UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study.
MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania, USA. yinghong_wang@merck.com
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D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002243:Carbolines / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D016903:Drug Monitoring; D005838:Genotype; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors
C554899:((7R)-7-(((4-fluorophenyl)sulfonyl)(methyl)amino)-6,7,8,9-tetrahydropyrido(1,2-a)indol-10-yl)acetic acid; D002243:Carbolines; D020719:Glucuronides; D015778:Minor Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human