METABOLISM OF THIENAMYCIN AND RELATED CARBAPENEM ANTIBIOTICS BY THE RENAL DIPEPTIDASE, DEHYDROPEPTIDASE-I
METABOLISM OF THIENAMYCIN AND RELATED CARBAPENEM ANTIBIOTICS BY THE RENAL DIPEPTIDASE, DEHYDROPEPTIDASE-I
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DOI：
10.1128/aac.22.1.62
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发表时间：
1982-01-01
影响因子：
4.9
通讯作者：
KAHAN, FM
中科院分区：
文献类型：
--
作者：
KROPP, H;SUNDELOF, JG;KAHAN, FM
Thienamycin （THM）、n -甲酰基Thienamycin衍生物MK0787以及相关的碳青霉烯类抗生素在小鼠、大鼠、家兔、狗、恒河猴和黑猩猩体内广泛代谢。THM的尿恢复率从狗的5%到恒河猴的58%不等。狗和黑猩猩的肾脏清除率异常低，低于肾小球滤过率。大鼠和家兔肾动脉结扎后血浆中THM和MK0787清除率的降低表明肾脏分别负责35%和92%的代谢性药物清除率。仅在肾脏匀浆中检测到降解。该酶的活性是膜结合的，对锌金属酶抑制剂如EDTA敏感。肾二肽酶脱氢肽酶- i (DHP-I), EC 3.4.13.11，被发现负责thm类抗生素的代谢，其表现出与脱氢肽的结构同源性。在猪和人肾皮质的增溶和纯化过程中，观察到对THM和dhp - 1底物甘酰基脱氢苯丙氨酸的比活性平行增加。dhp - 1催化了β的水解。-内酰胺环在THM和MK0787。通过高效液相色谱分析，酶反应的产物与尿液中的代谢产物完全相同。当暴露于dhp - 1酶解时，非碱性n -酰化THM和天然n -酰化碳青霉烯类（上皮霉素和橄榄酸）的降解速度比THM快4- 50倍。体外酶测定结果表明碳青霉烯类抗生素对DHP-I的敏感性增加与实验动物尿液中活性抗生素的回收率普遍较低之间存在良好的相关性。尽管这种不寻常的代谢程度局限于肾脏，但MK0787的血浆半衰期及其对实验性动物全身细菌感染的功效仍然令人满意。
Thienamycin (THM), the N-formimidoyl thienamycin derivative MK0787 and related carbapenem antibiotics were metabolized extensively in mice, rats, rabbits, dogs, rhesus monkeys and chimpanzees. Urinary recovery of THM ranged from a low of 5% in dogs to 58% in rhesus monkeys. Renal clearance rates in dogs and chimpanzees were unusually low, less than glomerular filtration rates. The reduction in clearance of THM and MK0787 from plasma of rats and rabbits after ligation of renal arteries indicate that the kidneys are responsible for 35 and 92%, respectively, of metabolic drug clearance. Degradation was detected only in kidney homogenates. The enzyme activity was membrane bound and sensitive to inhibitors of Zn-metalloenzymes such as EDTA. A renal dipeptidase, dehydropeptidase-I (DHP-I), EC 3.4.13.11, was found to be responsible for the metabolism of the THM-class antibiotics, which exhibit a structural homology to dehydropeptides. A parallel increase in specific activity against THM and the substrate of DHP-I, glycyldehydrophenylalanine, was observed during solubilization and purification of the enzyme from porcine and human renal cortex. DHP-I catalyzed the hydrolysis of the .beta.-lactam ring in THM and MK0787. The products of the enzyme reaction were identical by high-powered liquid chromatography to their respective metabolites found in the urine. Nonbasic N-acylated THM and natural N-acylated carbapenems (epithienamycins and olivanic acids) were degraded 4- to 50-fold faster than THM when exposed to the enzymatic hydrolysis of DHP-I. Good correlations were obtained between the increased susceptibility of the carbapenem antibiotics to DHP-I as measured in the in vitro enzyme assay and the generally lower recoveries of active antibiotic in the urine of test animals. Despite this unusual degree of metabolism localized in the kidney, the plasma half-life of MK0787 and its efficacy against experimental systemic bacterial infections in animals remain satisfactory.