HUMAN METABOLISM OF PENTAMIDINE

喷他脒的人体代谢

• 批准号: 3746778
• 负责人: RICHARD R TIDWELL
• 金额: --
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3746778
• 关键词: AIDS; HIV infections; bioassay; body fluids; cooperative study; cytochrome P450; drug metabolism; electrophoresis; electrospray ionization mass spectrometry; high performance liquid chromatography; human subject; interferons; intravenous administration; isozymes; nuclear magnetic resonance spectroscopy; pentamidine; pharmacokinetics; tumor necrosis factor alpha

The anti-Pneumocystis carinii drug pentamidine has generally been considered to be inert to metabolic transformation in mammals, with all therapeutic and toxic properties attributable to the unchanged molecule. Pentamidine, however, has now been shown to be extensively metabolized by the hepatic cytochrome P450 system of rats, with at least seven primary metabolites and additional secondary metabolites formed. Preliminary data suggests pentamidine is also metabolized by humans. One goal of the proposed research is to isolate, identify and quantify, using high performance liquid chromatography, capillary zone electrophoresis, tandem mass spectrometry, 13C nuclear magnetic resonance spectrometry and unequivocal chemical synthesis, the primary and secondary metabolites in body fluids of humans treated therapeutically and prophylactically with pentamidine. Metabolism of pentamidine appears to be mediated by the UTH isoenzyme in rats. The analogous isoenzyme in humans, P450IID6, is polymorphic in most populations studied. A second objective of the proposed research is to use safe, non-toxic probe drugs to examine in HIV infected populations the distribution of the cytochrome P450 isoenzyme responsible for metabolizing pentamidine. The ultimate goal is to determine if any relation exists between extent of metabolism and either therapeutic success or toxic manifestations of pentamidine administration. The use of specific and more general probes should also permit evaluation of the impact of HIV infection upon the overall drug metabolizing system of humans. The current clinical assays for pentamidine are inadequate for the analysis of most pentamidine metabolites. The final objective of the proposed research is to develop relatively simple, yet sensitive and specific new clinical assays for pentamidine and selected metabolites. Such assays, based upon high performance liquid chromatography and capillary electrophoresis methods developed in objective 1, could be used to accurately and comprehensively evaluate patient therapeutic and prophylactic regimes and to monitor patient compliance. The assays could be used to reassess pentamidine pharmacokinetics in humans, based upon the full pattern of metabolites observed. The proposed research should greatly alter current concepts of pentamidine pharmacokinetics and therapeutic and toxic activities in humans. The research is also important to our continuing efforts to develop safer, more effective pentamidine analogs for treatment of P. carinii pneumonia.

抗卡氏肺孢子虫药物扑热息痛通常是 被认为对哺乳动物的新陈代谢转化不起作用，所有 可归因于未改变的分子的治疗和毒性特性。 然而，现在已经证明，五烷双胺被广泛代谢为 大鼠肝细胞色素P450系统，至少有7个初级 代谢物和额外的次生代谢物形成。初步数据 这表明五烷双胺也会被人类代谢。目标之一就是 建议的研究是分离、鉴定和量化，使用高 高效液相色谱、毛细管区带电泳联用 质谱学、~(13)C核磁共振波谱和 明确的化学合成，初级和次级代谢物在 经过治疗和预防的人类体液 五烷双胺。 尿嘧啶脱氢酶同工酶可能参与了五烷双胺的代谢 老鼠。人类中类似的同工酶P450IID6在大多数情况下是多态的 被研究的种群。拟议研究的第二个目标是使用 安全、无毒的探测药物用于检测HIV感染人群 负责代谢的细胞色素P450同工酶的分布 五烷双胺。最终目标是确定是否存在任何关系 代谢程度与治疗成功或中毒之间的关系 给药后出现的临床表现。具体和更多的用法 一般调查还应允许评估艾滋病毒感染的影响。 对人类整体药物代谢系统的影响。 目前的临床检测方法不能满足分析的需要。 在大多数戊二胺代谢物中。建议的最终目标是 研究的目的是开发相对简单、敏感和具体的新技术 临床五烷双胺和选定代谢物的检测。这样的化验， 基于高效液相色谱和毛细管 目标1中开发的电泳法可用于 准确、全面地评估患者的治疗和 预防措施和监测患者的依从性。化验结果可能 用于重新评估扑热息痛在人体的药代动力学，基于 观察到代谢物的完整模式。 这项拟议的研究将极大地改变目前对五烷双胺的概念。 人体的药代动力学、治疗和毒性作用。这个 研究对我们继续努力开发更安全、更 有效的卡氏肺孢子虫肺炎的五烷双胺类似物。