Category: Preclinical Development
Purpose: Nowadays, overweight and obesity are well-known global health issues with major health, social and economic implications.
Lipophilic drugs whose apparent volume distribution markedly increase in obese subjects and prefer to distribute into excess adipose tissue (the peripheral compartment). In contrast, a non-lipophilic drugs whose distributions into the excess adipose tissue are limited, such that the volume of the peripheral compartment is similar in obese and lean individuals.
Propofol is distinguished by its very high oil/water partition coefficient of about 4715. As a result, this anesthesia drug distribution into fat tissue and thus altering pharmacodynamic effects (PD) will be expected when it is administered to patients with a high body fat content.
To better understand the obesity-induced changes in PD, the Zucker and Sprague Dawley rat model were used to study the kinetics and dynamics of propofol dosing. Zucker obese (ZO) rats not only increase body weight but also rise up in fat %. On the opposite, wild type Zucker lean (ZL) rats and Sprague Dawley (SD) rat do not build fat content and maintain low fat % in their life time. Pairwise comparison locked either body weight or body fat can help us to identify the critical factors that have impacts on propofol dosing calculation.
Methods: The propofol formulation (propofol : glycerin : Polysorbate-80 = 1:2:2 by volume) prepared in 1 ml saline and intravenous infused to rat at 3 mg/kg/min for 10 min. The tail reflex upon stimuli of each rat was monitored to assess the depth of anesthesia. The time of responsiveness loss and recovery were defined as the onset and offset of anesthesia. Duration is the time gap between onset and offset. The body weight, fat percentage and PD data were analyzed by ANOVA followed by tukey post-hoc test to locate the significant differences among groups at P < 0.05 as significant level. Here we controlled the rat body weight in the study with 2 levels (300 gram vs 500 gram) for each rat species. On the other hand, the 2 levels of fat contents (low fat vs high fat), were also distinguished.
Results: Body weight of ZO 500 were significantly larger than the other 3 groups (300 gram). Also both ZO 300 and ZO 500 groups contain higher fat ( > 34 %) than ZL and SD groups (< 13%) as in Figure 1. No remarkable difference was observed among the 4 rat groups (ZL 300, SD 300, ZO 300 and ZO 500) in the onset of anesthesia. It was remarkably quicker offset in high fat groups (ZO 500 and ZO 300) than in low fat groups (ZL 300 and SD 300). Whereas, there was no significant difference within two high fat groups or within two low fat groups. Correspondingly, the duration of anesthesia was much shorter for high fat groups when compared to low fat groups as in Figure 2.
Conclusion: Propofol dosing calculation only by body weight is insufficient and can be misleading, based on our PD data. Early offset and shorter duration observed on high fat rats, ZO 500 and ZO 300, implying body fat other than body weight is attributed to the difference. No difference of onset on propofol dosing when calculated by body weight. Fat content is required to be taken into the consideration while calculating the propofol dose.