Garlic Supplements, Protease Inhibitor Interactions Troublesome – NIH Study

A National Institutes of Health study finding garlic supplements reduce plasma concentration levels of an HIV protease inhibitor by approximately 50% could spur drug interaction warnings on such supplements.

Although the study was unable to define the mechanism for changes in plasma saquinavir levels, the researchers suggest that garlic, much like St. John's wort, could interact with drugs that are metabolized along the CYP450 metabolic pathway.

The findings suggest garlic "affected the bioavailability of saquinavir rather than its systemic clearance," say Stephen Piscitelli, Tibotec-Virco, Rockville, Md., et al.

"The effect may be caused by induction of CYP450 in the gut mucosa that results in diminished systemic levels; however, because saquinavir is a known substrate of P-glycoprotein, we cannot exclude contributions from P-glycoprotein," the researchers note.

"Not only should physicians and their patients be concerned about the use of garlic in patients receiving saquinavir, but there may be concerns about other drugs that are CYP450 substrates, as well as those metabolized by the CP3A4 isoform," Piscitelli and colleagues advise.

Piscitelli formerly was with NIH's Warren Grant Magnuson Clinical Center; the study was co-authored by researchers at the clinical center, National Institute of Allergy & Infectious Diseases and Axelson Biopharma Research in Vancouver. The findings appeared in the Dec. 5 online edition of Clinical Infectious Diseases and will be published in the Jan. 15 issue.

Clinical implications of the results could be blunted, however, because the study looked at garlic's impact on plasma levels of saquinavir when used alone. The protease inhibitor is commonly prescribed in combination with several other HIV drugs, and one NIAID researcher noted the need for additional studies, particularly with regard to combination regimens.

Explaining that garlic is used by HIV patients to combat the hypercholesterolemic effects of antiretroviral therapy, the researchers say they sought to investigate the supplement's effect on saquinavir alone "rather than on protease inhibitors that are in more common clinical use, both because saquinavir is a known substrate of CYP450 and because it does not appreciably induce or inhibit drug metabolism."

The researchers note that "because we did not know whether garlic might induce or inhibit CYP450, studying the effect of garlic on a protease inhibitor that itself affects CYP450 could have confounded the data."

Nine healthy, HIV-negative volunteers were administered saquinavir (Roche Labs' Fortovase ) on days 1-4, 22-25 and 36-39. Participants were given garlic supplements (Natrol's GarliPure Maximum Allicin Formula) on days 5-25, with a 10-day washout period during days 26-35. Blood samples were obtained on days 4, 25 and 39.

"In the presence of garlic, the mean saquinavir area under the curve during the eight-hour dosing interval decreased by 51%, trough levels at eight hours after dosing decreased by 49%, and the mean maximum concentrations decreased by 54%," Piscitelli and colleagues report.

In addition, pharmacokinetic parameters returned to only 60%-70% of their baseline values following the 10-day washout period, the researchers note.

In a similar finding announced in February 2000, the same researchers reported St. John's wort compromises indinavir's effectiveness by reducing plasma concentration levels of the protease inhibitor. In that study, published in The Lancet, Piscitelli et al. noted the herbal is believed to induce the 3A4 isoform of the P450 metabolic pathway (¹ (Also see "St. John's Wort/HIV Protease Inhibitor Use Warnings Issued By FDA, NIH" - Pink Sheet, 14 Feb, 2000.), p. 19).

A joint FDA/NIH warning issued with the release of the St. John's wort study results advised health care providers to alert patients about the botanical's potential interactions with other Rx drugs that are metabolized along the P450 pathway, including drugs for heart disease, depression, seizure, cancer and prevention of transplant rejection and pregnancy.

The Consumer Healthcare Products Association subsequently announced a voluntary supplement labeling program advising consumers who are taking a prescription drug to "ask a health professional" before using St. John's wort.

In a citizen petition filed in June 2000, the association asked FDA to require St. John's wort supplements to carry a label statement about potential Rx interactions (² (Also see "FDA Notices, Guidances Should Reflect St. John's Wort Interaction - CHPA" - Pink Sheet, 26 Jun, 2000.), p. 16).

Piscitelli et al. also have submitted for publication a study on milk thistle's effects on HIV drugs.