Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response

Objectives To (i) determine whether montelukast undergoes carrier-mediated uptake; (ii) classify the carrier protein(s) responsible for uptake; (iii) identify specific transporters that mediate transport of montelukast; and 00 evaluate whether variation in the gene encoding the transport protein(s) influences the pharmacokinetics and pharmacodynamics of montelukast. Methods In-vitro permeability studies of montelukast are carried out using Caco-2 cell culture, a standard model of human intestinal drug transport. In-vivo plasma concentrations of montelukast in an asthmatic population are determined by high-performance liquid chromatography, and genotyping of transport proteins is by LightTyper analysis. Results Permeability of montelukast has an activation energy of 13.7 +/- 0.7 kcal/mol, consistent with carrier-mediated transport. Permeability is saturable at high concentrations of montelukast and follows Michaelis-Mention kinetics. Permeability is subject to competition by sulfobromophthalein, estrone-3-sulfate, pravastatin, taurocholic acid, and cholic acid (P < 0.05, percentage of control: 72 +/- 7-86 +/- 7) and is inhibited by 5-10% citrus juice (P < 0.05, maximal inhibition percentage of control: 31 2). An MDCKII cell line expressing OATP2B1 (coded for by the SLCO2B1 gene) displays significantly increased permeability of montelukast (P < 0.05, percentage of control: 140 20). A nonsynonymous polymorphism in SLCO2B1, rs12422149; SLCO2B1{NM 007256.2}:c.935G > A, associates with significantly reduced plasma concentration in patients measured on the morning after an evening dose (P < 0.025, square root mean transformed plasma concentration SE; c.[935G > A] + [935G] = 3 +/- 1, c.[935G] + [935G] = 7.0 +/- 0.9) and differential response as assessed by change in baseline Asthma Symptom Utility Index scores after 1 month of therapy (delta mean Asthma Symptom Utility Index; c.[935G > A] + [935G] = 0.02 +/- 0.01, P=1.0; c.[935G] + (935G] = 1.0 +/- 0.3, P < 0.0001). Conclusion Altogether, these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast. Pharmacogenetics and Genomics 19:129-138 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.