PKPD modelling to predict altered disposition of 1α,25-dihydroxyvitamin D3 in mice due to dose-dependent regulation of CYP27B1 on synthesis and CYP24A1 on degradation.

Autor: Quach HP; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada., Yang QJ; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada., Chow EC; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada., Mager DE; Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA., Hoi SY; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada., Pang KS; Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2015 Jul; Vol. 172 (14), pp. 3611-26. Date of Electronic Publication: 2015 May 15.
DOI: 10.1111/bph.13153
Abstrakt: Background and Purpose: Concentrations of 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], the active ligand of the vitamin D receptor, are tightly regulated by CYP27B1 for synthesis and CYP24A1 for degradation. However, the dose-dependent pharmacokinetic (PK)-pharmacodynamic (PD) relationship between these enzymes and 1,25(OH)2 D3 concentrations has not been characterized.
Experimental Approach: The pharmacokinetics of 1,25(OH)2 D3 were evaluated after administration of single (2, 60 and 120 pmol) and repeated (2 and 120 pmol q2d ×3) i.v. doses to male C57BL/6 mice. mRNA expression of CYP27B1 and CYP24A1 was examined by quantitative PCR and 1,25(OH)2 D3 concentrations were determined by enzyme immunoassay.
Key Results: CYP27B1 and CYP24A1 changes were absent for the 2 pmol dose and biexponential decay profiles showed progressively shorter terminal half-lives with increasing doses. Fitting with a two-compartment model revealed decreasing net synthesis rates and increasing total clearances with dose, consistent with a dose-dependent down-regulation of renal CYP27B1 and the induction of renal/intestinal CYP24A1 mRNA expression. Upon incorporation of PD parameters for inhibition of CYP27B1 and induction of CYP24A1 to the simple two-compartment model, fitting was significantly improved. Moreover, fitted estimates for the 2 pmol dose, together with the PD parameters as modifiers, were able to predict profiles reasonably well for the higher (60 and 120 pmol) doses. Lastly, an indirect response model, which considered the synthesis and degradation of enzymes, adequately described the PK and PD profiles.
Conclusions and Implications: The unique PK of exogenously administered 1,25(OH)2 D3 led to changes in PD of CYP27B1 and CYP24A1, which hastened the clearance of 1,25(OH)2 D3 .
(© 2015 The British Pharmacological Society.)
Databáze: MEDLINE
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