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Abstract：
OBJECTIVE: The study was conducted to evaluate the influence of theophylline pre-treatment on serum pharmacokinetics and milk elimination of tylosin following single intramuscular (IM) administrations in lactating goats.
RESULTS: In a cross-over study, tylosin was injected via intramuscular (IM) at a single dose of 15 mg/kg b.wt. After a one-month washout period goats received theophylline at a daily IM dose of 2 mg/kg b.wt. for seven consecutive days then tylosin was injected IM dose of 15 mg/kg b.wt. two hours after the last theophylline dosing. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h post-injection. Samples were left to clot and then centrifuged to yield serum. Milk samples were collected before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h post-injection from each goat by hand milking. Tylosin serum concentrations were determined by high-performance liquid chromatography (HPLC). Tylosin concentrations versus time were analyzed by a noncompartmental method. Tylosin Cmax significantly declined from 1.73 ± 0.10 to 1.01 ± 0.11 µg/ml, and attained Tmax values of 2 and 1 h, respectively in theophylline-pretreated goats. Moreover, theophylline pretreatment significantly shortened the elimination half-life (t1/2el) from 6.94 to 1.98 h, t1/2ka from 0.62 to 0.36 h and the mean residence time (MRT) from 8.02 to 4.31 h, also Vz/F and AUCs decreased from 11.91 to 7.70 L/kg and from 12.64 to 4.57 µg*h/ml, respectively, consequently, theophylline enhanced the clearance (Cl/F) of tylosin from the body. Similarly, tylosin milk concentrations were significantly lower in theophylline-pretreated goats than in goats that received tylosin alone and were detected up to 24 and 72 h in both groups, respectively. Moreover, the t1/2el and AUCs were significantly decreased from 14.68 ± 1.97 to 4.72 ± 0.48 h, and from 181 to 67.20 µg*h/ml, respectively.
CONCLUSIONS: The withdrawal period for tylosin in goat milk is at least 72 h. Theophylline pretreatment significantly decreases serum and milk tylosin concentrations to subtherapeutic levels, which could have serious clinical consequences such as failure of therapy. This means that after administering tylosin to goats, milk from these animals should not be consumed for at least 96 h to ensure that the milk is free from residues of the antibiotic.
RESULTS: In a cross-over study, tylosin was injected via intramuscular (IM) at a single dose of 15 mg/kg b.wt. After a one-month washout period goats received theophylline at a daily IM dose of 2 mg/kg b.wt. for seven consecutive days then tylosin was injected IM dose of 15 mg/kg b.wt. two hours after the last theophylline dosing. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h post-injection. Samples were left to clot and then centrifuged to yield serum. Milk samples were collected before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h post-injection from each goat by hand milking. Tylosin serum concentrations were determined by high-performance liquid chromatography (HPLC). Tylosin concentrations versus time were analyzed by a noncompartmental method. Tylosin Cmax significantly declined from 1.73 ± 0.10 to 1.01 ± 0.11 µg/ml, and attained Tmax values of 2 and 1 h, respectively in theophylline-pretreated goats. Moreover, theophylline pretreatment significantly shortened the elimination half-life (t1/2el) from 6.94 to 1.98 h, t1/2ka from 0.62 to 0.36 h and the mean residence time (MRT) from 8.02 to 4.31 h, also Vz/F and AUCs decreased from 11.91 to 7.70 L/kg and from 12.64 to 4.57 µg*h/ml, respectively, consequently, theophylline enhanced the clearance (Cl/F) of tylosin from the body. Similarly, tylosin milk concentrations were significantly lower in theophylline-pretreated goats than in goats that received tylosin alone and were detected up to 24 and 72 h in both groups, respectively. Moreover, the t1/2el and AUCs were significantly decreased from 14.68 ± 1.97 to 4.72 ± 0.48 h, and from 181 to 67.20 µg*h/ml, respectively.
CONCLUSIONS: The withdrawal period for tylosin in goat milk is at least 72 h. Theophylline pretreatment significantly decreases serum and milk tylosin concentrations to subtherapeutic levels, which could have serious clinical consequences such as failure of therapy. This means that after administering tylosin to goats, milk from these animals should not be consumed for at least 96 h to ensure that the milk is free from residues of the antibiotic.
