HUMAN METABOLISM OF PENTAMIDINE

抗卡氏肺孢子虫药物喷他脒通常 被认为对哺乳动物的代谢转化呈惰性，所有 未改变的分子具有治疗和毒性。 然而，喷他脒现在已被证明是广泛代谢的， 大鼠肝细胞色素P450系统，至少有7个主要 代谢产物和额外的次级代谢产物形成。 初步数据 表明喷他脒也能被人体代谢 的一个目标 建议的研究是分离，识别和量化，使用高 高效液相色谱，毛细管区带电泳，串联 质谱法、13 C核磁共振光谱法和 明确的化学合成，初级和次级代谢产物， 治疗性和治疗性处理的人体液， 喷他脒 喷他脒的代谢似乎是由UTH同工酶介导的， 大鼠 人类中的类似同工酶P450 IID 6在大多数人中是多态的。 研究人群。 研究的第二个目的是使用 安全、无毒的探针药物，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 喷他脒 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毒性之间的关系 喷他脒给药的表现。 具体的使用和更多 一般的探针也可以用来评估HIV感染的影响 对人体整体药物代谢系统的影响。 目前的临床检测喷他脒是不够的分析 大多数喷他脒的代谢物。 建议的最终目标 研究是开发相对简单，但敏感和具体的新的 喷他脒和选定代谢物的临床测定。 这样的测定， 基于高效液相色谱和毛细管 在目标1中开发的电泳方法，可用于 准确、全面地评价患者的治疗效果， 预防方案和监测患者依从性。 这些测定可以 用于重新评估喷他脒在人体内的药代动力学， 观察到完整的代谢物模式。 拟议的研究将极大地改变目前对喷他脒的概念 药物代谢动力学和治疗和毒性活性。 的 研究对于我们继续努力开发更安全、更安全的 用于治疗卡氏肺孢子虫肺炎的有效喷他脒类似物。

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.