Milk thistle can reduce levels of indinavir in the blood

13 November 2002. Related: PK and drug interactions.

Hosein SR, for CATIE TreatmentUpdate

Background and summary

Some people with HIV/AIDS (PHAs) use vitamins, supplements and herbs to complement their drug-based therapy. One complementary therapy that is popular is the herb milk thistle. Traditionally, this herb has been used for the treatment of liver disorders such as jaundice (yellowing of the skin and whites of the eyes). Recent laboratory research on cells suggests that milk thistle extracts may be useful in helping the liver and kidneys recover from damage caused by certain drugs and alcohol.

A concern with herbal supplements is that they may interact with medications by either raising or lowering levels of medications used to treat HIV/AIDS and other conditions. Interactions can occur because many drugs are processed by enzymes in the liver. Herbs and drugs can speed up or slow down the activity of these enzymes, raising or lowering drug levels.

If an interaction raises drug levels, new or intensified side effects may occur. Similarly, if drug levels are lowered, the effectiveness of treatments will also be reduced. In the case of therapies for HIV/AIDS, this could lead to the development of drug-resistant HIV and reduced treatment options in the future.

This concern is not just a theory. The plant St John’s wort, often used for managing anxiety and mild depression, can interact with many drugs, including two classes used for the treatment of HIV/AIDS:

• protease inhibitors (PIs)
• non-nucleoside reverse transcriptase inhibitors (non-nukes or NNRTIs)

In laboratory experiments with cells, researchers found that extracts from milk thistle significantly reduced the activity of certain liver enzymes, specifically those used to process PIs and non-nukes. In theory, these extracts could raise levels of PIs and non-nukes in the blood.

To find out if this was the case in people, researchers at the National Institutes of Health in Bethesda, Maryland, conducted a small study. They found that, overall, milk thistle reduced levels of the PI indinavir (Crixivan) in the blood by about 9%. They also found that just before it was time to take the next dose of indinavir, in subjects using indinavir and milk thistle, blood levels of this drug fell 25% lower than they normally should. The implications of these findings are discussed later in this report.

Study details

Researchers enrolled 10 healthy, HIV negative subjects (four females, six males) whose average age was 35 years. At different times over a period of six weeks, subjects received the following regimens:

• indinavir 800 mg every eight hours on an empty stomach
• indinavir and milk thistle
• milk thistle only

The brand of milk thistle used in the study was Thisilyn, made by Nature’s Way. This product contained 80% silymarin – one of the compounds responsible for the herb’s beneficial effect. Subjects received 175 mg three times daily with meals.

A note about drug levels

The highest level a drug reaches in the blood is called the “peak” and the lowest level the “trough.” The level of a drug in the blood usually reaches the trough level when it’s time to take the next scheduled dose. If viral resistance is to develop, it often occurs when drug levels are at their lowest – the trough.

Results: indinavir and milk thistle

Overall, the total amount of indinavir that entered the blood was decreased by only 9% with the use of milk thistle. Perhaps more significant were the changes in trough levels of indinavir. Levels of this drug are at their lowest just before it’s time to take the next dose – eight hours after the last dose was taken. Milk thistle lowered indinavir trough levels by about 25% compared to their levels when indinavir was taken alone. This change was statistically significant, that is, not likely due to chance alone. In one subject, trough levels decreased by about 60%.

Results: side effects

Milk thistle was “generally well tolerated”; subjects using indinavir reported “an odd taste in their mouth” and nausea.

Why these results?

That milk thistle interacted with indinavir to cause a decrease in that drug’s level in the blood of people is surprising because experiments with cells suggested the opposite. The reasons for this difference may be due to the following:

• not using identical ingredients in both sets of studies (test-tube and people)
• using a concentration of substances in the lab that is much higher than that used in people
• experiments based solely on what’s happening in a test tube don’t always reflect the complexity of the organs and systems found in a body

Milk thistle and HIV/AIDS drugs

A decrease of 25% in trough levels may be a concern for some people who are using only one protease inhibitor in their HIV drug combination. However, in North America and perhaps the European Union, more doctors are increasingly prescribing indinavir along with another PI, ritonavir (Norvir). This is because ritonavir increases or boosts the level of indinavir in the blood and maintains this level for prolonged periods. As a result, ritonavir-indinavir need only be taken twice daily. Similarly, ritonavir is used to boost other PIs including the following:

• amprenavir (Agenerase)
• lopinavir (in Kaletra)
• saquinavir (Fortovase or Invirase)

When taken with ritonavir, because it is such a powerful booster, indinavir levels are not likely to be significantly affected by the dose of milk thistle used in this study.

The effect of milk thistle on unboosted protease inhibitors and non-nukes, until studied, is not clear.

References:

1. Venkataramanan R, Ramachandran V, Komoroski BJ, et al. Milk thistle, an herbal supplement, decreases the activity of CYP 3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metabolism and Disposition 2000;28(11):1270-1273.
2. Sonnenbichler J, Scalera F, Sonnenbichler I and Weyhenmeyer R. Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells. Journal of Pharmacology and Experimental Therapeutics 1999;290(3):1375-1383.
3. Flora K, Hahn M, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. American Journal of Gastroenterology 1998 February; 93(2):139-143.
4. Piscitelli SC, Formentini E, Burstein AH, et al. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;22(5):551-556.
5. Anderson PL, Brundage RC, Kakuda TN and Fletcher CV. CD4 response is correlated with peak plasma concentrations of indinavir in adults with undetectable human immunodeficiency virus ribonucleic acid. Clinical Pharmacokinetics 2002;71:280-285.
6. Anderson PL and Fletcher CV. Clinical Pharmacological considerations for HIV-1 protease inhibitors. Current Infectious Disease Reports 2001;3:381-387 [Medline].

Source:

CATIE Treatment Update 2002 Sept/Oct Volume 14 Issue 7