Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats

A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion-limited process whereas hepatic clearance and gastrointestinal absorption were described as first-order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h(-1) kg(-1)) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg(-1) i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg (-1) i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (K(a) 0.75 h(-1)), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg(-1). Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg(-1)) or lower doses (0.2 or 1.24 mg kg(-1)) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg(-1) as well as oral doses ranging from 0.2 to 100 mg kg(-1).