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).
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.
1. Asian male or female subjects between 18 and 49 years of age, who are in good
physical health with no significant medical problems or laboratory test
abnormalities. Subjects should have normal liver and kidney function.
2. Subjects with BMI <30 which will be determined by Metropolitan height and weight
tables. Subjects must weigh at least 110 pounds.
3. Subjects must agree to refrain from taking any prescription and over-the-counter
medications, as well as any herbal medications one week before the start of the study
and during the study period.
4. Subjects must agree to refrain from consuming alcohol 48 hours before the start of
the study and during the study period.
5. Subjects must be capable of satisfying protocol requirements and be able to sign
written informed consent.
1. Subjects who have a history of intolerance or allergy to the study drug:
2. Subjects who have donated blood within the last 60 days of the screening visit or
plan to donate blood during the course of the study or within 60 days after study
3. Subjects who have had treatment with any investigational drug within the past 30
4. Subjects who have used illegal drugs within three months prior to enrollment.
5. Female subjects currently taking oral contraceptive birth control pills and who are
unwilling or unable to stop oral contraceptives and use a barrier contraceptive
method (such as condom, contraceptive foams, etc.) starting from the time of
screening phase to the completion of the study.
6. Female subjects who are pregnant or lactating.
7. Subjects who are unreliable in the opinion of the study physician.