Transporter Mediated Uptake of Montelukast
| Status: | Completed |
|---|---|
| Conditions: | Asthma |
| Therapuetic Areas: | Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 15 - 18 |
| Updated: | 4/2/2016 |
| Start Date: | June 2007 |
| End Date: | September 2014 |
| Contact: | Stacey L Gray |
| Email: | slgray@nemours.org |
| Phone: | (904) 697-3683 |
Characterization of Transporter Mediated Uptake of Montelukast in Humans
Leukotriene receptor antagonists (LTRAs) are frequently prescribed to reduce the symptoms
associated with asthma. Singulair, manufactured by Merck, is a popular LTRA, however its
effectiveness varies greatly between individuals. We are interested in understanding why the
effectiveness of Singulair varies so greatly.
For an oral drug such as Singulair to be effective, the body must efficiently absorb it. We
have found that blood levels of Singulair vary greatly between individuals, and we think
that this variability is responsible for variability in response.
Drug absorption occurs primarily in the intestine. Due to differences in the chemical
properties of drugs, some drugs can be absorbed easily while other drugs require help from
special proteins produced by the cells that line the intestine. These proteins, or
transporters act like turnstiles to allow drugs to move from the intestine to the
bloodstream and are known to be inhibited by components of citrus juice. The activity of a
transporter can be influenced by individual genetic variability.
We think that Singulair requires help from a transport protein to be absorbed and that
genetic variability in this transporter leads to variability in the blood level of
Singulair. In this proposal we will use citrus juice (grapefruit and orange) to inhibit
intestinal membrane transport proteins and show that Singulair requires these transporters
to be efficiently absorbed. Eventually, what we learn from this work will allow doctors to
quickly test individuals with asthma to determine how well they will absorb Singulair and
possibly other LTRAs. Knowing this will allow the doctor to adjust the drug treatment on an
individual basis to maximize benefit in the treatment of asthma.
associated with asthma. Singulair, manufactured by Merck, is a popular LTRA, however its
effectiveness varies greatly between individuals. We are interested in understanding why the
effectiveness of Singulair varies so greatly.
For an oral drug such as Singulair to be effective, the body must efficiently absorb it. We
have found that blood levels of Singulair vary greatly between individuals, and we think
that this variability is responsible for variability in response.
Drug absorption occurs primarily in the intestine. Due to differences in the chemical
properties of drugs, some drugs can be absorbed easily while other drugs require help from
special proteins produced by the cells that line the intestine. These proteins, or
transporters act like turnstiles to allow drugs to move from the intestine to the
bloodstream and are known to be inhibited by components of citrus juice. The activity of a
transporter can be influenced by individual genetic variability.
We think that Singulair requires help from a transport protein to be absorbed and that
genetic variability in this transporter leads to variability in the blood level of
Singulair. In this proposal we will use citrus juice (grapefruit and orange) to inhibit
intestinal membrane transport proteins and show that Singulair requires these transporters
to be efficiently absorbed. Eventually, what we learn from this work will allow doctors to
quickly test individuals with asthma to determine how well they will absorb Singulair and
possibly other LTRAs. Knowing this will allow the doctor to adjust the drug treatment on an
individual basis to maximize benefit in the treatment of asthma.
Montelukast (Merck brand name Singulair) is a selective Cys-LT1 receptor antagonist that is
used to control asthma symptoms in children and adults. Although safe and effective, the
inter-patient variability in response is substantial (25-60% response rate), which is due in
part to genetic variability. For example, we recently reported that polymorphisms in
candidate genes that encode proteins in the LT pathway influence responsiveness to the drug.
The long-range goal of our studies is to determine the contribution of genetic variability
to the inter-patient variability in montelukast blood levels and responsiveness. In
preliminary studies, we found that the plasma concentration vs. time data in single and
multiple dose-studies vary more than 10-fold, which could contribute to inter-patient
variability in response.
Montelukast is about 64% bioavailable, is cleared by CYP2C9 and CYP3A4 in the liver, and is
nearly completely excreted into the bile. The physical properties of montelukast suggest
that the drug undergoes transport by solute carrier transporters (SLC family transporters)
and/or ATP-binding cassette transporters (ABC family transporters). Recent studies support
the idea that genetic variation in genes encoding SLC and ABC transporters can influence the
pharmacokinetics of drugs that are substrates for these transporters.
In the present submission, we propose to determine if montelukast is a substrate for SLC
and/or ABC transporters. To accomplish this we will coadminister Singulair with citrus juice
which contains known inhibitors of membrane transport proteins. If transporters are involved
in the absorption of montelukast, then citrus juice should decrease the absorption of
montelukast relative to Gatorade. Our working hypothesis for this study is that montelukast
is a substrate for SLC (OATP1B3, OATP1B1, OATP2B1, OATP1A2) and ABC (MRP1, MRP2, and MRP3,
BCRP) transporters. If true, then the pharmacokinetics of montelukast will be determined by
the genetics of the membrane transporters. This highly significant observation will have
important implications for understanding the disposition of montelukast in patients, and
ultimately will lead to individualization of montelukast therapy in asthma.
used to control asthma symptoms in children and adults. Although safe and effective, the
inter-patient variability in response is substantial (25-60% response rate), which is due in
part to genetic variability. For example, we recently reported that polymorphisms in
candidate genes that encode proteins in the LT pathway influence responsiveness to the drug.
The long-range goal of our studies is to determine the contribution of genetic variability
to the inter-patient variability in montelukast blood levels and responsiveness. In
preliminary studies, we found that the plasma concentration vs. time data in single and
multiple dose-studies vary more than 10-fold, which could contribute to inter-patient
variability in response.
Montelukast is about 64% bioavailable, is cleared by CYP2C9 and CYP3A4 in the liver, and is
nearly completely excreted into the bile. The physical properties of montelukast suggest
that the drug undergoes transport by solute carrier transporters (SLC family transporters)
and/or ATP-binding cassette transporters (ABC family transporters). Recent studies support
the idea that genetic variation in genes encoding SLC and ABC transporters can influence the
pharmacokinetics of drugs that are substrates for these transporters.
In the present submission, we propose to determine if montelukast is a substrate for SLC
and/or ABC transporters. To accomplish this we will coadminister Singulair with citrus juice
which contains known inhibitors of membrane transport proteins. If transporters are involved
in the absorption of montelukast, then citrus juice should decrease the absorption of
montelukast relative to Gatorade. Our working hypothesis for this study is that montelukast
is a substrate for SLC (OATP1B3, OATP1B1, OATP2B1, OATP1A2) and ABC (MRP1, MRP2, and MRP3,
BCRP) transporters. If true, then the pharmacokinetics of montelukast will be determined by
the genetics of the membrane transporters. This highly significant observation will have
important implications for understanding the disposition of montelukast in patients, and
ultimately will lead to individualization of montelukast therapy in asthma.
Inclusion Criteria:
- Doctor diagnosed asthma.
- Must not be taking any medications except for inhaled steroids.
Exclusion Criteria:
- Clinical conditions other than asthma.
- Upper respiratory tract infection within the past 30 days.
- Gastrointestinal conditions.
- Unable to stop taking or are required to begin taking any type of oral medication for
the duration of the trial
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