title: 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.
authors.affiliation: a SRC, Inc ., North Syracuse , New York , USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Diamond
authors.affiliation: b LONZA America, Inc ., Allendale , New Jersey , USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Skoulis
authors.affiliation: c RTI International, Research Triangle Park , North Carolina , USA.
authors.forename: A Robert
authors.initials: AR
authors.lastname: Jeffcoat
authors.affiliation: d The Procter & Gamble Company , Cincinnati , Ohio , USA.
authors.forename: J Frank
authors.initials: JF
authors.lastname: Nash
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008954:Models, Biological; D009942:Organometallic Compounds / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D000890:Anti-Infective Agents; D009942:Organometallic Compounds; D011725:Pyridines; C010423:pyrithione zinc