In this study, we evaluated inhibitory potentials of popularly-consumed berries (bilberry, blueberry, cranberry, elderberry, and raspberry ketones) as herbal supplements on UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in vitro. We also
investigated the potential herb-drug interaction via UGT1A1 inhibition by blueberry in vivo. We demonstrated that these berries had only weak inhibitory effects on the five UGTs. Bilberry and elderberry had no apparent inhibitions. Blueberry weakly inhibited UGT1A1 with an IC50 value of 62.4±4.40 μg/mL and a Ki value of 53.1 μg/mL. Blueberry also weakly inhibited UGT2B7 with an IC50 value of 147±11.1 μg/mL. In addition, cranberry weakly inhibited UGT1A9 activity (IC50=458±49.7 μg/mL) and raspberry ketones weakly inhibited UGT2B7 activity (IC50=248±28.2 μg/mL). Among tested berries, blueberry showed the lowest IC50 value in the inhibition of UGT1A1 in vitro. However, the co-administration of blueberry had no effect on the pharmacokinetics of irinotecan and its active metabolite, SN-38, which was mainly eliminated via UGT1A1, in vivo. Our data suggests that these five berries are unlikely to cause clinically significant herb-drug interactions mediated via inhibition of UGT enzymes involved in drug metabolism. These findings should enable an understanding of herb-drug interactions for the safe use of popularly-consumed berries.

BACKGROUND: The modern way of life exposes us to substantial oxidative stress, putting the focus on the research of antioxidant effects of dietary supplements. Recent studies have shown that the effectiveness of particular vitamins and herbal preparations might have an effect on paraoxonase activity. Paraoxonase 1 is an HDL associated enzyme which prevents the oxidation of LDL. Several studies have shown the beneficial effect of some dietary components to the activity of paraoxonase. The aim of this study was to analyze the effects of cranberry extract and vitamin C and zinc preparations (vitamin C + Zn) on serum paraoxonase 1 activity, antioxidant status, and glucose and lipid concentration.

METHODS: The study included 31 healthy volunteers (median age 24 years). They were divided into 3 groups according to the intervention type and smoking status and exposed to commercially available preparations of the cranberry extract (2 g/day) and vitamin C + Zn (300 mg/day) during 4 weeks.

RESULTS: The results have shown that there is a significant increase in the activity of the paraoxonase 1 in nonsmokers after the intervention with the cranberry extract as well as with vitamin C + Zn preparations. Also, total antioxidant status increased in the non-smokers subgroup after intervention with vitamin C + Zn. However, the lipid profile did not change significantly in response to antioxidant preparations.

CONCLUSIONS: Our results show that antioxidant supplements can increase the antioxidant potential of an organism as well as paraoxonase 1 activity. This observation is pointing to the potential complementary role of dietary supplements in the primary prevention of atherosclerosis.

Cranberry juice is a popular beverage with many health benefits. It has anthocyanins to supplement dietary needs. Based on in vitro evidence cranberry juice is an inhibitor of CYP enzymes and at higher amounts as potent as ketoconazole (CYP3A) and fluconazole (CYP2C9). There is, however, a discrepancy between in vitro and in vivo observations with respect to a number of substrates (cyclosporine, warfarin, flurbiprofen, tizanidine, diclofenac, amoxicillin, ceflacor); with the exception of a single report on midazolam, where there was a moderate increase in the AUC of midazolam in subjects pre-treated with cranberry juice. However, another study questions the clinical relevancy of in vivo pharmacokinetic interaction between cranberry juice and midazolam. The controversy may be due to a) under in vitro conditions all anthocyanin principles may be available to have a concerted effort in CYP inhibition; however, limited anthocyanin principles may be bioavailable with varying low levels in the in vivo studies; b) a faster clearance of the active anthocyanin principles under in vivo conditions may occur, leading to low threshold levels for CYP inhibition; c) efficient protein binding and/or rapid tissue uptake of the substrate may have precluded the drug availability to the enzymes in the in vivo studies. With respect to pharmacodynamic aspects, while the debate continues on the issue of an interaction between warfarin and cranberry juice, the summation of the pharmacodynamics data obtained in patients and healthy subjects from different prospectively designed and controlled clinical trials does not provide overwhelming support for the existence of a pharmacodynamic drug interaction for normal cranberry juice ingestion. However, it is apparent that consumption of large quantities of cranberry juice (about 1-2 L per day) or cranberry juice concentrates in supplements for an extended time period (>3-4 weeks) may temporally alter the effect of warfarin. Therefore, the total avoidance of cranberry juice by warfarin users may not be warranted by the published studies. However, in certain situations of higher intake of cranberry juice or concentrate there may be a need to monitor both warfarin doses and its effect.

