Garlic supplements are widely used by cancer patients for their purported immune enhancement and anticancer effects. Epidemiological evidence and laboratory studies suggest that dietary garlic or garlic extracts may prevent or halt cancer through multiple biochemical and cellular mechanisms, including inhibition of tumor promotion and proliferation, as well as suppression of carcinogen activation through inhibition of bioactivating enzymes and induction of detoxification enzymes. Garlic is particularly known for its induction of cytochrome P450 enzymes in the intestine and liver, which constitute a major detoxification system for drugs. In addition, recent reports suggest that garlic can also modulate the activity of the efflux membrane transporter P-gylcoproptein (Pgp), which plays an important gatekeeper's role in intestinal drug absorption. Hence, there is a high potential for undesirable interactions between garlic supplements and drugs used in the treatment of cancer and related medical complications. The main objective of this proposal is to assess the likelihood of a clinically significant interaction between garlic supplements and oxycodone-a commonly used oral opioid for the treatment of cancer pain. We hypothesize that garlic extract induces intestinal and hepatic CYP3A4 isoenzyme and Pgp, lowers opioid bioavailability, and attenuates the effectiveness of opioid analgesia. We propose a placebo-controlled, crossover trial in healthy human subjects to investigate whether acute (2 days) and chronic (4-weeks) treatment with 2 select commercial garlic supplements (dried garlic powder and garlic oil) would affect the pharmacokinetics as well as the analgesic response and side effects of a clinically relevant dose of oxycodone. Modulation of CYP3A4 and Pgp activities will be demonstrated by phenotyping tests with midazolam and digoxin. Pharmacokinetics of oxycodone and its metabolites derived from CYP3A4 pathways will be characterized. Oxycodone analgesia will be measured by subjective responses in an experimental pain paradigm-cold pressor test. A battery of biobehavioral instruments that have been specifically designed for opioid effects will be applied to obtain: 1) subjective measures of somatic and cognitive-affective side effects and mood disturbance, 2) measures of cognitive function (visual-motor coordination, memory, verbal reasoning), and 3) physiological responses (pupil constriction, respiration). The results will guide further studies on the liability of adverse herb-drug interactions with garlic in chemotherapy and palliative treatment of cancer. ? ?
