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

Background and PurposeConcentrations of 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], 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)D-3 concentrations has not been characterized. Experimental ApproachThe pharmacokinetics of 1,25(OH)(2)D-3 were evaluated after administration of single (2, 60 and 120pmol) and repeated (2 and 120pmol q2d x3) i.v. doses to male C57BL/6 mice. mRNA expression of CYP27B1 and CYP24A1 was examined by quantitative PCR and 1,25(OH)(2)D-3 concentrations were determined by enzyme immunoassay. Key ResultsCYP27B1 and CYP24A1 changes were absent for the 2pmol 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 2pmol dose, together with the PD parameters as modifiers, were able to predict profiles reasonably well for the higher (60 and 120pmol) doses. Lastly, an indirect response model, which considered the synthesis and degradation of enzymes, adequately described the PK and PD profiles. Conclusions and ImplicationsThe unique PK of exogenously administered 1,25(OH)(2)D-3 led to changes in PD of CYP27B1 and CYP24A1, which hastened the clearance of 1,25(OH)(2)D-3.