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 Km for glutathione conjugation of molinate sulfoxide in the liver compartment.

Determination of Tissue to Blood Partition Coefficients for Nonvolatile Herbicides, Insecticides, and Fungicides Using Negligible Depletion Solid-Phase Microextraction (nd-SPME) and Ultrafiltration

“…Included are 6 (atrazine, molinate, mesotrione, propiconazole, ametryn, and cyprodinil) of the 100 most used herbicides and fungicides in U.S. crop production in 2002, accounting for approximately 16% of the total usage (Gianessi and Reigner 2006). While no measured biological PC have been reported elsewhere for these compounds, PBPK-derived values for molinate and atrazine were previously noted (Campbell 2009;Zhoumeng et al 2011).…”

Development of Physiologically Based Organ Models to Evaluate the Pharmacokinetics of Drugs in the Testes and the Thyroid Gland

“…and Rodgers and Rowland4 are listed in Table 2 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40…”

Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

“…Our research attempted to use model extrapolation method from rats to human to predict moxifloxacin tissue distribution in the model of intra-abdominal infection. Compared with classical pharmacokinetic models, there were several advantages offered by PBPK models including (1) the capacity to provide simultaneous time versus concentration curves for a compound in various tissues; (2) the incorporation of anatomical and physiologic information as well as chemical specific in vitro derived parameters; (3) the ability to predict the time versus concentration curve of chemicals across species by allometric scaling; (4) the resultant PBPK model has the potential for extrapolations from observed data to predicted situations [13]. In rat PBPK model, it was interesting to note that the predicted Cmax of moxifloxacin in rat plasma (1195.9 μg/mL) was much higher than that observed (12.028 μg/mL).…”

“…A PBPK model is a body composed of organ compartments, and each compartment contains mathematical de- scriptions of a chemical's absorption, distribution, metabolism, and elimination (ADME) [13]. Movement of a drug between the organ compartments, as well as the steadystate distribution of drug into each organ, can be defined by both the physicochemical parameters of the drug itself and the content of lipid, water and protein in each organ [3].…”

“…Movement of a drug between the organ compartments, as well as the steadystate distribution of drug into each organ, can be defined by both the physicochemical parameters of the drug itself and the content of lipid, water and protein in each organ [3]. The difference lies in the PBPK models ability to substitute species-specific physiological and biochemical parameters into the model [13]. Therefore, moxifloxacin blood and tissue concentration predictions can be extrapolated from rats to humans by developing a PBPK model.…”