Transporter Mediated Uptake of Montelukast
Information source: Nemours Children's Clinic
Information obtained from ClinicalTrials.gov on October 19, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Asthma
Intervention: Grapefruit juice (Dietary Supplement); Orange Juice (Dietary Supplement); Gatorade (Dietary Supplement)
Phase: N/A
Status: Recruiting
Sponsored by: Nemours Children's Clinic Official(s) and/or principal investigator(s):
Edward B Mougey, Ph.D., Principal Investigator, Affiliation: Nemours Children's Clinic
Overall contact:
Laurie J Duckworth, ARNP, Phone: (904) 390-3465, Email: lduckworth@nemours.org
Summary
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.
Clinical Details
Official title: Characterization of Transporter Mediated Uptake of Montelukast in Humans
Study design: Basic Science, Randomized, Open Label, Active Control, Crossover Assignment, Pharmacokinetics Study
Primary outcome: Area under the concentration vs. time curve for the serum concentration of montelukast when coingested with grapefruit juice, orange juice, or Gatorade.
Secondary outcome: Improvement in respiratory function as assessed by spirometry, and impulse oscillometry vs. serum concentration of montelukast.
Detailed description:
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.
Eligibility
Minimum age: 15 Years.
Maximum age: 18 Years.
Gender(s): Both.
Criteria:
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
Locations and Contacts
Laurie J Duckworth, ARNP, Phone: (904) 390-3465, Email: lduckworth@nemours.org
Nemours Children's Clinic, Jacksonville, Florida 32207, United States; Recruiting
Ira J White, RN, BSN, Phone: 904-390-3966, Email: iwhite@nemours.org
Amber R Santos, RN, MSN, MBA, Phone: (904) 858-3985, Email: asantos@nemours.org
Edward B Mougey, Ph.D., Principal Investigator
John J Lima, PharmD, Sub-Investigator
Jason E Lang, MD, Sub-Investigator
Additional Information
Merck's Singulair site
Related publications: Lima JJ. Treatment heterogeneity in asthma: genetics of response to leukotriene modifiers. Mol Diagn Ther. 2007;11(2):97-104. Review. Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H, Wang J, Sylvester J, Holbrook J, Wise R, Weiss ST, Barnes K. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med. 2006 Feb 15;173(4):379-85. Epub 2005 Nov 17.
Starting date: June 2007
Ending date: June 2009
Last updated: March 6, 2009
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