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Comprehensive Pharmacogenomic Study Reveals an Important Role of UGT1A3 in Montelukast Pharmacokinetics
- Source :
- Clinical Pharmacology and Therapeutics
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
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.<br />published version<br />peerReviewed
- 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
Subjects
Details
- ISSN :
- 00099236
- Volume :
- 104
- Database :
- OpenAIRE
- Journal :
- Clinical Pharmacology & Therapeutics
- Accession number :
- edsair.doi.dedup.....125dd5bfbdd531cd4bf3296265640683