Abstract
We expanded our published physiologically-based pharmacokinetic model on 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], ligand of the vitamin D receptor (VDR), to appraise VDR-mediated pharmacodynamics in mice. Since 1,25(OH)2D3 kinetics was best described by a segregated-flow intestinal model (SFM) that described a low/partial intestinal (blood/plasma) flow to enterocytes, with feedback regulation of its synthesis (Cyp27b1) and degradation (Cyp24a1) enzymes, this PBPK(SFM) model was expanded to describe the VDR-mediated changes (altered/basal mRNA expression) of target genes/responses with the indirect response model. We examined data on a) renal Trpv5 and Trpv6 and intestinal Trpv6 (calcium channels) for calcium absorption, b) liver HmgCoA reductase (Hmgcr) and cytochrome 7α-hydroxylase (Cyp7a1) for cholesterol synthesis and degradation, respectively; and c) renal and brain Mdr1 (multidrug-resistance mRNA that encodes the P-glycoprotein, P-gp) for digoxin disposition after repetitive intraperitoneal doses of 120 pmol 1,25(OH)2D3. Fitting, performed with ADAPT5 (BMSR, USC), yielded reasonable predictions of a dominant role of intestinal Trpv6 on calcium absorption, circadian rhythms that are characterized by simple cosine models for Hmgcr and Cyp7a1 on liver cholesterol, and brain and renal Mdr1 on tissue efflux of digoxin. Fitted parameters on the Emax, EC50 and the turnover rate constants of VDR-target genes: zero-order production (kin) and first-order degradation (kout) rate constants, showed low coefficients of variation and acceptable median %prediction errors (4.5-40.6%). Sensitivity analyses showed that the Emaxs and EC50s are key parameters that could influence the pharmacodynamic responses. Conclusion: The PBPK(SFM)-PD model successfully characterized VDR gene-activation and serves as a useful tool to predict the therapeutic effects of 1,25(OH)2D3.
- cytochrome P450
- enzyme kinetics
- modeling and simulation
- pharmacokinetic/pharmacodynamic modeling/PKPD
- physiologically-based pharmacokinetic modeling/PBPK
- The American Society for Pharmacology and Experimental Therapeutics