Abstract
Deoxypodophyllotoxin (DPT) is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey, and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio) was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.
Highlights
Deoxypodophyllotoxin (Figure 1) is an active ingredient isolated from herbs like Anthriscus sylvestris, Pulsatilla koreana, and Podophyllum emodi (Wong et al, 2000; Khaled et al, 2013)
Our preliminary experiments proved that excretion of DPT in original form via urine and bile was less than 0.2% of the dose (4 mg/kg) following intravenous administration to rats, with high recoveries of M2 in the form of glucuronidated and sulfated conjugates
In this study we developed a whole-body physiologically based pharmacokinetic (PBPK) model for the prediction of DPT disposition in four common preclinical species, with parameters from in vitro and in silico study
Summary
Deoxypodophyllotoxin (Figure 1) is an active ingredient isolated from herbs like Anthriscus sylvestris, Pulsatilla koreana, and Podophyllum emodi (Wong et al, 2000; Khaled et al, 2013). Accumulating evidences have demonstrated that DPT possesses a variety of pharmacological activities, such as anti-tumor, anti-viral, anti-inflammatory, and anti-platelet aggregation effects. PBPK Model of DPT (Gordaliza et al, 1994; Chen et al, 2000; Jin et al, 2008), among which anti-tumor effect is the most attractive. DPT exerts its anti-tumor activity via affecting microtubule and modulating specific cell cycle-regulatory proteins (Khaled et al, 2013). As a promising anti-tumor candidate, DPT in an intravenous formulation of β-cyclodextrin inclusion complex (Zhu et al, 2010) has been developed and is undergoing its preclinical evaluation
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