| Roxithromycin (RXM), as a semisynthetic macrolide antibiotics, could disrupt bacterial protein synthesis by combining with 50s bacterial subunit, thereby exhibited antibacterial effects. In previous studies on RXM in vivo metabolism, RXM underwent metabolic pathways including geometric isomerization from (E)-configuration to (Z)-configuration, decladinose, N-demethylation, O-demethylation and O-dealkylether of oxime ether side chain. And some species differences were found in demethylation metabolism and geometric isomerization between rats and humans. All other metabolites including (Z)-isomer of RXM exhibited lower antibacterial potency than RXM, except that O-demethyl RXM showed similar antibacterial efficacy to parent drug. It is important for rational evaluation of animal data as well as extrapolation to humans, and for guiding clinical use, to gain further understanding of RXM metabolic mechanism and possible species differences.The thesis aimed to investigate RXM metabolism in different lab animals, to interpret the possible species differences in RXM metabolism among different animals and humans, and to reveal the mechanism of geometric isomerization of RXM, by applying liquid chromatography-mass spectrometry technique in sample analysis. It would offer some references and inspirations for drug design and dosage form modification.1. RXM metabolism in lab animalsThe metabolic profiles of RXM in rats, dogs, golden hamsters, Guinea pigs and mice were investigated. The metabolites were identified and the species differences were interpreted among animals and humans. Totally 17 metabolites were measured in the tested animals, and were identified as (Z)-isomer of RXM (M1), N-demethyl RXM (M2) and its (Z)-isomer (M3), oxime ether side chain O-demethyl RXM (M4) and its isomer (M5), decladinose O-demethyl RXM (M16), N,N-didemethyl RXM (M6) and its (Z)-isomer (M7), N,O-didemethyl RXM (M8) and its (Z)-isomer (M9), N,O(cladinose)-didemethyl RXM (M17), erythromycin oxime (M10) and its (Z)-isomer (M11), N-demethyl erythromycin oxime (M12) and its (Z)-isomer (M13), as well as decladinose RXM (M14) and its (2)-isomer (M15),ABSTRACTrespectively, by comparisons of LC behavior and MSn data with reference substances. It was found that RXM underwent similar metabolic pathways in the tested animals, including geometric isomerization of 9-oxime ether side chain from (E)-configuration to (Z)-configuration, decladinose, N-demethylation, cladinose O-demethylation, and oxime ether side chain O-demethylation as well as O-dealkylether. And some species differences were found in geometric isomerization and demethylation among animals and humans. The extent of geometric isomerization was markedly higher in dogs and humans than in other animals, the ratio of (Z)/(E) reached about 2 at maximum in dogs, and 1.7 in humans. The oxime ether side chain O-demethylation pathway was predominant in humans, while other demethylated metabolites were only in trace amount. N-demethylation and cladinose O-demethylation were main pathways in animals, while oxime ether side chain O-demethyl metabolite (M4) was at minor level.Some stereoselectivity was observed in the excretion routes of RXM. The general level of metabolites in bile and feces was higher than that in urine. The (Z)-isomer of RXM (M1), N-demethyl RXM (M2) and O-demethyl RXM (M4) were excreted preferentially by bile and by feces, while cladinose O-demethyl RXM was excreted mainly by urine.2. RXM metabolism in liver microsomes and in gastrointestinal contentsThe liver microsomes of rats, dogs, golden hamsters and Guinea pigs were prepared by applying ultracentrifugation approach. The in vitro metabolism study model of liver microsomes was established for the investigation of RXM and (Z)-RXM metabolism. N-Demethyl RXM (M2) , O-demethyl RXM (M4), N,N-didemethyl RXM (M6) and erythromycin oxime (M10) were detected in animal liver microsomes incubates. Additionally, cladinose O-demethyl RXM was detected in golden hamster and Guinea pig liver microsome incubations. (Z)-RXM...
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