Hyperforin content determines the magnitude of the St John's wort–cyclosporine drug interaction

Mai, Ingrid; Bauer, Steffen; Perloff, Elke S.; Johne, Andreas; Uehleke, Bernhard; Frank, Bruno; Budde, Klemens; Roots, Ivar

doi:10.1016/j.clpt.2004.07.004

Cited by 133 publications

(111 citation statements)

References 40 publications

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“…In these studies using other, less sensitive CYP3A substrates (alprazolam, ethinyl estradiol, and cyclosporine A) no interaction was found [12,20]. On the other hand, all 19 studies that used extracts with high hyperforin content showed relevant CYP3A induction [12].…”

Section: Discussionmentioning

confidence: 98%

“…For a mean 11% decrease in exposure to a CYP3A substrate to result in a clinically relevant change in efficacy would require an extremely steep concentration-effect relationship of that CYP3A substrate. In a drug interaction study with cyclosporin A (a narrow therapeutic range CYP3A substrate) and two St. John's wort preparations, cyclosporin A dosage was adjusted only when cyclosporin A trough levels changed by more than 20% [20]. In summary, a minor significant reduction in midazolam AUC (increase in oral midazolam clearance) was found after medication with a St. John's wort powder with low hyperforin content.…”

Section: Discussionmentioning

confidence: 98%

“…While the studies using hyperforin-rich St. John's wort extracts consistently reported clinically relevant interaction consistent with CYP3A induction, only a few studies with extracts with low hyperforin content have been performed [6,12]. All of these studies using either alprazolam, ethinyl estradiol, or cyclosporine A as CYP3A substrates demonstrated no significant effect on CYP3A [12,20,21].…”

Section: Introductionmentioning

confidence: 99%

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No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers

Mueller

Majcher-Peszynska

Mundkowski

et al. 2008

Eur J Clin Pharmacol

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Objective Induction of CYP3A by St. John's wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. Methods Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. Results Midazolam AUC 0-∞ slightly decreased from 124.0 ± 62.5 ng/ml·h at baseline to 105.6 ± 53.2 ng/ml·h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: −22.8 to 0.21). No significant change in midazolam C max , t 1/2 and t max was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70-1.43. Conclusion Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers

Mueller

Majcher-Peszynska

Mundkowski

et al. 2008

Eur J Clin Pharmacol

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“…Many cytochrome P450 (CYP) mediated interactions have been reported between drugs and herbal medicines [1][2][3]. CYP3A4 is the most important human enzyme in the CYP family due to its high relative abundance in the body and its broad substrate specificity [4].…”

Section: Introductionmentioning

confidence: 99%

Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

Qiu

Wang

Zhang

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Many cytochrome P450 mediated interactions have been reported between drug and herbal medicines. In particular, CYP3A4 is known to play a critical role in several clinically relevant herb-drug interactions. Midazolam has been reported to be one of the preferred in vivo CYP3A probes.• It has been reported that the lipophilic components of danshen could induce CYP3A in C57BL/6J mice, that cryptotanshinone and tanshinone IIA of danshen extract could activate human PXR and consequently induce the expression of the CYP3A4 gene. WHAT THIS STUDY ADDS• Co-administration of multiple doses of danshen tablets caused an increase in apparent oral clearance of midazolam by 35.4%, a corresponding decline in Cmax by 31.1% and a decline in AUC(0,•) by 27.0% in human volunteers. The t1/2 of midazolam and 1-hydroxymidazolam were not changed, and the Cmax and AUC(0,•) ratio of midazolam to 1-hydroxymidazolam were not affected. The results suggested that multiple dose administration of danshen tablets could induce CYP3A4 in the gut, thereby increasing the clearance of midazolam. Therefore, caution should be taken when danshen products containing lipophilic components are used in combination with therapeutic drugs metabolized by CYP3A. AIMSTo assess the effect of danshen extract on CYP3A4 activity using midazolam as an in vivo probe. METHODSA sequential, open-label, two-period pharmacokinetic interaction study design was used to compare midazolam pharmacokinetic parameters before and after 14 days of administration of danshen tablets. Twelve healthy volunteers received a single oral dose (15 mg) of midazolam followed by danshen tablets (four tablets orally, three times a day) for 14 days. On the last day of the study they received four danshen tablets with a 15 mg midazolam tablet and plasma concentrations of midazolam and its corresponding metabolite 1-hydroxylmidazolam were measured prior to and after the administration of danshen tablets periodically for 12 h. RESULTSThe 90% confidence intervals of Cmax, t1/2, CL/F and AUC(0,•) of midazolam before and after administration of danshen tablets were (0.559, 0.849), (0.908, 1.142), (1.086, 1.688) and (0.592, 0.921), respectively; and those of Cmax, t1/2 and AUC(0,•) of 1-hydroxylmidazolam after vs. before administration of danshen tablets were (0.633, 0.923), (0.801, 1.210) and (0.573, 0.980), respectively. Ratios of geometric LS means of Cmax(1OHMid) : Cmax(Mid) and AUCmax(1OHMid) : AUCmax(Mid) (after vs. before 14-day danshen) were 1.072 and 1.035, respectively. CONCLUSIONSOur findings suggest that multiple dose administration of danshen tablets may induce CYP3A4 in the gut. Accordingly, caution should be taken when danshen products are used in combination with therapeutic drugs metabolized by CYP3A. Danshen, the dried root of Salvia miltiorrhiza, has been used for more than 2000 years in China for the treatment of numerous ailments [6]. Danshen extract contains both hydrophilic components (danshensu, protocatechuic aldehyde and salvianolic a...

