Whole-body physiologically based pharmacokinetic modeling of the nonlinear pharmacokinetics of prednisolone and its reversible metabolite prednisone in rats

The pharmacokinetics (PK) and interconversion of prednisolone (PNL) and prednisone (PN) were assessed in the rat following single doses and intravenous infusions of PNL and PN. Their concentrations in blood and 11 tissues were determined by liquid chromatography–tandem mass spectrometry, and unbound drug by ultrafiltration. The PK of both steroids were nonlinear, featuring dose/concentration-dependent decreases in apparent steady-state plasma clearance and volume of distribution, with interconversion exhibiting continual rapid equilibria. The plasma and tissue profiles of PNL and PN were assessed with a comprehensive dual physiologically based pharmacokinetic model incorporating saturable plasma and tissue binding of PNL linked by their interconversion in liver and kidneys. All PK data were fitted jointly using Adapt software. Nonlinear tissue binding of PNL exhibited a range of equilibrium dissociation rate constants with highest in lung and 5 groups of binding capacity values. PN showed linear binding in most tissues, with a wide range of tissue-to-plasma partition coefficients with lowest in kidney to highest in lung. Conversion clearances of PN to PNL were found highest in liver and lesser in kidneys, whereas PNL to PN conversion occurred only in kidneys. Further irreversible elimination of PNL from venous plasma was nonlinear, whereas PN elimination was linear. The established physiologically based pharmacokinetic model well described the nonlinear whole-body disposition and interconversion of PNL and PN with relevance to humans and providing important insights into local steroid concentrations that drive diverse pharmacodynamic responses. Significance Statement: This work provides a detailed quantitative characterization of whole-body disposition of prednisolone and prednisone using a comprehensive dual physiologically based pharmacokinetic model that incorporates various complexities. This offers an instructive quantitative framework for other drugs that exhibit or affect metabolic interconversion and/or nonlinear disposition kinetics.