title: Characterization of in vitro metabolites of trimethoprim and diaveridine in pig liver microsomes by liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry.
abstract: Trimethoprim (TMP) and diaveridine (DVD) are used in combination with sulfonamides and sulfaquinoxlaine as an effective antibacterial agent and antiprotozoal agent, respectively, in humans and animals. To gain a better understanding of the metabolism of TMP and DVD in the food-producing animals, the metabolites incubated with liver microsomes of pigs were analyzed for the first time with high-performance liquid chromatography combined with hybrid ion trap/time-of-flight mass spectrometry. Seven TMP-related and six DVD-related metabolites were characterized based on the accurate MS² spectra and known structure of the parent drug, respectively. The metabolites of TMP were identified as two O-demethylation metabolites, a di-O-demethylation metabolite, two N-oxides metabolites, a hydroxylated metabolite on the methylene carbon and a hydroxylated metabolite on the methyl group. DVD was also biotransformed to two O-demethylation metabolites, a di-O-demethylation metabolite, an N-oxide metabolite, a hydroxylation metabolite on the methylene carbon and a hydroxylation metabolite followed by O-demethylation. The results indicate that the two compounds have similar biotransformation pathways in pigs. O-Demethylation was the major metabolic route of TMP and DVD in the pig liver microsomes. The proposed metabolic pathways of TMP and DVD in liver microsomes will provide a basis for further studies of the in vivo metabolism of the two drugs in food-producing animals.
authors.affiliation: Hunan Engineering Research Center of Veterinary Drug, College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, Hunan, China. liu_zhaoying@sina.com
authors.forename: Zhao-Ying
authors.initials: ZY
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhi-Liang
authors.initials: ZL
authors.lastname: Sun
authors.forename: Leren
authors.initials: L
authors.lastname: Wan
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D008297:Male; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics*; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013552:Swine; D014295:Trimethoprim / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D011743:Pyrimidines; C033222:diaveridine; D014295:Trimethoprim