inhibitory HS (black cohosh, black elderberry, echinacea). Similar results were obtained with the inhibitory HS in CHE. The results illustrate that CHIM and CHE represent physiologically relevant in vitro experimental models for the evaluation of drug interaction potential of herbal supplements. Based on the results, green tea extract, horehound, St. John's wort, and valerian root may cause drug interactions with orally administered drugs that are CYP3A substrates as observed for grapefruit juice. Significance Statement In vitro evaluation of 29 popular herbal supplements in cryopreserved human intestinal mucosa identified green tea extract, horehound, St. John's wort, valerian root to have CYP3A inhibitory potential similar to that for grapefruit juice, suggesting their potential to have clinically-significant pharmacokinetic interaction with orally administered drugs that are CYP3A substrates. The results suggest that CHIM can be used for in vitro evaluation of drug interactions involving enteric drug metabolism.

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Section: Discussionsupporting

confidence: 88%

Application of Cryopreserved Human Intestinal Mucosa and Cryopreserved Human Enterocytes in the Evaluation of Herb-Drug Interactions: Evaluation of CYP3A Inhibitory Potential of Grapefruit Juice and Commercial Formulations of Twenty-Nine Herbal Supplements

Loretz

Alam

et al. 2020

Drug Metab Dispos

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“…This was due to limited residual CYP3A activity which can further be inhibited in the former. Since imatinib undergoes little to no metabolism in the enterocytes (Barratt and Somogyi, 2017), inducers of CYP3A confined to intestinal enzymes (e.g., hyperforin in St John's wort) are unlikely to affect steady-state CL/F of imatinib (Adiwidjaja et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

2020

Self Cite

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Long-term use of imatinib is effective and well-tolerated in children with chronic myeloid leukaemia (CML) yet defining an optimal dosing regimen for imatinib in younger patients is a challenge. The potential interactions between imatinib and coadministered drugs in this "special" population also remains largely unexplored. This study implements a physiologically based pharmacokinetic (PBPK) modeling approach to investigate optimal dosing regimens and potential drug interactions with imatinib in the paediatric population. A PBPK model for imatinib was developed in the Simcyp Simulator (version 17) utilizing in silico, in vitro drug metabolism, and in vivo pharmacokinetic data and verified using an independent set of published clinical pharmacokinetic data. The model was then extrapolated to children and adolescents (aged 2-18 years) by incorporating developmental changes in organ size and maturation of drug-metabolising enzymes and plasma protein responsible for imatinib disposition. The PBPK model described imatinib pharmacokinetics in adult and paediatric populations and predicted drug interaction with carbamazepine, a cytochrome P450 (CYP)3A4 and 2C8 inducer, with a good accuracy (evaluated by visual inspections of the simulation results and predicted pharmacokinetic parameters that were within 1.25-fold of the clinically observed values). The PBPK simulation suggests that the optimal dosing regimen range for imatinib is 230-340 mg/m 2 /d in paediatrics, which is supported by the recommended initial dose for treatment of childhood CML. The simulations also highlighted that children and adults being treated with imatinib have similar vulnerability to CYP modulations. A PBPK model for imatinib was successfully developed with an excellent performance in predicting imatinib pharmacokinetics across age groups. This PBPK model is beneficial to guide optimal dosing regimens for imatinib and predict drug interactions with CYP modulators in the paediatric population.

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“…For example, Saint John's Wort, a well-studied example of such an HDI, and hyperforin is thought to be the uridine 5′-diphosphoglucuronisyl transferase (UGTs) enzyme activities [2,3]. For example, Saint John's Wort, a well-studied example of such an HDI, and hyperforin is thought to be the main component that modulates CYP3A and CYP2C9 enzymes [4]. Many wellknown herbal medicines including ginseng [5,6], ginkgo [7], green tea [8], and Schisandra [9] have also been reported to result in pharmacokinetic drug interactions with clinical drugs.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes

Seo

Kim

et al. 2021

Pharmaceutics

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Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known to possess anti-cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have reported the ability of some lignans to modulate some cytochrome P450 (P450) enzymes. Herein, we investigated the drug interaction potential of six dibenzocyclooctadiene lignans (schisandrin, gomisin A, B, C, and N, and wuweizisu C) on nine P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) and six uridine 5′-diphosphoglucuronosyl transferase (UGT) enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that lignans with one or two methylenedioxyphenyl groups inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 activities in a time- and concentration-dependent like their CYP3A inhibition. In comparison, these lignans do not induce time-dependent inhibition of CYP1A2, CYP2A6, and CYP2D6. The time-dependent inhibition of gomisin A against CYP2C8, CYP2C19, and CYP3A4 was also elucidated using glutathione as a trapping reagent of reactive carbene metabolites given that gomisin A strongly inhibits these P450 enzymes in a time-dependent manner. A glutathione conjugate of gomisin A was generated in reactions with human recombinant CYP2C8, CYP2C19, and CYP3A4. This suggests that the time-dependent inhibition of gomisin A against CYP2C8, CYP2C9, and CYP3A4 is due to the production of carbene reactive metabolite. Six of the lignans we tested inhibited the activities of six UGT to a limited extent (IC50 > 15 μM). This information may aid the prediction of possible drug interactions between Schisandra lignans and any co-administered drugs which are mainly metabolized by P450s.

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Physiologically Based Pharmacokinetic Modelling of Hyperforin to Predict Drug Interactions with St John’s Wort

Cited by 21 publications

References 61 publications

Application of Cryopreserved Human Intestinal Mucosa and Cryopreserved Human Enterocytes in the Evaluation of Herb-Drug Interactions: Evaluation of CYP3A Inhibitory Potential of Grapefruit Juice and Commercial Formulations of Twenty-Nine Herbal Supplements

Application of Cryopreserved Human Intestinal Mucosa and Cryopreserved Human Enterocytes in the Evaluation of Herb-Drug Interactions: Evaluation of CYP3A Inhibitory Potential of Grapefruit Juice and Commercial Formulations of Twenty-Nine Herbal Supplements

Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes

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