Anthocyanins are plant pigments occurring in flowers and berry fruits. Since a phenomenon of food-drug interactions is increasingly emerging, we examined the effects of 21 major anthocyanins and the extracts from 3 food supplements containing anthocyanins on the aryl hydrocarbon receptor (AhR)-cytochrome P450 CYP1A1 signaling pathway in human hepatocytes and human hepatic HepG2 and intestinal LS174T cancer cells. Pelargonidin-3-O-rutinoside (PEL-2) and cyanidin-3,5-O-diglucoside (CYA-3) dose-dependently activated AhR, as revealed by gene reporter assay. PEL-2 and CYA-3 induced CYP1A1 mRNA but not protein in HepG2 and LS174T cells. Neither compounds induced CYP1A1 mRNA and protein in four different primary human hepatocytes cultures. The effects of PEL-2 and CYA-3 on AhR occurred by ligand-dependent and ligand-independent mechanisms, respectively, as demonstrated by ligand binding assay. In a direct enzyme inhibition assay, none of the antocyanins tested inhibited the CYP1A1 marker activity to less than 50% even at 100 μM concentration. PEL-2 and CYA-3 at 100 μM inhibited CYP1A1 to 79% and 65%, respectively. In conclusion, with exception of PEL-2 and CYA-3, there were no effects of 19 major anthocyanins and 3 food supplements containing anthocyanins on AhR-CYP1A1 signaling, implying zero potential of these compounds for food-drug interactions with respect to AhR-CYP1A1 pathway.

infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and 10 microM, respectively, using HIM as the enzyme source and 2.8, 4.3, and 10 microM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study.

OBJECTIVE: To report a case of warfarin-cranberry juice interaction, which resulted in an international normalized ratio (INR) elevation on 2 separate occasions.
CASE SUMMARY: A 46-year-old female was receiving a total weekly dose of 56 mg of warfarin. During the 4 months prior to the incident INR, her average INR was 2.0, with a range of 1.6-2.2, while taking the same weekly dose of warfarin. Her INR increased to 4.6 after drinking approximately 1.5 quarts (1420 mL) of cranberry juice cocktail daily for 2 days. Her INR 14 days later without cranberry juice cocktail consumption was 2.3. For the next 3 months, while taking warfarin 56 mg per week, her average INR was 2.1, with a range of 1.4-2.5. At a subsequent visit, after drinking approximately 2 quarts (1893 mL) of cranberry juice cocktail daily for 3-4 days, her INR had increased to 6.5. Her INR after holding warfarin for 3 days was 1.86. Her INR 7 days after resuming the weekly dose of warfarin 56 mg was 3.2. During both of the elevated INR episodes, no other factors were identified that would have resulted in an elevated INR, such as drug, herbal, disease, or other food interactions. An objective causality assessment revealed the interaction was highly probable.
DISCUSSION: Warfarin is the most commonly used anticoagulant for chronic therapy. There have been several case reports of cranberry juice or cranberry sauce potentiating the effects of warfarin by elevating the INR; however, clinical trials evaluating this interaction have failed to demonstrate a significant effect on an INR.
CONCLUSIONS: Our case report describes INR elevations in a patient previously stable on warfarin after ingestion of cranberry juice cocktail daily for several days. This elevation occurred on 2 separate occasions, which distinguishes our case from other published literature.

