title: Interindividual variations in metabolism and pharmacokinetics of 3-(6-methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide, a glucokinase activator, in rats caused by the genetic polymorphism of CYP2D1.
abstract: 3-(6-Methylpyridine-3-yl-sulfanyl)-6-(4H-[1,2,4]triazole-3-yl-sulfanyl)-N-(1,3-thiazole-2-yl)-2-pyridine carboxamide (Cpd-D) is a novel glucokinase activator that is being developed for the treatment of type 2 diabetes. Large interindividual variations were observed in the pharmacokinetics of Cpd-D in male Sprague-Dawley (SD) rats, which were subsequently divided into two phenotypes; >6-fold longer terminal-phase half-life and ∼10-fold larger AUC0-∞ values were observed in slow metabolizers (SM) than in fast metabolizers (FM) after the oral administration of Cpd-D. The thiohydantoic acid analog (M2) was the predominant metabolite detected in the urine, bile, and plasma after the oral administration of [(14)C]Cpd-D to the FM phenotypes of bile-duct cannulated SD rats. The liver microsomes prepared from FM phenotyped rats extensively formed M2 with the highest affinity (Km = 0.09 μM) and largest Vmax/Km value in primary metabolism, whereas those from SM phenotypes had little capacity to form M2. Of the rat cytochrome P450 isoforms tested, the formation of M2 was only catalyzed by recombinant CYP2D1. Sequence substitutions (418A/421C and 418G/421T) were detected in the CYP2D1 gene and were designated F and S alleles, respectively. The genotype-phenotype correlation analysis indicated that two S alleles were homozygous (S/S) in the SM phenotypes, whereas the FM phenotypes were either homozygous for the F-alleles (F/F) or heterozygous (F/S). These results indicated that the CYP2D1 polymorphism caused by nucleotide substitutions (418A/421C versus 418G/421T) was responsible for interindividual variations leading to the polymorphism in the major metabolism and pharmacokinetics of Cpd-D in male SD rats.
authors.affiliation: Banyu Tsukuba Research Institute, MSD K.K., Tsukuba, Ibaraki, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Banyu Tsukuba Research Institute, MSD K.K., Tsukuba, Ibaraki, Japan junichi_eiki@merck.com.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Eiki
authors.affiliation: Banyu Tsukuba Research Institute, MSD K.K., Tsukuba, Ibaraki, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Chiba
mesh_terms: D000284:Administration, Oral; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D056726:Genetic Association Studies; D005941:Glucokinase / Q000378:metabolism*; D006207:Half-Life; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011725:Pyridines / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; D000429:Alcohol Oxidoreductases; C504568:Cyp2d1 protein, rat; D000072467:Cytochrome P450 Family 2; D005941:Glucokinase; C023666:pyridine