PMID- 32883831 OWN - NLM STAT- MEDLINE DCOM- 20201214 LR - 20211102 IS - 1521-0103 (Electronic) IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 375 IP - 2 DP - 2020 Nov TI - Physiologically Based Pharmacokinetic Modeling Involving Nonlinear Plasma and Tissue Binding: Application to Prednisolone and Prednisone in Rats. PG - 385-396 LID - 10.1124/jpet.120.000191 [doi] AB - The pharmacokinetics (PK) of prednisolone (PNL) exhibit nonlinearity related to plasma protein binding, tissue binding, metabolic interconversion with prednisone (PN), and renal elimination. Blood and 11 tissues were collected from male Wistar rats after steady-state (SS) infusion and after subcutaneous boluses of 50 mg/kg of PNL. Concentrations of PNL and PN were measured by liquid chromatography-tandem mass spectrometry. Plasma and tissue profiles were described using a complex physiologically based pharmacokinetics (PBPK) model. Concentrations of PN and PNL were in rapid equilibrium in plasma and tissues. The tissue partition coefficients (K (p) ) of PNL calculated from most subcutaneously dosed tissue and plasma areas were similar to SS infusion and in silico values. The blood-to-plasma ratio of PNL was 0.71 with similar red blood cell and unbound-plasma concentrations. Plasma protein binding (60%-90%) was related to corticosteroid-binding globulin (CBG) saturation. Tissue distribution was nonlinear. The equilibrium dissociation constant (K (d) ) of PNL shared by all tissues was 3.01 ng/ml, with the highest binding in muscle, followed by liver, heart, intestine, and bone and the lowest binding in skin, spleen, fat, kidney, lung, and brain. Fat and bone distribution assumed access only to interstitial space. Brain PNL concentrations (K (p) = 0.05) were low owing to presumed P-glycoprotein-mediated efflux. Clearances of CBG-free PNL were 1789 from liver and 191.2 ml/h from kidney. The PN/PNL ratio was nonlinear for plasma, spleen, heart, intestine, bone, fat, and linear for the remaining tissues. Our PBPK model with multiple complexities well described the PK profiles of PNL and PN in blood, plasma, and diverse tissues. SIGNIFICANCE STATEMENT: Because steroids, such as prednisolone and prednisone, have similar and complex pharmacokinetics properties in various species, receptors in most tissues, and multiple therapeutic and adverse actions, this physiologically based pharmacokinetics (PBPK) model may provide greater insights into the pharmacodynamic complexities of corticosteroids. The complex properties of these compounds require innovative PBPK modeling approaches that may be instructive for other therapeutic agents. CI - Copyright (c) 2020 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Li, Xiaonan AU - Li X AD - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences (X.L., D.C.D., R.R.A., W.J.J.) and Department of Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York. FAU - DuBois, Debra C AU - DuBois DC AD - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences (X.L., D.C.D., R.R.A., W.J.J.) and Department of Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York. FAU - Almon, Richard R AU - Almon RR AD - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences (X.L., D.C.D., R.R.A., W.J.J.) and Department of Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York. FAU - Jusko, William J AU - Jusko WJ AD - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences (X.L., D.C.D., R.R.A., W.J.J.) and Department of Biological Sciences (D.C.D., R.R.A.), State University of New York at Buffalo, Buffalo, New York wjjusko@buffalo.edu. LA - eng GR - R35 GM131800/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20200903 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 9PHQ9Y1OLM (Prednisolone) RN - VB0R961HZT (Prednisone) SB - IM MH - Animals MH - Male MH - *Models, Biological MH - *Nonlinear Dynamics MH - Prednisolone/*blood/*pharmacokinetics MH - Prednisone/*blood/*pharmacokinetics MH - Rats MH - Rats, Wistar MH - Tissue Distribution PMC - PMC7604337 EDAT- 2020/09/05 06:00 MHDA- 2020/12/15 06:00 PMCR- 2021/11/01 CRDT- 2020/09/05 06:00 PHST- 2020/07/01 00:00 [received] PHST- 2020/08/21 00:00 [accepted] PHST- 2020/09/05 06:00 [pubmed] PHST- 2020/12/15 06:00 [medline] PHST- 2020/09/05 06:00 [entrez] PHST- 2021/11/01 00:00 [pmc-release] AID - jpet.120.000191 [pii] AID - JPET_AR2020000191 [pii] AID - 10.1124/jpet.120.000191 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2020 Nov;375(2):385-396. doi: 10.1124/jpet.120.000191. Epub 2020 Sep 3.