Transporter Mediated Uptake of Montelukast
Condition: Asthma
Study type: Interventional

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.
    

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.
    

Intervention name(s): Grapefruit juice; Orange Juice; Gatorade
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Coingestion of 240 ml of grapefruit juice with 10 mg of montelukast.; Coingestion of 240 ml of orange juice with 10 mg of montelukast.; Coingestion of 240 ml of Gatorade with 10 mg of montelukast.
Other intervention name(s): Brand: Great Value frozen concentrated grapefruit juice(Walmart).; Brand: Winn Dixie orange juice (Winn Dixie).; Brand: Gatorade Rain.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Pharmacogenetics; Singulair; montelukast; Leukotriene Antagonists; Anti-Asthmatic Agents; Intestinal Absorption; pharmacokinetics; absorption; biochemical transport; Membrane Transport Proteins; Drug Interactions