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

Edward B. Mougey, Hua Feng, Mario Castro, Charles G. Irvin, John J. Lima

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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 (iv) 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-Menten 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.

Original languageEnglish
Pages (from-to)129-138
Number of pages10
JournalPharmacogenetics and Genomics
Issue number2
StatePublished - Feb 2009


  • Asthma
  • Human OATP2B1 protein
  • Intestinal absorption
  • Leukotriene antagonists
  • Membrane transport proteins
  • Montelukast
  • Pharmacodynamics
  • Pharmacokinetics
  • Single nucleotide polymorphism


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