Wilson S, Cronk D W, Dodd I, Esmail A F, Kalindjian S B, McMurdo L, Browne M J, Smith R A, Robinson J H
Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK.
Thromb Haemost. 1993 Dec 20;70(6):984-8.
Recombinant hybrid plasminogen activators consisting of the "A" chain of plasminogen linked to the "B" chain of t-PA that are inhibited rapidly by plasma protease inhibitors have recently been described (Robinson et al. Circulation 1992; 86: 548-552). We have now shown that following bolus administration of native hybrid to guinea pigs, fibrinolytic activity was cleared rapidly from the circulation. Active centre acylation appeared to protect the hybrid from inhibition and allowed material to circulate as potentially active species for prolonged periods. Clearance rates of a range of acyl derivatives of the hybrid were 7-35-fold slower than for native hybrid and 20-100-fold slower than for t-PA. Clearance rates were influenced markedly by deacylation rate, such that clearance half-life correlated well with deacylation half-life. We have thus shown that it is feasible to control the pharmacokinetic profile of a recombinant hybrid plasminogen activator over a wide range by selection of an appropriate acyl group for attachment to the active site. Such control is not possible with plasminogen activators that are cleared predominantly by mechanisms other than inhibition.
最近已描述了由与组织型纤溶酶原激活剂（t-PA）的“B”链相连的纤溶酶原“A”链组成的重组杂合纤溶酶原激活剂，其可被血浆蛋白酶抑制剂迅速抑制（Robinson等人，《循环》1992年；86：548 - 552）。我们现已表明，向豚鼠推注天然杂合剂后，纤溶活性迅速从循环中清除。活性中心酰化似乎可保护杂合体不被抑制，并使物质作为潜在活性物质长时间在循环中存在。该杂合体一系列酰基衍生物的清除率比天然杂合体慢7 - 35倍，比t-PA慢20 - 100倍。清除率受脱酰化速率的显著影响，因此清除半衰期与脱酰化半衰期密切相关。因此，我们已表明通过选择合适的酰基连接到活性位点，在很宽范围内控制重组杂合纤溶酶原激活剂的药代动力学特征是可行的。对于主要通过抑制以外的机制清除的纤溶酶原激活剂，这种控制是不可能的。
