1. Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics
- Author
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Tuija Tapaninen, Jussi Pihlajamäki, Ville Männistö, Maria Paile-Hyvärinen, Mikko Niemi, Päivi Hirvensalo, Janne T. Backman, Vesa Kärjä, Aleksi Tornio, Mikko Neuvonen, School of Medicine / Clinical Nutrition, Medicum, Department of Clinical Pharmacology, University of Helsinki, Janne Backman / Principal Investigator, Clinicum, and HUSLAB
- Subjects
Cyclopropanes ,Male ,0301 basic medicine ,Acetates ,Pharmacology ,Sulfonylurea Receptors ,030226 pharmacology & pharmacy ,RECEPTOR ANTAGONIST ,0302 clinical medicine ,Polymorphism (computer science) ,Pharmacology (medical) ,Glucuronosyltransferase ,REDUCED PLASMA-CONCENTRATIONS ,biology ,Liver-Specific Organic Anion Transporter 1 ,NONALCOHOLIC STEATOHEPATITIS ,Cytochrome P-450 CYP1A2 Inducers ,Articles ,3. Good health ,317 Pharmacy ,Area Under Curve ,GLUCURONOSYLTRANSFERASE UGT1A3 ,Quinolines ,Female ,Candidate Gene Analysis ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Adult ,BODY-SURFACE ,In Vitro Techniques ,Sulfides ,Polymorphism, Single Nucleotide ,Article ,Cytochrome P-450 CYP2C8 ,Young Adult ,03 medical and health sciences ,Pharmacokinetics ,SLCO1B1 POLYMORPHISM ,medicine ,Humans ,CYP2C8 ,DRUG-DRUG INTERACTIONS ,Montelukast ,HAPLOTYPE RECONSTRUCTION ,business.industry ,Research ,COMMON VARIANT ,Pharmacogenomic Testing ,respiratory tract diseases ,Minor allele frequency ,CYP2C8 GENOTYPE ,030104 developmental biology ,Pharmacogenomics ,biology.protein ,SLCO1B1 ,business - Abstract
To identify the genetic basis of interindividual variability in montelukast exposure, we determined its pharmacokinetics and sequenced 379 pharmacokinetic genes in 191 healthy volunteers. An intronic single nucleotide variation (SNV), strongly linked with UGT1A3*2, associated with reduced area under the plasma concentration–time curve (AUC0-∞) of montelukast (by 18% per copy of the minor allele; P = 1.83 × 10−10). UGT1A3*2 was associated with increased AUC0-∞ of montelukast acyl-glucuronide M1 and decreased AUC0-∞ of hydroxymetabolites M5R, M5S, and M6 (P < 10−9). Furthermore, SNVs in SLCO1B1 and ABCC9 were associated with the AUC0-∞ of M1 and M5R, respectively. In addition, a candidate gene analysis suggested that CYP2C8 and ABCC9 SNVs also affect the AUC0-∞ of montelukast. The found UGT1A3 and ABCC9 variants associated with increased expression of the respective genes in human liver samples. Montelukast and its hydroxymetabolites were glucuronidated by UGT1A3 in vitro. These results indicate that UGT1A3 plays an important role in montelukast pharmacokinetics, especially in UGT1A3*2 carriers., published version, peerReviewed
- Published
- 2017