A Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Paraoxon in Rainbow Trout

Trout were exposed to an aqueous solution of 75 ng/ml paraoxon for 5 days at 12°C. The relationships among paraoxon concentration in water and target organs, AChE inhibition, and carboxylesterase (CaE) detoxification of paraoxon were characterized quantitatively by development of a PBPK–PD model. The PKPD model structure consisted of brain, heart, liver, kidney, and remainder of the body, which were interconnected by blood circulation. The paraoxon tissue/blood partition coefficients were: plasma/water, 1.46; liver/plasma, 5.89; brain/plasma, 3.90; heart/plasma, 2.91; kidney/plasma, 0.45; and blood/plasma, 0.91. Turnover of AChE was characterized from a dose–response study, in which its zero-order synthesis rate and first-order degradation rate constant were determined in several tissues; for brain they were 7.67 pmol/min and 7.31 × 10−5hr−1. The uptake and depuration clearances of paraoxon (Clu= 0.651 and Cld= 0.468 ml min−1g body wt−1) were determined using a compartmental model. During continuous water exposure to paraoxon, AChE activity in the tissues declined to new steady state values that were maintained by the synthesis of new AChE. CaE was shown by simulation to be an important pathway for detoxification of paraoxon.