TY - JOUR
T1 - Absorption of montelukast is transporter mediated
T2 - A common variant of OATP2B1 is associated with reduced plasma concentrations and poor response
AU - Mougey, Edward B.
AU - Feng, Hua
AU - Castro, Mario
AU - Irvin, Charles G.
AU - Lima, John J.
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/2
Y1 - 2009/2
N2 - 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.
AB - 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.
KW - Asthma
KW - Human OATP2B1 protein
KW - Intestinal absorption
KW - Leukotriene antagonists
KW - Membrane transport proteins
KW - Montelukast
KW - Pharmacodynamics
KW - Pharmacokinetics
KW - Single nucleotide polymorphism
UR - http://www.scopus.com/inward/record.url?scp=59549106159&partnerID=8YFLogxK
U2 - 10.1097/FPC.0b013e32831bd98c
DO - 10.1097/FPC.0b013e32831bd98c
M3 - Article
C2 - 19151602
AN - SCOPUS:59549106159
VL - 19
SP - 129
EP - 138
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 2
ER -