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In Vivo Inhibition Profile of CYP2C9 by Pineapple Juice

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2012 by Universitaire Ziekenhuizen Leuven.
Recruitment status was  Not yet recruiting
Sponsor:
Information provided by (Responsible Party):
Isabelle Spriet, Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier:
NCT01649492
First received: July 20, 2012
Last updated: NA
Last verified: July 2012
History: No changes posted
  Purpose

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.


Condition Intervention Phase
Healthy Volunteers
Dietary Supplement: pineapple juice (Carrefour n°1) 500 ml/day 5 days
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: In Vivo Inhibition Profile of CYP2C9 by Pineapple Juice

Resource links provided by NLM:


Further study details as provided by Universitaire Ziekenhuizen Leuven:

Primary Outcome Measures:
  • a) AUC 4-OH-diclofenac / AUC diclofenac quantified in plasma, on days 1 (without pineapple juice) and 11 (after pretreatment with pineapple juice) [ Time Frame: day 1 and day 11 ] [ Designated as safety issue: No ]
    see above


Secondary Outcome Measures:
  • (b) AUC 4-OH-diclofenac/ AUC diclofenac quantified in urine, on days 1 (without pineapple juice) and 11 (after pretreatment with pineapple juice) [ Time Frame: day 1 and day 11 ] [ Designated as safety issue: No ]
    see above


Other Outcome Measures:
  • c) Bromelain activity quantified in plasma, measured on days 1 and 11 [ Time Frame: day 1 and day 11 ] [ Designated as safety issue: No ]
    see above


Estimated Enrollment: 10
Study Start Date: September 2012
Estimated Study Completion Date: October 2012
Estimated Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01649492

Contacts
Contact: Isabel Spriet, PharmD PhD 0032 16 34 30 80 isabel.spriet@uzleuven.be
Contact: Pieter Annaert, PharmD PhD 0032 16 33 03 03 pieter.annaert@pharm.kuleuven.be

Locations
Belgium
University Hospitals Leuven Not yet recruiting
Leuven, Belgium, 3000
Sponsors and Collaborators
Universitaire Ziekenhuizen 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
  More Information

No publications provided

Responsible Party: Isabelle Spriet, PharmD, PhD, Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT01649492     History of Changes
Other Study ID Numbers: S54465
Study First Received: July 20, 2012
Last Updated: July 20, 2012
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products

Keywords provided by Universitaire Ziekenhuizen Leuven:
diclofenac
CYP2C9
bromelain
pineapple juice

Additional relevant MeSH terms:
Diclofenac
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antirheumatic Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 19, 2014