Fagiolino Pietro, Eiraldi Rosa, Vázquez Marta
Pharmacology and Biopharmaceutics, Faculty of Chemistry, University of the Republic of Uruguay, Montevideo, Uruguay.
Clin Pharmacokinet. 2006;45(5):433-48. doi: 10.2165/00003088-200645050-00001.
Inter- and intraindividual variability in the relationship between dose and clinical--or pharmacodynamic--response of a drug can be analysed in two steps: firstly, by considering the plasma pharmacokinetic response to a given dose and, secondly, by the connection between both pharmacokinetic and pharmacodynamic responses. As the cardiovascular system is the means of transport of endogenous and exogenous substances, blood flow fraction destined to each organ determines the relative mass of solute in plasma, which is constantly in contact with the tissue. Hence, not only the rate but also the extent of drug transfer would be increased when tissues are irrigated by a higher fraction of cardiac output. Aging and circadian rhythms present similar cardiac output distribution patterns when moving from young to aged adult and from nocturnal to diurnal hours. These two changes lead to an increased blood flow delivery to the extra-splanchnic-renal region in the elderly and in the morning, but with a decreased cardiac output in aged individuals and an increased one during the day. This scenario allows us to forecast substance concentrations outside the blood vessels, which are responsible for the extent of drug elimination and the intensity of drug effect. So available data on disposition and pharmacodynamics of drugs might be explained from another point of view that challenges current knowledge. Furthermore, the administration of cardiovascular active drugs might reverse the chronological sequence between pharmacokinetic and pharmacodynamic responses, since they could modify blood flow distribution.
药物剂量与临床（或药效学）反应之间的个体间和个体内变异性可通过两个步骤进行分析：首先，考虑对给定剂量的血浆药代动力学反应；其次，考虑药代动力学和药效学反应之间的联系。由于心血管系统是内源性和外源性物质的运输手段，流向每个器官的血流分数决定了与组织持续接触的血浆中溶质的相对质量。因此，当组织由较高比例的心输出量灌注时，不仅药物转运的速率而且其程度都会增加。从年轻人到老年人以及从夜间到白天，衰老和昼夜节律呈现出相似的心输出量分布模式。这两种变化导致老年人和早晨流向肝外肾区域的血流增加，但老年个体的心输出量减少，白天则增加。这种情况使我们能够预测血管外的物质浓度，而血管外物质浓度决定了药物消除的程度和药物作用的强度。因此，关于药物处置和药效学的现有数据可能会从另一个角度得到解释，这对当前的知识提出了挑战。此外，心血管活性药物的给药可能会颠倒药代动力学和药效学反应之间的时间顺序，因为它们可以改变血流分布。
