Dataset Information

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

ABSTRACT: 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.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.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).Altogether, these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast.

SUBMITTER: Mougey EB

PROVIDER: S-EPMC2641037 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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

Mougey Edward B EB Feng Hua H Castro Mario M Irvin Charles G CG Lima John J JJ

Pharmacogenetics and genomics 20090201 2

<h4>Objectives</h4>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.<h4>Methods</h4>In-vitro permeability studies of montelukast are carried out using Caco-2 cell culture, a standard model o ...[more]

PMID: 19151602

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Project description:Transport of choline via the neuronal high-affinity choline transporter (CHT; SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional control as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed, in vivo, CHT-mediated choline transport, and ACh release. Relative to wild-type (WT) mice, CHT-mediated clearance of choline in male and female mice expressing one or two Val89 alleles was reduced by over 80% in cortex and over 50% in striatum. Choline clearance in CHT Val89 mice was further reduced by neuronal inactivation. Deficits in ACh release, 5 and 10 min after repeated depolarization at a low, behaviorally relevant frequency, support an attenuated reloading capacity of cholinergic neurons in mutant mice. The density of CHTs in total synaptosomal lysates and neuronal plasma-membrane-enriched fractions was not impacted by the Val89 variant, indicating a selective impact on CHT function. When challenged with a visual disruptor to reveal attentional control mechanisms, Val89 mice failed to adopt a more conservative response bias. Structural modeling revealed that Val89 may attenuate choline transport by altering conformational changes of CHT that support normal transport rates. Our findings support the view that diminished sustained cholinergic signaling capacity underlies perturbed attentional performance in individuals expressing CHT Val89. The CHT Val89 mouse serves as a valuable model to study heritable risk for cognitive disorders arising from cholinergic dysfunction.SIGNIFICANCE STATEMENT Acetylcholine (ACh) signaling depends on the functional capacity of the neuronal choline transporter (CHT). Previous research demonstrated that humans expressing the common CHT coding variant Val89 exhibit attentional vulnerabilities and attenuated fronto-cortical activation during attention. Here, we find that mice engineered to express the Val89 variant exhibit reduced CHT-mediated choline clearance and a diminished capacity to sustain ACh release. Additionally, Val89 mice lack cognitive flexibility in response to an attentional challenge. These findings provide a mechanistic and cognitive framework for interpreting the attentional phenotype associated with the human Val89 variant and establish a model that permits a more invasive interrogation of CNS effects as well as the development of therapeutic strategies for those, including Val89 carriers, with presynaptic cholinergic perturbations.

Dataset Information

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

Publications

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

Similar Datasets

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