In Vivo Inhibition Profile of CYP2C9 by Pineapple Juice

The goal of this study is to evaluate the actual potential for in vivo pineapple juice inhibition with CYP2C9 substrates in human volunteers with use of diclofenac as a marker of CYP2C9 activity.

Study Overview

• Status: Unknown
• Conditions: Healthy Volunteers
• Intervention / Treatment: Dietary supplement: pineapple juice (Carrefour n°1) 500 ml/day 5 days

Detailed Description

For ovarian cancer, colorectal and gastric cancers presenting with peritoneal metastases, complete tumor removal at surgery is the most important independent prognostic factor. Consequently, accurate detection of tumors often compromising resectability, like extra-abdominal metastases, liver metastases, portal and superior mesenteric artery deposits and extensive intestinal serosal invasion is pivotal prior to treatment selection. Computed tomography (CT) has variable accuracy for staging, due to the difficult detection of low-contrast or small-sized peritoneal or nodal metastases. Fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) improves detection of thoraco-abdominal lymphadenopathy and liver metastases, but inconsistently detects small (<5mm) peritoneal metastases. Therefore a diagnostic staging laparoscopy under general anesthesia is currently the necessary standard of clinical practice in addition to imaging for assessment of operability.

Whole body diffusion-weighted magnetic resonance imaging is researched at the department of radiology, University Hospitals Leuven in collaboration with the departments of abdominal surgery, oncologic surgery, oncologic gynaecology and digestive oncology. The technique holds high promise to combine a high accuracy in systemic thoraco-abdominal staging and peritoneal assessment of operability. Technological progress has enabled time-efficient WB-DWI with thin-slice-acquisition and multiplanar image reformatting. DWI depicts lesions by measuring water diffusion differences, correlating with cellular density. Tumors are depicted with high signal compared to background by combining a short-T1-inversion-time inversion recovery (STIR) prepulse - suppressing ascites, blood vessels, fat, bowel and visceral organs - and heavy diffusion weighting. However, due to contraction and mucosal cellularity, the bowel wall can show increased signal-intensity (SI), hampering the detection of serosal deposits. This is overcome by suppressing contractions by intravenous antispasmodic and by distending the bowel wall and suppressing the signal of bowel content by peroral pineapple juice which shows negative contrast properties due to the manganese-content. In a first pilot study in ovarian cancer at this center in 32 patients, an accuracy for detection of intestinal serosal metastases of 90% was reached by WB-DWI combined with peroral pineapple juice. As such, the pineapple juice plays a pivotal role as a peroral contrast in addition to WB-DWI for accurate peritoneal staging.

To date, the inhibitory potential of pineapple juice on cytochrome P450 2C9 activity has only been described in vitro in human microsomes. In this model, in which diclofenac and its metabolite 4-OH-diclofenac have been used as probes for CYP2C9 activity, it has been shown that pineapple juice is capable to inhibit CYP2C9 very potently (IC50 0.08%) in an irreversible manner. It has been suggested that the main effect is caused by bromelain, a 24-26 kDa cysteine protease enzyme present in pineapple juice. The intestinal absorption of intact bromelain after oral intake has been described in 19 healthy men, which is surprising as the adult intestinal epithelium has traditionally been described as non-permeable to proteins. The (limited) absorption is thought to occur via the paracellular route, which could explain that the catalytic activity bromelain is preserved following absorption into the blood circulation. Although no effects of bromelain on CYP2C9 activity are expected in vivo (due to low oral bioavailability), no in vivo trials have been undertaken to elucidate if pineapple juice, and more specifically bromelain, is capable of inhibiting intestinal and, more importantly, hepatic CYP2C9 in a clinically relevant manner.

The in vivo inhibitory profile of CYP2C9 by pineapple juice will be evaluated in this study in 10 healthy volunteers, by examining the impact on the area-under-the-curves (AUCs) of diclofenac and its metabolite 4-OH diclofenac.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Isabel Spriet, PharmD PhD; Phone Number: 0032 16 34 30 80; Email: isabel.spriet@uzleuven.be
• Study Contact Backup: Name: Pieter Annaert, PharmD PhD; Phone Number: 0032 16 33 03 03; Email: pieter.annaert@pharm.kuleuven.be

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • University Hospitals Leuven

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult healthy volunteers

Exclusion Criteria:

• younger than 18 yrs
• older than 60 yrs
• pregnant or lactating women
• medical history of gastric or duodenal ulcers, gastro-oesofageal reflux disease, dyspepsia, asthma, any allergy to NSAIDS
• patients taking co-medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: diclofenac without pineapple juice; single dose of diclofenac 25 mg without pre-exposure to pineapple juice
Active Comparator: diclofenac with pineapple juice; single dose of diclofenac 25 mg with pre-exposure to pineapple juice	Dietary supplement: pineapple juice (Carrefour n°1) 500 ml/day 5 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
a) AUC 4-OH-diclofenac / AUC diclofenac quantified in plasma, on days 1 (without pineapple juice) and 11 (after pretreatment with pineapple juice)	see above	day 1 and day 11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(b) AUC 4-OH-diclofenac/ AUC diclofenac quantified in urine, on days 1 (without pineapple juice) and 11 (after pretreatment with pineapple juice)	see above	day 1 and day 11

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
c) Bromelain activity quantified in plasma, measured on days 1 and 11	see above	day 1 and day 11

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Isabel Spriet, PharmD PhD, Pharmacy Dpt, University Hospitals Leuven; Study Chair: Hans Prenen, MD PhD, Digestive Oncology, University Hospitals Leuven; Study Chair: Vincent Vandecaveye, MD PhD, Radiology Dpt, University Hospitals Leuven; Study Chair: Pieter Annaert, PharmD PhD, Laboratory for Pharmacotechnology and Biopharmacy, Catholic University Leuven

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (Anticipated): October 1, 2012
• Study Completion (Anticipated): October 1, 2012

Study Registration Dates

• First Submitted: July 20, 2012
• First Submitted That Met QC Criteria: July 20, 2012
• First Posted (Estimate): July 25, 2012

Study Record Updates

• Last Update Posted (Estimate): July 25, 2012
• Last Update Submitted That Met QC Criteria: July 20, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: CYP2C9; diclofenac; bromelain; pineapple juice
• Other Study ID Numbers: S54465