H-MAP促进肺部胰岛素吸收：大鼠体内的药代动力学和药效学

Facilitation of pulmonary insulin absorption by H-MAP: pharmacokinetics and pharmacodynamics in rats.

作者信息

Suarez S, Garcia-Contreras L, Sarubbi D, Flanders E, O'Toole D, Smart J, Hickey A J

机构信息

University of North Carolina at Chapel Hill, 27599, USA.

出版信息

Pharm Res. 2001 Dec;18(12):1677-84. doi: 10.1023/a:1013362227548.

DOI:10.1023/a:1013362227548

PMID:11785686

Abstract

PURPOSE

Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined.

METHODS

Aliquots (100 microl) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined.

RESULTS

The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (Cmax) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG0-->t) was achieved for H-MAP/insulin combination (66+/-5%) compared to insulin alone (47+/-10 %).

CONCLUSION

H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.

摘要

目的

先前有报道称几种低分子量氨基酸能够实现蛋白质的口服递送。在本研究中，已确定了羟甲基氨基丙酸（H - MAP）对通过喷雾滴注（SI）递送至大鼠肺部的猪胰岛素的药代动力学（PK）和药效学（PD）的影响。

方法

将单独的不同剂量猪胰岛素（0.26、1.3、2.6、13和26 U/kg）或与不同剂量的H - MAP（5、10、16和25 mg/kg）混合，在pH 7.2 - 7.6条件下，取100微升等分试样，使用微量喷雾滴注器经气管内给予禁食麻醉的大鼠。在特定时间间隔从颈静脉采集血样，测定血浆中胰岛素和葡萄糖的浓度。还测定了皮下（SC）给予不同剂量猪胰岛素后的PK和PD。

结果

通过SI给予肺部或SC注射的胰岛素的PK取决于吸收速率，导致峰后半衰期比报道的静脉消除半衰期（3分钟）大10至25倍。单独通过SI给予胰岛素时，最低和最高胰岛素剂量的相对生物利用度（F'）分别为23.8%至80%。将H - MAP与胰岛素共同给予肺部显著改变了胰岛素的PK和PD，且呈剂量依赖性。在H - MAP剂量为16 mg/kg和胰岛素剂量为1.3 U/kg时获得了最大的PK和PD反应。在此组合下，相对于相同剂量的单独胰岛素，胰岛素的相对生物利用度增加了2.5倍以上，最大浓度（Cmax）增加了2倍，最低血浆葡萄糖浓度（%MPGC）降低了2倍以上。与单独使用胰岛素（47±10%）相比，H - MAP/胰岛素组合实现了更大的血浆葡萄糖总降低量（%TRPG0→t）（66±5%）。