Uccellini D A, Raymond K, Morgan D J
J Pharmacokinet Biopharm. 1986 Jun;14(3):323-34. doi: 10.1007/BF01106710.
The influence of intravenous infusion duration of a single dose of drug on the time course of drug concentration in the peripheral compartment of the classical two-compartment pharmacokinetic model was studied by computer simulation. The aim was to illustrate the general relationships among infusion duration T, dose, minimum effective concentration MEC at the effector (tissue) site, maximum tissue drug concentration C2,max, and the duration of effective tissue concentrations tD,tiss for those drugs where there is an equilibration delay between concentration at the effector site and plasma. Simulations of C2,max vs. T for meperidine, sulfamethoxazole, ampicillin, and metronidazole showed that, although maximum plasma concentration may decrease markedly with increasing T, C2,max decreased only slightly with increasing T. Simulations of the influence of T on the duration of effective plasma concentrations tD and tD,tiss of metronidazole showed that for a given T, tD,tiss may be greater than or less than tD, depending on the dose, and that it is possible to obtain effective concentrations in the tissue compartment even though the infusion duration is too long to achieve effective concentrations in plasma. It was found that, depending on the dose, it was possible to cause an increase in tD,tiss compared with bolus administration by increasing the infusion duration of the dose. It was also found that increasing T could cause opposite changes in tD and tD,tiss (compared with bolus administration, respectively), e.g., an increase in tD and a decrease in tD,tiss or vice versa, depending on the dose. It should thus be possible to make precise predictions of the influence of T on drug concentration at the effector site for individual drugs by incorporating effect compartment modeling into the analysis.
通过计算机模拟研究了单剂量药物静脉输注持续时间对经典二室药代动力学模型外周室药物浓度时程的影响。目的是阐明输注持续时间T、剂量、效应（组织）部位的最低有效浓度MEC、最大组织药物浓度C2,max以及效应部位与血浆浓度之间存在平衡延迟的那些药物的有效组织浓度持续时间tD,tiss之间的一般关系。对哌替啶、磺胺甲恶唑、氨苄西林和甲硝唑的C2,max与T的模拟表明，尽管最大血浆浓度可能随T的增加而显著降低，但C2,max仅随T的增加而略有降低。对T对甲硝唑有效血浆浓度持续时间tD和tD,tiss的影响的模拟表明，对于给定的T，tD,tiss可能大于或小于tD，这取决于剂量，并且即使输注持续时间过长以至于无法在血浆中达到有效浓度，也有可能在组织室中获得有效浓度。研究发现，根据剂量，通过增加剂量的输注持续时间，与推注给药相比，有可能使tD,tiss增加。还发现增加T可能导致tD和tD,tiss发生相反的变化（分别与推注给药相比），例如，tD增加而tD,tiss减少，反之亦然，这取决于剂量。因此，通过将效应室建模纳入分析，应该能够对T对个体药物效应部位药物浓度的影响做出精确预测。
