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.

Disclosures

Pharmacotherapy. 2003;23(7) 

In This Article

Discussion

Milk thistle extract is a common herbal supplement. Milk thistle is a biennial herb that consists of a mixture of flavonolignans that are present in the fruit, seeds, and leaves of the plant. Flavonolignans are produced in plants through coupling of a flavonoid and a phenylpropanoid. Silymarin, a mixture of flavonolignans (silybin, silydianin, silychristin), is primarily composed of silybin, and typical extracts of milk thistle contain 70-80% silymarin.[3] Milk thistle is considered a hepatoprotectant, and purported to be active against acute or chronic viral hepatitis, toxin- and drug-induced hepatitis and cirrhosis, and alcoholic liver disease. Silymarin is reported to inhibit nitric oxide production, increase levels of glutathione in liver and intestines, scavenge free radicals, prevent lipid peroxidation, and stimulate ribosomal RNA polymerase and subsequent protein synthesis.[3,13,14,15]

Preliminary data suggest that silymarin may influence the metabolic capacity of CYP3A4, a CYP isoenzyme responsible for hepatic and intestinal metabolism of many important classes of drugs.[4,5] Most protease inhibitors, including indinavir, are primarily metabolized by CYP3A4. In vitro it is both an inhibitor and substrate for P-gp, an active drug transporter of the adenosine triphosphate-binding cassette transporter family. Both infection of T cells with HIV-1 and administration of zidovudine to HIV-infected T cells resulted in elevated expression of P-gp.[16,17] Since P-gp limits the bioavailability and the brain, testis, intracellular, and fetal penetration of drugs, effective inhibition of P-gp may increase the concentration of indinavir in blood and possibly in viral sanctuary sites. The importance of investigating potential herbal-antiretroviral drug interactions is further highlighted by trials in which St. John's wort significantly decreased indinavir plasma concentrations, and garlic significantly decreased plasma concentrations of the protease inhibitor saquinavir in healthy adults.[18,19]

Administration of silymarin failed to influence either indinavir AUC0-8 or Cmax; therefore, at the dosage given in this study it does not appear to have a significant influence on CYP3A4-mediated hepatic or intestinal metabolism of indinavir. With the same indinavir dosage, others also failed to detect an influence of silymarin on the pharmacokinetics of indinavir in healthy adults.[20] Although neither the geometric mean ratio [90% CI] of AUC0-8 (0.93 mg/L [0.72-1.2 mg/L]) nor Cmax (0.89 mg/L [0.72-1.1 mg/L]) met the definition of bioequivalence, this study was not powered to test for bioequivalence. We also saw no apparent trend in the intersubject variability of AUC0-8 regardless of silymarin coadministration; therefore, the most likely reasons for failing to claim bioequivalence appear to be small sample size and intrasubject and intersubject variability in indinavir exposure.

The Cmin or trough value of a protease inhibitor such as indinavir may be an important marker for clinical outcome. Interest in this relationship is highlighted by the mounting body of evidence suggesting that Cmin or ratio of Cmin to viral genotypic, phenotypic, or virtual phenotypic results may be an important predictor of clinical outcome.[21,22,23] Milk thistle administration failed to influence indinavir Cmin.

Limitations of this trial include small sample size, no evaluation of the effect of higher dosages of silymarin on indinavir pharmacokinetics, omission of assaying silymarin blood concentrations, and the fact that indinavir is now commonly administered with drugs that inhibit its metabolism so as to provide a pharmacokinetic boosting effect. Although the trial had only 10 subjects, pharmacokinetic parameters were almost identical between the agents, and it is doubtful that even a large trial would find a clinically relevant difference.

The dosage we administered approximates the recommended hepatoprotectant dosage of silymarin at the time this trial was designed (480 mg/day) and falls within the range of common milk thistle extract dosages (300-600 mg/day).[3,24] However, we cannot conclude that silymarin would not have influenced the pharmacokinetics of indinavir at higher dosages. Milk thistle is poorly absorbed after oral administration (bioavailability 23-47%); therefore, silymarin blood concentrations may have been too low to achieve an appreciable effect on either CYP3A4 or P-gp.[25] Although the silymarin content in the capsules was determined before administration, in the absence of silymarin blood samples we cannot rule out the possibility that inadequate silymarin absorption led to the observed absence of effect. Furthermore, protease inhibitors are commonly administered with drugs that alter CYP3A4-dependent metabolism; therefore, we cannot rule out the possibility that milk thistle may alter the pharmacokinetics of indinavir indirectly by influencing the pharmacokinetics of concomitant drugs.

Finally, although this trial failed to show an influence of silymarin on the pharmacokinetics of indinavir, it was not designed to examine P-gp-dependent alterations in the distribution of indinavir to potential viral sanctuary sites. More study is necessary before concluding that an herbal supplement with P-gp-inhibitory properties, such as milk thistle, will not increase intracellular or potential viral sanctuary site concentrations of indinavir.

In summary, silymarin 160 mg 3 times/day failed to influence the pharmacokinetics of indinavir in healthy subjects. Concomitant administration of milk thistle at this dosage would not be expected to alter indinavir AUC, Cmax, or Cmin to clinically significant extents.

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