Jones R H, Dron D I, Ellis M J, Sönksen P H, Brandenburg D
Diabetologia. 1976 Dec;12(6):601-8. doi: 10.1007/BF01220637.
Beef insulin, pork proinsulin and four derivatives of beef insulin modified at the A1-B29 site on the molecular surface have been studied. Three derivatives had a synthetic crosslink between the A and B chains. Previous studies with these materials [2, 3 and 5] had demonstrated in vivo bioactivities which were much higher than those displayed in vitro. This paper reports experiments which explain this discrepancy. The analogues were administered at equimolar rates to anaesthetised greyhounds by a priming-dose constant infusion technique and the plasma concentrations achieved were estimated by radioimmunoassay. Proinsulin and the modified insulins were metabolised more slowly than insulin. Biopotency values, which related fall in plasma glucose concentration to the total administered dose of analogue, agreed broadly with published results of conventional in vivo bioassays. On the other hand, calculation of potency in relation to the serum concentration of analogue actually achieved, yielded results which agreed more closely with in vitro assay data. We conclude that for these analogues, reported discrepancies between in vitro and in vivo biopotencies can be largely explained by the different rates at which these materials are metabolised.
对牛胰岛素、猪胰岛素原以及在分子表面A1 - B29位点修饰的四种牛胰岛素衍生物进行了研究。三种衍生物在A链和B链之间有一个合成交联。此前对这些物质的研究[2、3和5]已证明其体内生物活性远高于体外显示的活性。本文报道了解释这种差异的实验。通过首剂量恒速输注技术，以等摩尔速率给麻醉的灵缇犬注射类似物，并通过放射免疫测定法估算所达到的血浆浓度。胰岛素原和修饰胰岛素的代谢比胰岛素更慢。生物效价数值（将血浆葡萄糖浓度下降与类似物的总给药剂量相关联）与已发表的传统体内生物测定结果大致相符。另一方面，根据实际达到的类似物血清浓度计算效价，得出的结果与体外测定数据更接近。我们得出结论，对于这些类似物，体外和体内生物效价之间报道的差异在很大程度上可以通过这些物质代谢速率的不同来解释。
