Influence of intravenous infusion duration on the tissue drug concentration profile

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Abstract
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. Tfor 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 Ton 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 Tcould 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 Ton drug concentration at the effector site for individual drugs by incorporating effect compartment modeling into the analysis.

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