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

Abstract

AIMSTurmeric 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. METHODSA 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. RESULTSCompared with placebo, the curcuminoid/piperine treatment produced no meaningful changes in plasma Cmax, AUC, clearance, elimination half-life or metabolite levels of midazolam, flurbiprofen or paracetamol (a = 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 mM and 0.6 mM, respectively). CONCLUSIONThe 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Curcumin and other curcuminoids derived as extracts of turmeric (Curcumina longa) are being developed as potential treatments for cancer and Alzheimer's dementia.• The curcuminoids demonstrate low oral bioavailability in part because of extensive metabolism.• Curcuminoid oral bioavailability can be enhanced by combining with piperine, a black pepper extract.• In vitro studies indicate that both the curcuminoids and piperine could interfere with the metabolism of drugs by CYP3A, CYP2C9, UGT and/or SULT in vivo. WHAT THIS STUDY ADDS• The results of this study indicate that short term use of a piperine-enhanced curcuminoid preparation is unlikely to result in a clinically significant interaction involving drugs metabolized by CYP3A, CYP2C9 or the paracetamol (acetaminophen) conjugation enzymes.• The lack of interaction might be related to the short duration of therapy (2 days) and/or the low (unconjugated) curcuminoid and piperine plasma concentrations that were observed in the subjects despite the use of a standardized piperine-enhanced cur...

Piperine’s mitigation of obesity and diabetes can be explained by its up-regulation of the metabolic rate of resting muscle

“…Piperine is efficiently absorbed by the gut and is widely distributed in the various tissues (29,30). However, most of the piperine has been conjugated with glucuronic acid, which may influence its activity.…”

Piperine activates human pregnane X receptor to induce the expression of cytochrome P450 3A4 and multidrug resistance protein 1

“…The dichotomous effects of PIP could help explain the observations from several clinical studies attempting to use PIP as a bioavailability enhancer for drugs that are CYP3A4 substrates. A recent human study showed that an herbal extract containing PIP (24 mg) failed to enhance the bioavailability of midazolam (a CYP3A4-selective substrate); the plasma pharmacokinetics of midazolam remained unchanged in the presence of PIP (Volak et al, 2013). Similarly, in two other human studies, co-administration of 20 mg PIP showed no significant inhibition on the rate of metabolism of two CYP3A4 substrates, nevirapine (200 mg) and carbamazepine (500 mg), as indicated by the unchanged elimination constant rate (K el ) (Kasibhatta and Naidu, 2007; Pattanaik et al, 2009), suggesting that PIP at this dose probably had no significant effect on inhibiting CYP3A4 activity in human.…”

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

“…We selected acetaminophen [since its main metabolic pathway is glucuronidation by UGT1A1/1A6/1A9 (Court et al 2001) and also UGT2B15 (Navarro et al 2011)], instead of a more specific substrate of only one UGT isoform because acetaminophen is widely available, inexpensive and well tolerated, and also because these three UGT1A isoforms are involved in the metabolism of many clinically relevant drugs. In the case of lack of change in the acetaminophen/acetaminophen glucuronide phenotyping index, the investigator will have relevant information on the UGT1A pool, as previously studied using acetaminophen as a probe (Volak et al 2013). In the case that there is a change, additional investigations could be performed using more specific probes such as endogenous bilirubin (UGT1A1) or propofol (UGT1A9) as already reported in neonates (Allegaert et al 2009).…”