Physiologically Based Pharmacokinetic Modeling of Vitamin D 3 and Metabolites in Vitamin D-Insufficient Patients.

Autor: Sawyer CW; Department of Mathematics, Southern New Hampshire University, Manchester, New Hampshire (C.W.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (S.M.T., M.S.J.); and University of Pittsburgh, School of Pharmacy, Department of Pharmacy and Therapeutics, Pittsburgh Pennsylvania (R.E.W., T.D.N.) c.sawyer1@snhu.edu., Tuey SM; Department of Mathematics, Southern New Hampshire University, Manchester, New Hampshire (C.W.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (S.M.T., M.S.J.); and University of Pittsburgh, School of Pharmacy, Department of Pharmacy and Therapeutics, Pittsburgh Pennsylvania (R.E.W., T.D.N.)., West RE 3rd; Department of Mathematics, Southern New Hampshire University, Manchester, New Hampshire (C.W.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (S.M.T., M.S.J.); and University of Pittsburgh, School of Pharmacy, Department of Pharmacy and Therapeutics, Pittsburgh Pennsylvania (R.E.W., T.D.N.)., Nolin TD; Department of Mathematics, Southern New Hampshire University, Manchester, New Hampshire (C.W.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (S.M.T., M.S.J.); and University of Pittsburgh, School of Pharmacy, Department of Pharmacy and Therapeutics, Pittsburgh Pennsylvania (R.E.W., T.D.N.)., Joy MS; Department of Mathematics, Southern New Hampshire University, Manchester, New Hampshire (C.W.S.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (S.M.T., M.S.J.); and University of Pittsburgh, School of Pharmacy, Department of Pharmacy and Therapeutics, Pittsburgh Pennsylvania (R.E.W., T.D.N.).
Jazyk: angličtina
Zdroj: Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2022 Sep; Vol. 50 (9), pp. 1161-1169. Date of Electronic Publication: 2022 Jul 02.
DOI: 10.1124/dmd.121.000609
Abstrakt: A physiologically based pharmacokinetic (PBPK) model of vitamin D 3 and metabolites [25(OH)D 3 , 1,25(OH) 2 D 3 , and 24,25(OH) 2 D 3 ] is presented. In this study, patients with 25(OH)D 3 plasma concentrations below 30 ng/ml were studied after a single dose of 5000 I.U. (125 µ g) cholecalciferol, provided with 5000 I.U. daily cholecalciferol supplementation until vitamin D replete [25(OH)D 3 plasma concentrations above 30 ng/ml], and had serial plasma samples were collected at each phase for 14 days. Total concentrations of vitamin D 3 and metabolites were measured by ultra-high performance liquid chromatography tandem mass spectrometry. A nine-compartment PBPK model was built using MATLAB to represent the triphasic study nature (insufficient, replenishing, and sufficient). The stimulatory and inhibitory effect of 1,25(OH) 2 D 3 were incorporated by fold-changes in the primary metabolic enzymes CYP27B1 and CYP24A1, respectively. Incorporation of dynamic adipose partition coefficients for vitamin D 3 and 25(OH)D 3 and variable enzymatic reactions aided in model fitting. Measures of model predictions agreed well with data from metabolites, with 97%, 88%, and 98% of the data for 25(OH)D 3 , 24,25(OH) 2 D 3 , and 1,25(OH) 2 D 3 , respectively, within twofold of unity ( fold error values between 0.5 and 2.0). Bootstrapping was performed and optimized parameters were reported with 95% confidence intervals. This PBPK model could be a useful tool for understanding the connections between vitamin D and its metabolites under a variety of clinical situations. SIGNIFICANCE STATEMENT: This study developed a physiologically based pharmacokinetic (PBPK) model of vitamin D 3 and metabolites for patients moving from an insufficient to a repleted state over a period of 16 weeks.
(Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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