Effect of Milk Thistle on the Pharmacokinetics
Study Objective. To characterize the pharmacokinetics of indinavir in the presence and absence of milk thistle and to determine the offset of any effect of milk thistle on indinavir disposition.
Design. Prospective open-label drug interaction study.
Setting. Outpatient clinic.
Subjects. Ten healthy volunteers.
Intervention. Blood samples were collected over 8 hours after the volunteers took four doses of indinavir 800 mg every 8 hours on an empty stomach for baseline pharmacokinetics. This dosing and sampling were repeated after the subjects took milk thistle 175 mg (confirmed to contain silymarin 153 mg, the active ingredient) 3 times/day for 3 weeks. After an 11-day washout, indinavir dosing and blood sampling were repeated to evaluate the offset of any potential interaction.
Measurements and Main Results. Indinavir concentrations were measured by using a validated high-performance liquid chromatography method. The following pharmacokinetic parameters were determined: highest concentration (Cmax), hour-0 concentration, hour-8 concentration (C8), time to reach Cmax, and area under the plasma concentration-time curve over the 8-hour dosing interval (AUC8). Milk thistle did not alter significantly the overall exposure of indinavir, as evidenced by a 9% reduction in the indinavir AUC8 after 3 weeks of dosing with milk thistle, although the least squares mean trough level (C8) was significantly decreased by 25%.
Conclusion. Milk thistle in commonly administered dosages should not interfere with indinavir therapy in patients infected with the human immunodeficiency virus.
Patients infected with the human immunodeficiency virus (HIV) often take complementary and alternative drugs, despite limited data on efficacy and an increasing body of literature suggesting that many of these compounds can alter the metabolism of antiretroviral drugs. We previously showed that St. John's wort and garlic supplements decrease the exposure of protease inhibitors. These interactions could lead to a suboptimal antiretroviral response and the development of antiretroviral resistance. In light of these data, other popular herbal remedies must be evaluated for their interaction potential with HIV-related drugs.
Milk thistle (Silybum marianum) is an herbal remedy commonly taken by patients with HIV infection for the treatment or prevention of liver disease caused by hepatitis and hepatotoxic drugs. The active constituent of milk thistle, silymarin, consists of a mixture of three biologically active flavonoids that are found in the fruit, seeds, and leaves of the plant. Clinical data are limited with regard to milk thistle's effects on drugs that are metabolized by the cytochrome P450 (CYP) system, although in vitro evidence suggests that silymarin inhibits drug metabolism. Because of the widespread use of milk thistle, we wanted to evaluate the effect of milk thistle on protease inhibitors. We sought to characterize the pharmacokinetics of indinavir in the presence and absence of a commercial milk thistle preparation and to determine the offset of any effect of milk thistle on indinavir disposition.
Study Objective. To characterize the pharmacokinetics of indinavir in the presence and absence of milk thistle and to determine the offset of any effect of milk thistle on indinavir disposition.
Design. Prospective open-label drug interaction study.
Setting. Outpatient clinic.
Subjects. Ten healthy volunteers.
Intervention. Blood samples were collected over 8 hours after the volunteers took four doses of indinavir 800 mg every 8 hours on an empty stomach for baseline pharmacokinetics. This dosing and sampling were repeated after the subjects took milk thistle 175 mg (confirmed to contain silymarin 153 mg, the active ingredient) 3 times/day for 3 weeks. After an 11-day washout, indinavir dosing and blood sampling were repeated to evaluate the offset of any potential interaction.
Measurements and Main Results. Indinavir concentrations were measured by using a validated high-performance liquid chromatography method. The following pharmacokinetic parameters were determined: highest concentration (Cmax), hour-0 concentration, hour-8 concentration (C8), time to reach Cmax, and area under the plasma concentration-time curve over the 8-hour dosing interval (AUC8). Milk thistle did not alter significantly the overall exposure of indinavir, as evidenced by a 9% reduction in the indinavir AUC8 after 3 weeks of dosing with milk thistle, although the least squares mean trough level (C8) was significantly decreased by 25%.
Conclusion. Milk thistle in commonly administered dosages should not interfere with indinavir therapy in patients infected with the human immunodeficiency virus.
Patients infected with the human immunodeficiency virus (HIV) often take complementary and alternative drugs, despite limited data on efficacy and an increasing body of literature suggesting that many of these compounds can alter the metabolism of antiretroviral drugs. We previously showed that St. John's wort and garlic supplements decrease the exposure of protease inhibitors. These interactions could lead to a suboptimal antiretroviral response and the development of antiretroviral resistance. In light of these data, other popular herbal remedies must be evaluated for their interaction potential with HIV-related drugs.
Milk thistle (Silybum marianum) is an herbal remedy commonly taken by patients with HIV infection for the treatment or prevention of liver disease caused by hepatitis and hepatotoxic drugs. The active constituent of milk thistle, silymarin, consists of a mixture of three biologically active flavonoids that are found in the fruit, seeds, and leaves of the plant. Clinical data are limited with regard to milk thistle's effects on drugs that are metabolized by the cytochrome P450 (CYP) system, although in vitro evidence suggests that silymarin inhibits drug metabolism. Because of the widespread use of milk thistle, we wanted to evaluate the effect of milk thistle on protease inhibitors. We sought to characterize the pharmacokinetics of indinavir in the presence and absence of a commercial milk thistle preparation and to determine the offset of any effect of milk thistle on indinavir disposition.
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