Transporter Mediated Uptake of Montelukast

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.