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

Background and Purpose Concentrations of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], 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)₂D₃ concentrations has not been characterized. Experimental Approach The pharmacokinetics of 1,25(OH)₂D₃ 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)₂D₃ 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)₂D₃ led to changes in PD of CYP27B1 and CYP24A1, which hastened the clearance of 1,25(OH)₂D₃.