Based on anecdotal reports, the question of whether cranberry juice interacts with warfarin has been raised. This article discusses the potential mechanism, and systematically reviews case reports as well as clinical trials examining the possible interaction. We systematically searched MEDLINE via PubMed, and the Cochrane Library database. Fifteen case reports were summarized, including the initial unpublished brief reports to the Committee on Safety of Medicines and the subsequent 6 published case reports. Seven clinical trials were analyzed, including 3 studies using warfarin and 4 surrogate drugs. Only 2 cases had a validation scale suggesting a "probable" interaction, but even in these patients there were many reasons to question the validity of a relevant drug interaction. Randomized clinical trials and surrogate markers found no evidence to support the interaction between cranberry juice and warfarin. Because the moderate consumption of cranberry juice does not affect anticoagulation, we encourage the reexamination of initial warnings based on scientific evidence. We conclude that the initial precautionary warnings by administrating bodies are limited to anecdotal case reports and represent misleading conclusions.

The potential risk of herb drug interactions is of particular focus today owing to the increasing and inadvertent use of herbs in recent times. It is a major safety concern for the drugs with narrow therapeutic index like warfarin, a most common anticoagulant with the maximum number of interactions reported. The objective of the present study was to conduct a systemic review of literature to consolidate the clinical case reports of warfarin–herb interactions and to assess the report reliabilities. We reviewed the published clinical literature to consolidate and
assess the interactions between various herbs and warfarin, based on reported adverse events, descriptions of the clinical case reports and case series using electronic databases as well as hand picked references from the year 1971 to year 2007 and ranked them on likely causality
using Naranjo’s algorithm. Out of 72 cases of documented case reports of warfarin with various herbs, 84.7% cases were evaluated as possible interactions (61/72) and 15.3% cases (11/72) as probable interactions. Cranberry juice was most commonly involved in interactions with warfarin with 34.7% of cases (25/72) of which 92% cases were possible interactions (23/25) and 8% cases (2/25) were probable
interactions. Hence, we conclude that combining anticoagulant medicines with herbs appears to be a risky proposition. The number of herbs reported to interact with warfarin continues to expand. Patients on warfarin are specifically advised to avoid taking herbal medicines or to
have their INR measured within two weeks of starting the drug, to be on a safer side. Further, more systematic studies pertaining to warfarin herb interactions are urgently warranted.

Background and purpose: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb–drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Experimental approach: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. Key results: Cranberry significantly increased the area under the INR–time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation.Conclusions and implications: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effectssignificantly. Co-administration of warfarin and cranberry requires careful monitoring.

OBJECTIVE: To investigate the effects of hypochlorhydria and acidic drink ingestion on protein-bound vitamin B12 absorption in elderly subjects.

METHODS: Absorption of protein-bound vitamin B12 was examined in elderly normal subjects (n = 8), and in hypochlorhydric subjects due to omeprazole treatment (n = 8) or with atrophic gastritis (n = 3). Subjects underwent absorption tests of protein-bound vitamin B12 ingested with water, cranberry juice and 0.1 N hydrochloric acid.

RESULTS: Protein-bound vitamin B12 absorption was lower in the omeprazole-treated group (0.50%) compared to the normal group (1.21%; p 0.001). With cranberry juice ingestion, the omeprazole-treated group showed an increase in absorbed protein-bound vitamin B12 (p = 0.025). With dilute hydrochloric acid ingestion, there was a further increase in vitamin B12 absorption (p 0.001).

CONCLUSION: Omeprazole causes protein-bound vitamin B12 malabsorption, and ingestion of an acidic drink improves protein-bound vitamin B12 absorption.