Development of PBPK model of molinate and molinate sulfoxide in rats and humans

Abstract

Molinate has been widely used as a pre-emergent herbicide in the rice fields of California’s Central Valley. In rat studies, the metabolite molinate sulfoxide is suspected of causing testicular toxicity after exposure to molinate. The sulfoxide is generated in the liver and can circulate in the blood, eventually reaching the testis. Man qualitatively produces the same molinate metabolites as the rat. To extrapolate the reproductive risk to man, the present study outlines the development of a preliminary PBPK (physiologically-based pharmacokinetic) model, validation in the rat and extrapolation to man. The preliminary seven-compartment PBPK model for molinate was constructed for the adult, male Sprague–Dawley rat that employed both flow-limited (blood, kidney, liver, rapid-perfused tissues and slowly perfused tissues) and diffusion-limited (fat) rate equations. The systemic circulation connects the various compartments. The simulations predict the molinate blood concentrations of the rat blood and testes compartment favorably with the profiles obtained from 10 and 100 mg/kg po or 1.5 and 15 mg/kg iv doses. Human physiological parameters were substituted into the oral dosed model and the simulations closely predicted the molinate blood concentration obtained from 5.06 mg oral dose. A sensitivity analysis determined for an oral dose that peak blood molinate concentrations were most responsive to the blood flows to kidney and fat compartments while testicular molinate sulfoxide concentrations depended on molinate sulfoxide partition coefficients for the testes compartment and the K m for glutathione conjugation of molinate sulfoxide in the liver compartment.