摘要：
目的：本研究旨在评估茶碱预处理对泌乳山羊单次肌内（IM）给药后泰乐菌素的血清药代动力学和牛奶消除的影响。
结果：在一项交叉研究中，通过肌内（IM）以15mg/kgb.wt.的单剂量注射泰乐菌素。经过一个月的冲洗期后，山羊以每天2mg/kgb.wt.的IM剂量接受茶碱。连续7天，然后注射15mg/kgb.wt.的IM剂量的泰乐菌素。在最后一次茶碱给药两小时后.在注射前和注射后0.25、0.5、0.75、1、2、4、6、8、10、12和24小时收集血样。使样品凝结,然后离心以产生血清。在注射前和注射后0.5、1、2、4、6、8、10、12、24、48和72小时时，通过手工挤奶从每只山羊收集牛奶样品。通过高效液相色谱法(HPLC)测定泰乐菌素血清浓度。通过非隔室方法分析泰乐菌素浓度与时间的关系。泰乐菌素Cmax从1.73±0.10显著下降至1.01±0.11µg/ml，并达到2和1小时的Tmax值，分别在茶碱预处理的山羊中。此外，茶碱预处理显著缩短消除半衰期(t1/2el)从6.94到1.98h,t1/2ka从0.62到0.36h，平均停留时间（MRT）从8.02到4.31h，Vz/F和AUC也从11.91降至7.70L/kg，从12.64降至4.57µg*h/ml，分别,因此,茶碱增强了泰乐菌素从体内的清除（Cl/F）。同样，在茶碱预处理的山羊中，泰乐菌素乳浓度显着低于仅接受泰乐菌素的山羊，并且在两组中检测到长达24和72小时，分别。此外，t1/2el和AUC从14.68±1.97显著下降到4.72±0.48h，从181到67.20µg*h/ml，分别。
结论：羊奶中泰乐菌素的停药期至少为72小时。茶碱预处理可将血清和牛奶中的泰乐菌素浓度显着降低至亚治疗水平，这可能会产生严重的临床后果，例如治疗失败。这意味着在给山羊服用泰乐菌素后，来自这些动物的牛奶不应食用至少96小时，以确保牛奶不含抗生素残留。
结果：在一项交叉研究中，通过肌内（IM）以15mg/kgb.wt.的单剂量注射泰乐菌素。经过一个月的冲洗期后，山羊以每天2mg/kgb.wt.的IM剂量接受茶碱。连续7天，然后注射15mg/kgb.wt.的IM剂量的泰乐菌素。在最后一次茶碱给药两小时后.在注射前和注射后0.25、0.5、0.75、1、2、4、6、8、10、12和24小时收集血样。使样品凝结,然后离心以产生血清。在注射前和注射后0.5、1、2、4、6、8、10、12、24、48和72小时时，通过手工挤奶从每只山羊收集牛奶样品。通过高效液相色谱法(HPLC)测定泰乐菌素血清浓度。通过非隔室方法分析泰乐菌素浓度与时间的关系。泰乐菌素Cmax从1.73±0.10显著下降至1.01±0.11µg/ml，并达到2和1小时的Tmax值，分别在茶碱预处理的山羊中。此外，茶碱预处理显著缩短消除半衰期(t1/2el)从6.94到1.98h,t1/2ka从0.62到0.36h，平均停留时间（MRT）从8.02到4.31h，Vz/F和AUC也从11.91降至7.70L/kg，从12.64降至4.57µg*h/ml，分别,因此,茶碱增强了泰乐菌素从体内的清除（Cl/F）。同样，在茶碱预处理的山羊中，泰乐菌素乳浓度显着低于仅接受泰乐菌素的山羊，并且在两组中检测到长达24和72小时，分别。此外，t1/2el和AUC从14.68±1.97显著下降到4.72±0.48h，从181到67.20µg*h/ml，分别。
结论：羊奶中泰乐菌素的停药期至少为72小时。茶碱预处理可将血清和牛奶中的泰乐菌素浓度显着降低至亚治疗水平，这可能会产生严重的临床后果，例如治疗失败。这意味着在给山羊服用泰乐菌素后，来自这些动物的牛奶不应食用至少96小时，以确保牛奶不含抗生素残留。
