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

ABSTRACT

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.

Supplemental Data

Supplemental data for this article can be access at the publisher’s website

Supplemental Data

The supplemental data include equations used in ZnPT rat PBPK model (Appendix A); a summary of noncompartmental pharmacokinetic estimates for oral and dietary routes of ZnPT administration for single and repeat dosing (Table S-1); hindlimb weakness in rats following 3- and 9-d oral and dietary ZnPT administration (Table S-2); BMDS model predictions for relationship between plasma PT AUC in plasma (Table S-3) or muscle (Table S-4) and muscle tone following oral or dietary administration of ZnPT; comparisons of predicted and observed kinetics of [¹⁴C]PT in repeat-dose oral rat studies (Figures S-1–S-5); logistic regression for relationship between AUC for PT concentration in skeletal muscle and muscle tone response in rats (Figure S-6) and for relationship between C_max plasma PT concentration and muscle tone response in rats (Figure S-7); and summary of results of sensitivity analysis of the PBPK rat model (Figure S-8).

Funding

The studies were funded by Lonza (formerly Arch Chemical) and the Procter & Gamble Company. J. Frank Nash is an employee of the Procter & Gamble Company, Nicholas Skoulis is employed by Lonza, and Gary Diamond is an independent consultant. The authors thank John Troutman, Drs. Sheppard Martin, George Daston, and Laura McIlroy for their thoughtful comments and assistance.

Notes

¹ Arch Chemical is now Lonza America Inc.