Gutiérrez José María, León Guillermo, Lomonte Bruno
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
Clin Pharmacokinet. 2003;42(8):721-41. doi: 10.2165/00003088-200342080-00002.
Parenteral administration of horse- and sheep-derived antivenoms constitutes the cornerstone in the therapy of envenomations induced by animal bites and stings. Depending on the type of neutralising molecule, antivenoms are made of: (i) whole IgG molecules (150 kDa), (ii) F(ab')(2) immunoglobulin fragments (100 kDa) or (iii) Fab immunoglobulin fragments (50 kDa). Because of their variable molecular mass, these three types of antivenoms have different pharmacokinetic profiles. Fab fragments have the largest volume of distribution and readily reach extravascular compartments. They are catabolised mainly by the kidney, having a more rapid clearance than F(ab')(2) fragments and IgG. On the other hand, IgG molecules have a lower volume of distribution and a longer elimination half-life, showing the highest cycling through the interstitial spaces in the body. IgG elimination occurs mainly by extrarenal mechanisms. F(ab')(2) fragments display a pharmacokinetic profile intermediate between those of Fab fragments and IgG molecules. Such diverse pharmacokinetic properties have implications for the pharmacodynamics of these immunobiologicals, since a pronounced mismatch has been described between the pharmacokinetics of venoms and antivenoms. Some venoms, such as those of scorpions and elapid snakes, are rich in low-molecular-mass neurotoxins of high diffusibility and large volume of distribution that reach their tissue targets rapidly after injection. In contrast, venoms rich in high-molecular-mass toxins, such as those of viperid snakes, have a pharmacokinetic profile characterised by a rapid initial absorption followed by a slow absorption process from the site of venom injection. Such delayed absorption has been linked with recurrence of envenomation when antibody levels in blood decrease. This heterogeneity in pharmacokinetics and mechanism of action of venom components requires a detailed analysis of each venom-antivenom system in order to determine the most appropriate type of neutralising molecule for each particular venom. Besides having a high affinity for toxicologically relevant venom components, an ideal antivenom should possess a volume of distribution as similar as possible to that of the toxins being neutralised. Moreover, high levels of neutralising antibodies should remain in blood for a relatively prolonged time to assure neutralisation of toxins reaching the bloodstream later in the course of envenomation, and to promote redistribution of toxins from extravascular compartments to blood. Additional studies are required on different venoms and antivenoms in order to further understand the pharmacokinetic-pharmacodynamic relationships of antibodies and their fragments and to optimise the immunotherapy of envenomations.
注射用马源和羊源抗蛇毒血清是治疗动物咬伤和蜇伤所致中毒的基石。根据中和分子的类型，抗蛇毒血清由以下成分组成：（i）完整的IgG分子（150 kDa），（ii）F(ab')(2)免疫球蛋白片段（100 kDa）或（iii）Fab免疫球蛋白片段（50 kDa）。由于它们的分子量不同，这三种类型的抗蛇毒血清具有不同的药代动力学特征。Fab片段的分布容积最大，容易到达血管外间隙。它们主要通过肾脏分解代谢，清除速度比F(ab')(2)片段和IgG更快。另一方面，IgG分子的分布容积较低，消除半衰期较长，在体内间质间隙中的循环率最高。IgG的消除主要通过肾外机制进行。F(ab')(2)片段的药代动力学特征介于Fab片段和IgG分子之间。这种多样的药代动力学特性对这些免疫生物制品的药效学有影响，因为毒液和抗蛇毒血清的药代动力学之间存在明显的不匹配。一些毒液，如蝎子和眼镜蛇科蛇的毒液，富含低分子量、高扩散性和大分布容积的神经毒素，注射后能迅速到达其组织靶点。相比之下，富含高分子量毒素的毒液，如蝰蛇科蛇的毒液，其药代动力学特征是初始吸收迅速，随后从毒液注射部位缓慢吸收。当血液中的抗体水平下降时，这种延迟吸收与中毒症状的复发有关。毒液成分在药代动力学和作用机制上的这种异质性需要对每个毒液-抗蛇毒血清系统进行详细分析，以便确定针对每种特定毒液最合适的中和分子类型。除了对毒理学相关的毒液成分具有高亲和力外，理想的抗蛇毒血清应具有与被中和毒素尽可能相似的分布容积。此外，高水平的中和抗体应在血液中保持相对较长的时间，以确保在中毒过程后期到达血流的毒素被中和，并促进毒素从血管外间隙重新分布到血液中。需要对不同的毒液和抗蛇毒血清进行更多研究，以进一步了解抗体及其片段的药代动力学-药效学关系，并优化中毒的免疫治疗。
