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.

Comparative pharmacokinetics of diaveridine in pigs and chickens following single intravenous and oral administration

“…But the pharmacokinetic behaviors of trimethoprim (TMP), another amino pyrimidines drug, have been recorded in sheep at the dosage of 15 and 20 mg/kg bodyweight (Atef et al ., ), followed by buffalo calves at the dosage of 10 mg/kg bodyweight (Iqbal et al ., ), or in combined with sulphadiazine at the ratio of 1:5 in pigs (Baert et al ., ), ostriches (Abu‐Basha et al ., ), broiler chickens (Baert et al ., ), sheep (Batzias et al ., ), fish (Wang et al ., ) and other animals. Furthermore, the metabolism of TMP in animals was also further studied (Schwartz et al ., ; Meshi & Sato, ; Klooster et al ., ; Liu et al ., ).…”

“…Only in recent years, the metabolic characteristics of DVD in farm animal species have been paid more attention. Six metabolites of DVD in vitro were identified in pig microsomes using high‐performance liquid chromatography (HPLC) combined with ion trap/time‐of‐flight mass spectrometry (Liu et al ., ). Our team members previously identified the structure of in vivo metabolites and proposed fragmentation metabolic pathways of DVD in chickens (Hui et al ., ).…”

Establishment of a monoclonal antibody-based indirect enzyme-linked immunosorbent assay for the detection of trimethoprim residues in milk, honey, and fish samples

“…In animal husbandry, the single administration of TMP causes microbial resistance; therefore, TMP is widely administered in combination with sulfonamides or other antibiotics for the therapy of animal diseases, including fowl cholera, respiratory tract secondary bacterial infection, and pullorum disease (Liu, Wu, Sun, & Wan, 2012). The potency of TMP is enhanced 10× when administered with sulfonamides.…”

Metabolites and Transformation Products of Pharmaceuticals in the Aquatic Environment as Contaminants of Emerging Concern

“…Another issue is that even if individual antibiotics are assessed for their quality, efficacy, toxicity, and safety, the information is not sufficient since they are rarely used alone, but rather in combination with others to improve their action (e.g., trimethoprim with sulfonamides). This may significantly modify the properties and ecotoxicity values noted for a component in the natural environment mixture of pure antibiotics, their metabolites and TPs (additivity, synergism) [85,86].…”