Herb–drug interaction of silymarin or silibinin on the pharmacokinetics of trazodone in rats

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Abstract

Silymarin, one of the most popular herbal medicines, has been widely used for its hepatoprotective effects. This study investigates the effects of repeated dose of silymarin and its major ingredient, silibinin, on the pharmacokinetics of the antidepressant trazodone. Treatment groups included vehicle control group, concomitant silymarin at 1.0 g/kg dose, and four 7-day repeated dose induction groups of 0.5 and 1.0 g/kg silymarin and 0.175 and 0.35 g/kg silibinin. Microdialysis coupled with high performance liquid chromatography (HPLC) was used to simultaneously monitor blood and bile concentrations of trazodone in the rats. Results indicate that pretreatment with an extremely high dose of 1.0 g/kg silymarin significantly decreases trazodone's area under concentration curve (AUC), distribution half-life (t1/2,α), elimination half-life (t1/2,β), and mean residence time (MRT). In conclusion, the present study finds no marked effects of silymarin and silibinin on the pharmacokinetics of trazodone under normal daily doses and the relative safety of taking the herb with trazodone.

Introduction

Silymarin extracted from the seeds of milk thistle (Silybum marianum) is composed of many polyphenolic flavonoids, including silibinin (the major one), isosilybin, silychristin and silidianin [1]. Silymarin has been used for centuries due to its well-known hepatoprotective effect, and it has various pharmacological properties, such as being an anti-oxidant [2], anti-inflammatory [2], anti-fibrotic [3], and inhibiting the generation of oxidized low-density lipoproteins [4]. Recently, silymarin and silibinin have been approved for clinical studies in treating the hepatitis C virus [5], [6]. The current standard treatment for hepatitis C is based on pegylated interferon-α (IFN-α) together with ribavirin, and the incidence of depression caused by IFN-α is 21–58%, so antidepressants are necessary for depression management [7]. Silymarin is undergoing clinical trials as a treatment for hepatitis C, and other treatments for this disease cause depression, so the interaction between silymarin and antidepressants is being investigated.

Trazodone hydrochloride is one of the second-generation antidepressants, and it acts as a 5-HT2A antagonist and 5-HT reuptake inhibitor. Trazodone is metabolized by cytochrome P450 (P450) enzymes, specifically CYP3A4 and CYP1A2 [8], [9]. Zalma et al. demonstrated that CYP3A4-mediated clearance of trazodone is inhibited by ketoconazole, ritonavir and indinavir [10]. Previous studies have indicated that trazodone exhibits a biphasic excretion pattern [11], [12], and it is widely metabolized in rats [8]. Thus, affecting CYP 3A4 may underlie pharmacokinetic interactions of trazodone. Trazodone is 85–95% protein-bound [11], [13], which means that tremendous changes in pharmacology or adverse effects will occur when its relatively small “protein-unbound” portion is altered.

The frequent use of silymarin has a potential to interact with other medications, and more information is needed for its safe usage when co-administration with other drugs. Previous in vitro study indicated that silymarin inhibited the activity of CYP3A4 and uridine diphosphoglucuronic acid [14]. In addition, a clinical study revealed that silymarin may induce both intestine P-glycoprotein and CYP3A4 with repeated administrations [15]. An herb–drug interaction might occur when silymarin and trazodone are co-administered, since trazodone is mainly metabolized by CYP3A4. Therefore, we hypothesize that pretreated silymarin may affect trazodone level in the body in vivo.

The protein-unbound form is also called the free form or therapeutic portion of the drug because generally it can be distributed into the tissues, exert pharmacological or toxic effects, be metabolized and excreted [16], [17]. Since trazodone is highly protein-bound, a microdialysis technique was used to more precisely describe the pharmacokinetics of protein-unbound trazodone. To our knowledge, there has been limited investigation of whether the pharmacokinetics of trazodone will be affected by silymarin. Thus, this study investigates the effect of silymarin and its main active flavonolignan, silibinin, on the pharmacokinetics of trazodone in rats.

Section snippets

Chemicals and reagents

Trazodone hydrochloride, silymarin, silibinin, α-chloralose, urethane, and polythene glycol 200 (PEG 200) were purchased from Sigma–Aldrich Chemicals (St. Louis, MO, USA). The silibinin content in silymarin determined by HPLC in our laboratory was about 35%, and the assay was modified from our previous study [18]. Briefly, the mobile phase consisted of acetonitrile and 10 mM NaH2PO4 (39:61, v/v) with a 1.2 mL/min flow rate, and silibinin was separated by a reversed-phase column (Purospher STAR

Analytical method validation

HPLC-fluorescence detection method separated trazodone from the matrix within 10 min, indicating good selectivity. Fig. 1A represents the blank blood dialysate, and Fig. 1B shows the blank dialysate spiked with trazodone (0.05 μg/mL). Fig. 1C shows the blood sample containing trazodone (0.043 μg/mL) after administration of trazodone (5 mg/kg, i.v.). The chromatogram of bile was similar. The linear range of trazodone in blood and bile dialysates was 2–1000 and 5–500 ng/mL, respectively. Good linear

Discussion

It is inevitable that the surgical procedure and the concurrent anesthesia may affect the pharmacokinetics of trazodone. Therefore, a control group, which received vehicle only, was included in this study. The statistical comparison of data against the control group was performed to know the influence of silymarin or silibinin on the pharmacokinetics of trazodone. In addition, a concomitant silymarin group (1.0 g/kg silymarin, 4 h before trazodone administration) was conducted to observe the

Conflict of interest statement

None.

Acknowledgments

Funding for this study was provided in part by Research Grants: NSC96-2113-M-010-003-MY3 and NSC96-2628-B-010-006-MY3 from the National Science Council, Taiwan; TCH 97002-62-037 from Taipei City Hospital, Taiwan and V98E2-010 from Taipei Veterans General Hospital, Taiwan. The authors also would like to thank Christof Karrick Arnold for editing this manuscript.

References (31)

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