Coadministration of Milk Thistle and Indinavir in Healthy Subjects

Robert DiCenzo, Pharm.D., Mark Shelton, Pharm.D., Kelly Jordan, Pharm.D., Christine Koval, M.D., Alan Forrest, Pharm.D., Richard Reichman, M.D., Gene Morse, Pharm.D.


Pharmacotherapy. 2003;23(7) 

In This Article

Abstract and Introduction

Study Objective: To determine if milk thistle (silymarin) alters the pharmacokinetics of indinavir.
Design: Sequential crossover trial.
Setting: General clinical research center.
Subjects: Ten healthy subjects.
Intervention: Indinavir 800 mg 3 times/day was given for four doses on days 1 and 2. Silymarin 160 mg 3 times/day was given on days 3-15. On day 16 and for one dose on day 17, both drugs were given at the same dosages.
Measurements and Main Results: Indinavir's pharmacokinetic parameters were evaluated at steady state both before and after administration of 14 days of silymarin. Blood samples were collected -0.25, 0.5, 1, 2, 3, 4, and 5 hours after indinavir dosing and assayed by high-performance liquid chromatography. The final pharmacokinetic model had first-order absorption after a lag time, and two compartments with first-order elimination from the central compartment. When given alone and combined with silymarin, respectively, the geometric mean (95% confidence interval [CI]) steady-state indinavir area under the plasma concentration-time curve was 20.7 hr mg/L (15.3-28.2 hr mg/L) and 19.4 hr mg/L (15.8-23.6 hr mg/L) and the trough plasma concentration was 0.340 mg/L (0.232-0.497 mg/L) and 0.232 mg/L (0.129-0.419 mg/L).
Conclusion: Silymarin has no apparent effect on indinavir plasma concentrations.

As complementary alternative medicine (CAM) is practiced increasingly among adults infected with human immunodeficiency virus (HIV), it is ever more necessary to know if CAM will influence antiretroviral therapy. A recent survey of 118 HIV-infected patients receiving highly active antiretroviral therapy (HAART) showed that 38% of respondents were taking CAM. Of particular concern is that physicians were unaware of this in 67% of patients taking herbal products.[1]

Approximately one third of HIV infected patients are coinfected with hepatitis C virus (HCV). Hepatitis C infection can progress to liver failure, and this progression may be especially rapid in coinfected patients.[2] Milk thistle, an herbal supplement, is purported to decrease the risk of developing liver failure; therefore, a number of HIV-infected patients who are also infected with HCV are interested in taking the supplement.[3]

The active component of milk thistle is thought to be silymarin. Silymarin has the potential to influence drug metabolism by decreasing the metabolic activity of cytochrome P450 (CYP) 3A4, a ubiquitous enzyme responsible for hepatic and intestinal metabolism of many antiretroviral agents, including indinavir.[4,5] Silymarin also may alter drug absorption, distribution, and elimination through inhibition of P-glycoprotein (P-gp).[6] P-glyco-protein is an active drug transporter, has a wide substrate range, and is abundant in the apical membrane of many pharmacologically important barriers such as intestinal epithelium, and the blood-brain, blood-nerve, blood-testis, and maternofetal barriers.[7] Flow cytometric analysis confirmed significant P-gp expression in both CD4+ and CD8+ cells; therefore, in addition to playing a role in limiting drug bioavailability, P-gp may limit brain, testis, fetal, and intracellular penetration of drugs.[8]

Indinavir belongs to the protease inhibitor class of antiretroviral drugs and is an effective component of HAART. It is also a substrate of both CYP450 and P-gp.[5,7,9] The purpose of this trial was to determine if silymarin influences the pharmacokinetics of indinavir.


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