A physiologically based pharmacokinetic model for the broad-spectrum antimicrobial zinc pyrithione: I. Development and verification

The broad-spectrum antimicrobial zinc pyrithione (ZnPT) is used in numerous products ranging from in-can preservative/mildicide in paints to antidandruff shampoo. Although products containing ZnPT have a long history of safe use, regulatory agencies routinely set limits of exposure based upon toxicological considerations. The objective of this study was to create a physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose-response analysis of ZnPT-induced toxicity, reversible hindlimb weakness, the endpoint that has been used as the basis for ZnPT risk assessments. A rat oral PBPK model was developed that includes compartments for plasma, liver, kidneys, muscle, brain, and rapidly and slowly perfused tissues. Pyrithione metabolism to 2-(methylsulfonyl)pyridine (MSP) and glucuronide conjugates was incorporated into the model. The model was parameterized and optimized based upon data from single-dose intravenous (iv) and oral gavage pharmacokinetic studies of radiolabeled pyrithione ([¹⁴C]PT) administered as zinc [¹⁴C]-pyrithione (Zn-[¹⁴C]PT) to adult female rats. It was further evaluated and refined using data from repeated, multidose oral gavage and dietary studies of Zn[¹⁴C]PT in the adult female rat that included measurements of plasma PT concentration, the putative toxic species. The model replicated the observed short-term elimination kinetics of PT in plasma and [¹⁴C]PT in whole blood following single doses and longer term temporal patterns of plasma and blood concentrations during repeated dosing schedules. The model also accounted for production and rapid elimination of S-glucuronide conjugates (SG) of 2-pyridinethiol and 2-pyridinethiol-1-oxide in urine, as well as production and slower elimination of MSP, the major [¹⁴C]PT species in blood within several hours following administration of ZnPT. The model provided internal dosimetry predictions for a benchmark dose (BMD) analysis of hindlimb weakness in rats, and was used to combine gavage and dietary studies into a single internal dose-response model with area under the curve (AUC) for plasma PT as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [¹⁴C]PT from different routes of exposure in the rat.