Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response.
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Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ
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.
- PubMed ID
- 19151602 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Montelukast Solute carrier organic anion transporter family member 2B1 Protein Humans UnknownSubstrateDetails Pravastatin Solute carrier organic anion transporter family member 2B1 Protein Humans NoSubstrateDetails