Rapid Screening Phenotype Test To Evaluate CYP 2C19 Enzyme Activity Using Stable Isotope [13C]Pantoprazole
Condition: Healthy
Study type: Interventional

Summary: 
      The purpose of this study is to determine the function of an enzyme that breaks down drugs
      and helps the removal of drugs from your body. This enzyme is called cytochrome P450 2C19 and
      is located in your liver. Exposure to other medications or variations in genes that you have
      inherited from your parents, may speed up or slow the function of this enzyme. As a result,
      some patients may develop unwanted effects from a drug while some other patients may not get
      benefit from taking the same drug. The aim of this study is to determine the function of this
      enzyme in your liver. We will do this by performing a series of breath tests and blood
      samples after you take pantoprazole. Pantoprazole is approved as an oral and intravenous drug
      by the Food and Drug Administration (FDA).
    

Detailed description: 
      The goal of this study is to develop a quick and reliable method that will diagnose hepatic
      CYP2C19 function and could be used routinely in clinical practice. Specifically, we propose
      to test pantoprazole - 13C as a probe for determining CYP2C19 phenotype. Pantoprazole,
      5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)-methyl]sulfinyl]-1H -benzimidazole, is a
      substituted benzimidazole sulfoxide and a selective and long-acting proton pump inhibitor.
      This drug is widely used clinically in the treatment of severe gastroesophageal reflux
      disease, and for treatment of duodenal and gastric ulceration. Pantoprazole is extensively
      metabolized in the liver, with almost 80% of an oral or intravenous dose is excreted as
      metabolites in urine. The main metabolite is formed by O-demethylation at the 4-position of
      the pyridine ring by CYP2C19, followed by conjugation with sulphate (M2), while pantoprazole
      sulfone formed by CYP3A represents a minor metabolic pathway(20). The critical role of
      CYP2C19 in the in vivo clearance of the drugs is further demonstrated by the fact that
      healthy volunteers that are PMs of this enzyme achieve approximately 6-fold higher
      pantoprazole exposure than those who are extensive metabolizers of CYP2C19(20). This concept
      proposal exploits the use of the 13C-label that is incorporated at the O-methyl site of
      pantoprazole, which specifically designed for the CYP2C19-mediated O-demethylation (Figure
      1). Then, during catalysis, CYP2C19-pantoprazole reaction in the liver results in the release
      of 13CO2 which is then eliminated from the body via the lung expired breath. The subsequent
      quantification of 13CO2 allows indirect determination of the hepatic CYP2C19 enzyme and thus
      the pharmacokinetics of its substrates. The salient features of the 13C-breath test means
      that this test would be non-invasive, non-radioactive, safe and simple. The protocol in
      general can be performed rapidly (one hour or less after pantoprazole administration) and can
      be determined directly at the point of care (e.g., hospitals and physicians' offices) using
      relatively inexpensive instrumentation (UBiT-IR300IR spectrometer; Meretek), and patients do
      not require waiting for hours or days for diagnostic results. This test may be particularly
      important to probe the activity of CYP2C19 for infants, children, pregnant and lactating
      women, seniors averse to the use of needles or in poor health and subjects scared of blood
      draws.
    

Intervention name(s): [13C]Pantoprazole
Intervention type(s): Drug
Intervention description(s): [13C]Pantoprazole was administered to EM, IM and PM of CYP2C19 and enzyme activity was measured through breath test and compared among the genotypes
Other intervention name(s): Breath test
Intervention MeSH terms: Pantoprazole
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: CYP2C19; Pantoprazole; Genotype; Pharmacokinetics; Metabolism