Effects of St. John's wort extract on indinavir pharmacokinetics in rats: Differentiation of intestinal and hepatic impacts

Ho, Yunn‐Fang; Huang, D K; Hsueh, Wei; Lai, Ming Yen; Yu, Hsiu Ying; Tsai, Tung Hu

doi:10.1016/j.lfs.2009.06.008

Cited by 22 publications

(10 citation statements)

References 36 publications

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“…The decrease of C max suggested that S. flavescens could enhance intestinal drug efflux and/or first-pass metabolism, thereby reducing the portion of indinavir entering systemic circulation. A similar observation was reported in the study between St. John's wort and indinavir [16], in which both intestinal and hepatic first-pass metabolism contributed to the reduction of indinavir bioavailability. Our findings also showed a dose-dependent increase in the CL/F value of indinavir after Sophora treatment, which can be interpreted as an enhancement of systemic clearance, reduction of absorption, and/or induction of first-pass metabolism.…”

Section: Discussionsupporting

confidence: 86%

“…Piscitelli et al [15] reported that the plasma levels of indinavir were reduced in healthy volunteers after co-administration of St. John's wort. A recent study in rats confirmed that St. John's wort decreased plasma indinavir concentrations, and the interaction was attributed to the induction of indinavir metabolism in liver and intestine [16]. The therapeutic range of PIs is relatively narrow, and the antiretroviral activity correlates closely to their plasma concentrations [17].…”

Section: Introductionmentioning

confidence: 96%

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Impact of the Herbal Medicine Sophora flavescens on the Oral Pharmacokinetics of Indinavir in Rats: The Involvement of CYP3A and P-Glycoprotein

Yang

Xian

et al. 2012

PLoS ONE

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Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic stranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease inhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or 0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma indinavir concentrations, with 55%–83% decrease in AUC0-∞ and 38%–78% reduction in Cmax. The CL (Clearance)/F (fraction of dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/kg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary indinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to the controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and liver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on CYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A activity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma indinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of intestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural products and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study suggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 96%

Impact of the Herbal Medicine Sophora flavescens on the Oral Pharmacokinetics of Indinavir in Rats: The Involvement of CYP3A and P-Glycoprotein

Yang

Xian

et al. 2012

PLoS ONE

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“…Induction of CYP3A was also reported in this study [80] [82]. Studies on the influence of HP on CYP isozymes failed to demonstrate the induction of CYP1A2 by HP [13,29].…”

Section: Antiandrogenics 22121 Finasteridesupporting

confidence: 58%

“…Indinavir [80] In vivo Ivabradine [61] Open-label, nonrandomized 12 healthy volunteers 10 mg single dose Extract/tablet 300 mg t.i.d.…”

Section: Weeksmentioning

confidence: 99%

An update on the ability of St. John's wort to affect the metabolism of other drugs

Rahimi

Abdollahi

2012

Expert Opinion on Drug Metabolism & Toxicology

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There are a number of drugs whose metabolism is reduced by HP. The authors point out that metabolic interactions between HP and drugs are not always unfavorable and sometimes have benefits (e.g., reduction of irinotecan toxicity and increase in clopidogrel responsiveness). HP does not have a significant influence on the kinetics of drugs such as carbamazepine, ibuprofen and theophylline. The use of HP preparations is not recommended in people who are taking immunosuppressants or cardiovascular drugs. With other medications, it is recommended that practitioners should only use HP preparations with a low hyperforin content and under careful monitoring. It is also recommended that because of the reduction in the bioavailability of oral contraceptives administered concurrently with HP, women who use HP preparations should use additional preventive methods to avoid unintended pregnancy.

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“…This result may be partially affected by the difference in the time course of CYP3A induction level between liver and intestine. In many studies, an inducer was administered multiple times to induce CYP3A (Ho et al, 2009;Minocha et al, 2011;Nieminen et al, 2009); however, administration of only a single dose of an inducer may be sufficient to increase the hepatic CYP3A level. These results may be because of the difference in DEX-P absorption between single and multiple-dose groups.…”

Section: Discussionmentioning

confidence: 99%

Time-dependent changes in hepatic and intestinal induction of cytochrome P450 3A after administration of dexamethasone to rats

et al. 2013

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We investigated the effects of the dose of and the number of times an inducer was administered and the duration of induction of hepatic and intestinal cytochrome P450 3A (CYP3A) in rats using dexamethasone 21-phosphate (DEX-P) and midazolam (MDZ) as an inducer and a substrate to CYP3A, respectively. The number of times DEX-P was administered was not a significant factor in the induction of either hepatic or intestinal CYP3A; however, administration of DEX-P multiple times markedly decreased the bioavailability of DEX-P by self-induction of CYP3A. CYP3A induction in the liver increased depending on the dose of DEX-P, whereas that in intestine showed a mild increase, but the induction level was almost constant regardless of the dose of DEX-P. Administration of a single dose of DEX-P showed a temporal increase in CYP3A activity in both tissues and the induction ratios reached maximum values at 12 h after DEX-P administration. On the other hand, a mild increase of CYP3A activity, which lasted for at least 48 h, was observed in both tissues after administration of multiple doses. Some physiological compounds such as cytokines might be involved in decreasing the CYP3A activity to maintain homeostasis of the body.

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Effects of St. John's wort extract on indinavir pharmacokinetics in rats: Differentiation of intestinal and hepatic impacts

Cited by 22 publications

References 36 publications

Impact of the Herbal Medicine Sophora flavescens on the Oral Pharmacokinetics of Indinavir in Rats: The Involvement of CYP3A and P-Glycoprotein

Impact of the Herbal Medicine Sophora flavescens on the Oral Pharmacokinetics of Indinavir in Rats: The Involvement of CYP3A and P-Glycoprotein

An update on the ability of St. John's wort to affect the metabolism of other drugs

Time-dependent changes in hepatic and intestinal induction of cytochrome P450 3A after administration of dexamethasone to rats

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