Shi X G, Fawcett J P, Chen X Y, Zhong D F
Laboratory of Drug Metabolism and Pharmacokinetics, Shenyang Pharmaceutical University, Shenyang, PR China.
Xenobiotica. 2005 Apr;35(4):343-58. doi: 10.1080/00498250500087580.
Bitespiramycin is a macrolide antibiotic consisting of a mixture of some nine spiramycin ester derivatives. It has a similar spectrum of antibiotic activity to that of spiramycin but has superior pharmacokinetic properties. In this study, a rapid and facile LC/ESI-MSn method was applied to study the metabolism of bitespiramycin in rat following a single oral dose (80 mg kg-1). Concentrations of parent drug constituents and metabolites were determined in plasma, urine, feces and bile. Concentrations of parent drug constituents and metabolites in plasma were very low. In urine, feces and bile, parent drug constituents and 38 metabolites were identified on the basis of their chromatographic and mass spectrometric properties. The identity of 17 metabolites was confirmed by comparison with reference substances. The principal metabolites were the corresponding spiramycins formed by hydrolysis of the 4''-(3-methylbutanoate) groups. Other important metabolic pathways were: hydrolytic loss of the forosamine and mycarose sugars; aldehyde reduction; cysteine conjugation of the aldehyde group; and hydrolysis of the lactone ring. Products formed by lactone ring opening were found only in urine, and those formed by aldehyde reduction were found only in feces. Aldehyde reduction and hydrolytic loss of forosamine represent novel biotransformation pathways for spiramycin derivatives.
必特螺旋霉素是一种大环内酯类抗生素，由约九种螺旋霉素酯衍生物的混合物组成。它具有与螺旋霉素相似的抗菌活性谱，但具有更优越的药代动力学性质。在本研究中，应用一种快速简便的液相色谱/电喷雾串联质谱法研究大鼠单次口服剂量（80 mg·kg-1）后必特螺旋霉素的代谢情况。测定了血浆、尿液、粪便和胆汁中母体药物成分及代谢物的浓度。血浆中母体药物成分及代谢物的浓度非常低。在尿液、粪便和胆汁中，根据其色谱和质谱性质鉴定出母体药物成分及38种代谢物。通过与对照品比较，确认了17种代谢物的结构。主要代谢物是由4''-(3-甲基丁酸酯)基团水解形成的相应螺旋霉素。其他重要的代谢途径包括：福洛糖胺和霉糖的水解丢失；醛还原；醛基与半胱氨酸的结合；以及内酯环的水解。内酯环开环形成的产物仅在尿液中发现，醛还原形成的产物仅在粪便中发现。醛还原和福洛糖胺的水解丢失代表了螺旋霉素衍生物新的生物转化途径。
