Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers.

AIMS: Turmeric extract derived curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) are currently being evaluated for the treatment of cancer and Alzheimer's dementia. Previous in vitro studies indicate that curcuminoids and piperine (a black pepper derivative that enhances curcuminoid bioavailability) could inhibit human CYP3A, CYP2C9, UGT and SULT dependent drug metabolism. The aim of this study was to determine whether a commercially available curcuminoid/piperine extract alters the pharmacokinetic disposition of probe drugs for these enzymes in human volunteers. METHODS: A randomized placebo-controlled six way crossover study was conducted in eight healthy volunteers. A standardized curcuminoid/piperine preparation (4 g curcuminoids plus 24 mg piperine) or matched placebo was given orally four times over 2 days before oral administration of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (acetaminophen) (dual UGT and SULT probe). Plasma and urine concentrations of drugs, metabolites and herbals were measured by HPLC. Subject sedation and electroencephalograph effects were also measured following midazolam dosing. RESULTS: Compared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma C(max), AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (α = 0.05, paired t-tests). There was also no effect of curcuminoid/piperine treatment on the pharmacodynamics of midazolam. Although curcuminoid and piperine concentrations were readily measured in plasma following glucuronidase/sulfatase treatment, unconjugated concentrations were consistently below the assay thresholds (0.05-0.08 µM and 0.6 µM, respectively). CONCLUSION: The results indicate that short term use of this piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes.

Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies.

OBJECTIVES: Recent anecdotal, unvalidated case reports have suggested potentiation of warfarin-induced anticoagulation by cranberry juice, possibly through inhibition of human cytochrome P450 (CYP) 2C9, the enzyme responsible for the clearance of the active S-enantiomer of warfarin. To address this question, the effect of cranberry juice and other beverages on CYP2C9 activity was evaluated in vitro and in vivo. METHODS: The effects of 4 beverages on CYP2C9 activity were studied in human liver microsomes, by use of flurbiprofen hydroxylation as the index reaction. In a clinical study 14 healthy volunteers received 100 mg flurbiprofen on 5 occasions in a crossover fashion, with at least 1 week separating the 5 trials. Flurbiprofen was preceded in random sequence by the following: (1) cranberry juice placebo (8 oz), (2) cranberry juice (8 oz), (3) brewed tea (8 oz), (4) grape juice (8 oz), and (5) fluconazole, a CYP2C9 inhibitor serving as a positive control, with 8 oz of water. RESULTS: Flubiprofen hydroxylation in vitro was reduced to 11% +/- 8% of control by 2.5% (vol/vol) brewed tea, to 10% +/- 7% of control by grape juice, to 56% +/- 16% of control by cranberry juice, to 85% +/- 5% of control by cranberry juice placebo, and to 21% +/- 6% of control by the index inhibitor sulfaphenazole (2.5 micromol/L) (P <.01 for all comparisons versus control). Flurbiprofen clearance (29-33 mL/min) and elimination half-life (3.3-3.4 hours) did not differ significantly among trials 1, 2, 3, and 4. However, clearance in the fluconazole treatment condition (trial 5) was significantly reduced compared with the placebo control (17 +/- 5 mL/min versus 31 +/- 8 mL/min, P <.05), and the half-life was prolonged (5.3 +/- 1.6 hours versus 3.3 +/- 0.8 hours, P <.05). Formation of 4-hydroxyflurbiprofen was correspondingly reduced by fluconazole (P <.05). CONCLUSIONS: Although grape juice and tea impaired CYP2C9 activity in vitro, none of the 3 beverages altered CYP2C9-mediated clearance of flurbiprofen in humans, making a pharmacokinetic interaction with warfarin highly unlikely.

Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate.

The effect of Ginkgo biloba on the activity of CYP2C9, the isoform responsible for S-warfarin clearance, was assessed in 11 healthy volunteers who received single 100-mg doses of flurbiprofen, a probe substrate for CYP2C9. Subjects also received either a standardized G biloba leaf preparation (Ginkgold, 3 doses of 120 mg) or matching placebo in a randomized, double-blind, 2-way crossover study. Mean kinetic variables for flurbiprofen with either placebo or G biloba were elimination half-life, 3.9 versus 3.5 hours; total AUC, 57 versus 55 microg/mL h; and oral clearance, 32.9 versus 31.6 mL/min. None of these differences was significant. Based on highperformance liquid chromatography analysis, each 60-mg Ginkgold tablet contained 6.6 mug of amentoflavone and 61.2 microg of quercetin, both previously identified as CYP2C9 inhibitors. These amounts were apparently too low to inhibit CYP2C9 function in vivo. The results confirm previous controlled clinical studies showing no effect of ginkgo on the kinetics or dynamics of warfarin.

Inhibition of human cytochromes P450 by components of Ginkgo biloba.

The extraction, isolation and characterization of 29 natural products contained in Ginkgo biloba have been described, which we have now tested for their in-vitro capacity to inhibit the five major human cytochrome P450 (CYP) isoforms in human liver microsomes. Weak or negligible inhibitory activity was found for the terpene trilactones (ginkgolides A, B, C and J, and bilobalide), and the flavonol glycosides. However 50% inhibitory activity (IC50) was found at concentrations less than 10 microg L(-1) for the flavonol aglycones (kaempferol, quercetin, apigenin, myricetin, tamarixetin) with CYP1A2 and CYP3A. Quercetin, the biflavone amentoflavone, sesamin, as well as (Z,Z)-4,4'-(1,4-pentadiene-1,5-diyl)diphenol and 3-nonadec-8-enyl-benzene-1,2-diol, were also inhibitors of CYP2C9. The IC50 of amentoflavone for CYP2C9 was 0.019 microg mL(-1) (0.035 microM). Thus, the principal components of Ginkgo biloba preparations in clinical use (terpene trilactones and flavonol glycosides) do not significantly inhibit these human CYPs in-vitro. However, flavonol aglycones, the biflavonol amentoflavone and several other non-glycosidic constituents are significant in-vitro inhibitors of CYP. The clinical importance of these potential inhibitors will depend on their amounts in ginkgo preparations sold to the public, and the extent to which their bioavailability allows them to reach the CYP enzymes in-situ.