Herb–drug interaction of silymarin or silibinin on the pharmacokinetics of trazodone in rats
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)
- et al.
Drug–drug interactions of silymarin on the perspective of pharmacokinetics
J. Ethnopharmacol.
(2009) - et al.
Milk thistle (Silybum marianum) for the therapy of liver disease
Am. J. Gastroenterol.
(1998) - et al.
Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1
J. Hepatol.
(2001) - et al.
Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin
Gastroenterology
(2007) - et al.
Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy
Gastroenterology
(2008) - et al.
In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and human immunodeficiency viral protease inhibitors
Biol. Psychiatry
(2000) - et al.
High throughput and sensitive determination of trazodone and its primary metabolite, m-chlorophenylpiperazine, in human plasma by liquid chromatography-tandem mass spectrometry
J. Chromatogr. B: Anal. Technol. Biomed. Life Sci.
(2008) - et al.
Determination of trazodone in urine and pharmaceuticals using micellar liquid chromatography with fluorescence detection
J. Chromatogr. A
(2007) Assaying protein unbound drugs using microdialysis techniques
J. Chromatogr. B: Anal. Technol. Biomed. Life Sci.
(2003)- et al.
In vivo microdialysis as a tool for monitoring pharmacokinetics
Trends Anal. Chem.
(2000)
Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application
J. Pharm. Biomed. Anal.
Determination of trazodone in human plasma by liquid chromatography with fluorescence detection
J. Chromatogr.
Validation of liquid chromatographic and gas chromatographic methods. Applications to pharmacokinetics
J. Chromatogr. B: Biomed. Appl.
MDR- and CYP3A4-mediated drug-herbal interactions
Life Sci.
The role of transporters in drug interactions
Eur. J. Pharm. Sci.
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