Silje Engdal

Introduction: This survey aims to identify herb-chemotherapeutic drug combinations in a defined group of cancer patients and to explore possible clinical consequences of these combinations. Methods: Herb-chemotherapeutic drug combinations were identified among adult cancer patients, and clinical consequences of the combinations were explored by literature searches in medical databases on possible mutual effects on similar cytochrome P-450 metabolising enzymes (CYPs) and/or the P-glycoprotein (P-gp) transporter. Results: Among 42 cancer patients using herbal remedies concurrently with chemotherapy, 136 two-agent herb-drug combinations were registered and 47 different potential herb-drug interactions were identified on the level of CYP metabolism and P-gp transport in vitro. Garlic, ginger, green tea and noni juice were the herbal remedies most frequently used in such combinations. For 48 % of the herbal remedies identified no literature data exist on their interaction potentials. Clinical studies were available for four herbal remedies only. Minor clinical potential for CYP interactions in humans was indicated for green tea and Echinacea. P-gp interactions were only investigated for garlic, which showed a significant interaction potential both in vivo and in vitro. Conclusion: The large number of in vitro potential herb-drug interactions identified urge for more clinical pharmacokinetic interaction studies in humans.

The herbal remedies Natto K2,Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for theirin vitroinhibition potential of cytochrome P‐450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c‐DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6‐β‐OH‐testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC₅₀: 73 µg/mL), followed byAgaricus,mistletoe and noni juice (1324, 3594, >10 000 µg/mL, respectively). All IC₅₀values were high compared with those determined for crude extracts of other herbal remedies. The IC₅₀/IC₂₅ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non‐inhibitors. AlthoughAgaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolismin vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. Copyright © 2009 John Wiley & Sons, Ltd.

1. The herbal products Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic were investigated for in vitro inhibitory potential on P-glycoprotein (P-gp)-mediated transport of digoxin (30 nM) in differentiated and polarized Caco-2 cells. 2. Satisfactory cell functionality was demonstrated through measurements of assay linearity, transepithelial electric resistance (TEER), cytotoxicity, mannitol permeability, and inclusion of the positive inhibition control verapamil. 3. The most potent inhibitors of the net digoxin flux (IC(50)) were mistletoe > Natto K2 > Agaricus > green tea (0.022, 0.62, 3.81, >4.5 mg ml(-1), respectively). Mistletoe also showed the lowest IC(25) value, close to that obtained by verapamil (1.0 and 0.5 microg ml(-1), respectively). The IC(50)/IC(25) ratio was found to be a good parameter for the determination of inhibition profiles. Garlic and noni juice were classified as non-inhibitors. 4. This study shows that mistletoe, Natto K2, Agaricus and green tea inhibit P-gp in vitro. Special attention should be paid to mistletoe due to very low IC(50) and IC(25) values and to Natto K2 due to a low IC(50) value and a low IC(50)/IC(25) ratio.

This survey aims to explore the differences between cancer patients undergoing chemotherapeutic treatment with palliative or curative intention with respect to concurrent herbal use, experiences of adverse effects, motives of herbal intake, and communication about herbal use with health care providers. One hundred and twelve adult cancer patients from the west coast of Central Norway, currently undergoing chemotherapeutic treatment, were recruited to a cross-sectional descriptive survey. Palliative and curative patients used herbal remedies concurrent with chemotherapy equally frequent (37% and 38%). One palliative patient reported adverse effects when doubling the dose of injected mistletoe used. Garlic was only used by palliative patients (p = 0.009) who also tended to have a more frequent everyday herbal use (78% vs 67%, respectively) than curative patients (p = 0.075). Curative patients, however, used herbal remedies more often to counteract adverse reactions (31% vs 3%, respectively; p = 0.026). A bivariate logistic regression, which was adjusted for age, showed that palliative patients used herbal remedies more frequently to improve their immune system (adjusted OR = 7.5, 95% CI = 1.1–49.7). This is the first survey comparing concurrent herbal use between cancer patients undergoing palliative or curative chemotherapy. Both groups frequently use herbal remedies concurrent with chemotherapy, but with a slightly different intent. The frequent concurrent use emphasizes the need for clinicians to include questions on complementary and alternative medicine in routine history taking and for further studies on possible herb–drug interactions among the cancer patient.