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


CONCLUSIONS
Altogether, these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast.
Mougey
Edward B
EB
Nemours Children's Clinic, Pharmacogenetics Center, Nemours Biomedical Research, Jacksonville, University of Florida, Gainesville, Florida, USA.
Feng
Hua
H
Castro
Mario
M
Irvin
Charles G
CG
Lima
John J
JJ
D000042:Absorption; D000085:Acetates / Q000097:blood* / Q000493:pharmacokinetics*; D000328:Adult; D018938:Caco-2 Cells; D003521:Cyclopropanes; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011804:Quinolines / Q000097:blood* / Q000493:pharmacokinetics*; D013440:Sulfides
D000085:Acetates; D003521:Cyclopropanes; D027361:Organic Anion Transporters; D011804:Quinolines; C512988:SLCO1A2 protein, human; C450859:SLCO2B1 protein, human; D013440:Sulfides; C093875:montelukast