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

Pharmacogenet Genomics. 2009 Feb;19(2):129-38. doi: 10.1097/FPC.0b013e32831bd98c.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Acetates / blood*
  • Acetates / pharmacokinetics*
  • Adult
  • Caco-2 Cells
  • Genetic Variation*
  • Genotype
  • Humans
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / metabolism
  • Phenotype
  • Quinolines / blood*
  • Quinolines / pharmacokinetics*


  • Acetates
  • Organic Anion Transporters
  • Quinolines
  • SLCO1A2 protein, human
  • SLCO2B1 protein, human
  • montelukast