Bulgin M S, Lane V M, Archer T E, Baggot J D, Craigmill A L
Caldwell Veterinary Teaching and Research Center, University of Idaho 83605.
J Vet Pharmacol Ther. 1991 Mar;14(1):36-45. doi: 10.1111/j.1365-2885.1991.tb00802.x.
Concentration-time profiles and the rates of absorption, extent of distribution and half-lives of sulfamethazine (SMZ), administered intravenously, orally as a water solution and as a sustained-release formulation (CalfSpan) were determined in 10 healthy sheep. The geometric mean half-life of elimination of i.v. SMZ was 10.8 h, compared to 14.3 h for the sustained-release preparation (CalfSpan) and 4.3 h for the oral water solution. Blood levels of SMZ were at or above 50 micrograms/ml for more than 48 h for CalfSpan, for 24 h after i.v. SMZ (100 mg/kg body wt), and for less than 24 h after p.o. SMZ (100 mg/kg body wt). The mean bioavailability of the oral SMZ solution was 58.3% (AUCp.o./AUCi.v.). The estimated bioavailability of the CalfSpan preparation was 52.5%. The safety of the sustained-release preparation was tested by dosing sheep with multiples (one, three and five times) of the recommended dose (one tablet, 8 g SMZ, per 20 kg body wt), once a day for 3 days. Clinical blood chemistries showed a significant increase in serum iron, and a decrease in serum phosphorus in animals treated at the 3x and 5x dose levels. Necropsies of the 5x dose animals did not show any gross signs that could be attributed to SMZ, and histological examination of tissues from the 5x animals revealed no organ pathology. Residues of SMZ in liver, fat, kidney and skeletal muscle were measured in 20 animals that received one bolus per 20 kg body wt. The results indicate that SMZ residues are cleared rapidly, and are at or below the tolerance level of 0.1 mg/kg within 8 days after dosing so that the 18-day withdrawal time used in cattle would provide an appropriate margin of safety if used in sheep.
在10只健康绵羊中测定了静脉注射、口服水溶液和口服缓释制剂（CalfSpan）的磺胺二甲嘧啶（SMZ）的浓度-时间曲线以及吸收速率、分布范围和半衰期。静脉注射SMZ的几何平均消除半衰期为10.8小时，相比之下，缓释制剂（CalfSpan）为14.3小时，口服水溶液为4.3小时。对于CalfSpan，SMZ的血药浓度在50微克/毫升及以上的时间超过48小时；静脉注射SMZ（100毫克/千克体重）后为24小时；口服SMZ（100毫克/千克体重）后不到24小时。口服SMZ溶液的平均生物利用度为58.3%（AUC口服/AUC静脉）。CalfSpan制剂的估计生物利用度为52.5%。通过给绵羊每日一次、连续3天给予推荐剂量（每20千克体重1片，8克SMZ）的倍数（1倍、3倍和5倍）来测试缓释制剂的安全性。临床血液化学分析显示，在接受3倍和5倍剂量治疗的动物中，血清铁显著升高，血清磷降低。对接受5倍剂量的动物进行尸检未发现任何可归因于SMZ的明显体征，对接受5倍剂量动物的组织进行组织学检查未发现器官病变。在20只每20千克体重接受一次大剂量给药的动物中测量了肝脏、脂肪、肾脏和骨骼肌中的SMZ残留量。结果表明，SMZ残留清除迅速，给药后8天内处于或低于0.1毫克/千克的耐受水平，因此，如果用于绵羊，牛所用的18天停药期将提供适当的安全边际。