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“…Fortes evidências demonstradas em estudos pré-clínicos e ensaios clínicos, sugerem que o extrato de HP interfere no metabolismo citocromodependente de vários fármacos, especialmente por modular o sistema de isoenzimas do citocromo P450 (CYP 450), em especial o CYP3A4, um dos mais importantes desta família (Moore, 2000;Gurley, 2002;Watkins, 2003;Mai, 2004;Gurley, 2005).…”

Section: Interações Medicamentosasunclassified

Aspectos botânicos, químicos, farmacológicos e terapêuticos do Hypericum perforatum L.

Alves

Moraes

Freitas

et al. 2014

Rev. bras. plantas med.

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RESUMO: Estima-se que aproximadamente 25% das drogas prescritas em todo o mundo são oriundas de espécies vegetais. Dentre as plantas com alto potencial medicinal, se destaca o Hypericum perforatum L. (HP), planta herbácea perene, pertencente à família Hypericaceae. Extratos orgânicos e aquosos de HP têm sido utilizados na medicina popular e em testes pré-clínicos para o tratamento e prevenção de diversas doenças através de efeitos nefroprotetores, atividades antioxidante, antifúngica, ansiolítica, antiviral e cicatrizante. Estudos clínicos indicaram que esta espécie pode ser útil no tratamento de desordens originadas do sistema nervoso central, especialmente na depressão unipolar. HP contém, ao menos, dez classes de compostos biologicamente ativos, dentre eles antraquinonas/naftodiantronas, derivados de floroglucinol, flavonoides, biflavonas, xantonas, óleos voláteis, aminoácidos, vitamina C, cumarinas, taninos e carotenoides. Ao mesmo tempo em que os constituintes possuem relevantes efeitos farmacológicos, os mesmos podem prejudicar, por antagonismo farmacocinético (interação com algumas enzimas do citocromo), a eficácia de outros fármacos. Devido a relevante importância do HP como agente terapêutico, ressalta-se a importância do desenvolvimento de novos estudos com o intuito de elucidar questões ainda controversas acerca do extrato de HP, e.g., dose, melhor horário para colheita, padronização dos extratos, e possíveis efeitos tóxicos, podendo assim, definir claramente os riscos e benefícios da utilização desta planta. Palavras-chave:Hypericum perforatum, depressão, hiperforina, hipericina.ABSTRACT: Botanical, chemical, pharmacological and therapeutic aspects of Hypericum perforatum L. It is estimated that approximately 25% of prescribed drugs are derived from plant species. Among the plants with high medicinal potential, it highlights the Hypericum perforatum L. (HP), perennial herbaceous plant belonging to the family Hypericaceae. Organic and aqueous extracts of HP have been used in folk medicine and in pre-clinical testing for the treatment and prevention of several diseases through effects nefroprotetores, antioxidant, antifungal, anxiolytic, wound healing and antiviral activities. Clinical studies indicated that this specie can be useful in the treatment of central nervous system disorders, especially to unipolar depression. HP contains at least ten classes of biologically active compounds, including anthraquinones/ naftodiantronas, phloroglucinol derivatives, flavonoids, biflavones, xanthones, volatile oils, amino acids, vitamin C, coumarins, carotenoids and tannins. At the same time that the secondary metabolites have important pharmacological effects, they can impair the effectiveness of other drugs by pharmacokinetic antagonism.

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Hyperforin content determines the magnitude of the St John's wort–cyclosporine drug interaction

Abstract: HYF content of SJW extracts significantly affects the extent of the pharmacokinetic interaction between CSA and SJW.

Cited by 133 publications

References 40 publications

No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers

No clinically relevant CYP3A induction after St. John’s wort with low hyperforin content in healthy volunteers

Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

Aspectos botânicos, químicos, farmacológicos e terapêuticos do Hypericum perforatum L.

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