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Research ArticleArticle

Physiologically-Based Pharmacokinetic-Pharmacodynamic Modeling of 1α,25-Dihydroxyvitamin D3 in Mice

Vidya Ramakrishnan, Qi Joy Yang, Holly P. Quach, Yanguang Cao, Edwin C. Y. Chow, Donald E. Mager and K. Sandy Pang
Drug Metabolism and Disposition February 2016, 44 (2) 189-208; DOI: https://doi.org/10.1124/dmd.115.067033
Vidya Ramakrishnan
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., H.P.Q., E.C.Y.C., K.S.P.); and Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (V.R., Y.C., D.E.M.)
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Qi Joy Yang
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., H.P.Q., E.C.Y.C., K.S.P.); and Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (V.R., Y.C., D.E.M.)
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Holly P. Quach
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., H.P.Q., E.C.Y.C., K.S.P.); and Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (V.R., Y.C., D.E.M.)
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Yanguang Cao
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., H.P.Q., E.C.Y.C., K.S.P.); and Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (V.R., Y.C., D.E.M.)
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Edwin C. Y. Chow
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., H.P.Q., E.C.Y.C., K.S.P.); and Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (V.R., Y.C., D.E.M.)
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Donald E. Mager
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., H.P.Q., E.C.Y.C., K.S.P.); and Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (V.R., Y.C., D.E.M.)
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K. Sandy Pang
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., H.P.Q., E.C.Y.C., K.S.P.); and Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (V.R., Y.C., D.E.M.)
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Abstract

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3] concentrations are regulated by renal CYP27B1 for synthesis and CYP24A1 for degradation. Published plasma and tissue 1,25(OH)2D3 concentrations and mRNA fold change expression of Cyp24a1 and Cyp27b1 following repetitive i.p. injections to C57BL/6 mice (2.5 μg × kg−1 every 2 days for 4 doses) were fitted with a minimal and full physiologically-based pharmacokinetic-pharmacodynamic models (PBPK-PD). The minimal physiologically-based pharmacokinetic-pharmacodynamic linked model (mPBPK-PD) related Cyp24a1 mRNA fold changes to linear changes in tissue/tissue baseline 1,25(OH)2D3 concentration ratios, whereas the full physiologically-based pharmacokinetic-pharmacodynamic model (PBPK-PD) related measured tissue Cyp24a1 and Cyp27b1 fold changes to tissue 1,25(OH)2D3 concentrations with indirect response, sigmoidal maximal stimulatory effect/maximal inhibitory effect functions. Moreover, the intestinal segregated flow model (SFM) that describes a low and partial intestinal (blood/plasma) flow to enterocytes was nested within both models for comparison with the traditional model for intestine (TM) where the entire flow perfuses the intestine. Both the mPBPK(SFM)-PD and full PBPK(SFM)-PD models described the i.p. plasma and tissue 1,25(OH)2D3 concentrations and fold changes in mRNA expression significantly better than the TM counterparts with F test comparisons. The full PBPK(SFM)-PD fits showed estimates with good precision (lower percentage of coefficient of variation), and the model was more robust in predicting data from escalating i.v. doses (2, 60, and 120 pmol) and the rebound in 1,25(OH)2D3 tissue concentrations after dosing termination. The full PBPK(SFM)-PD model performed the best among the tested models for describing the complex pharmacokinetic-pharmacodynamic interplay among Cyp27b1, Cyp24a1, and 1,25(OH)2D3.

Footnotes

    • Received August 31, 2015.
    • Accepted November 18, 2015.
  • ↵1 V.R. and Q.J.Y. are co-first authors, and D.E.M. and K.S.P. are co-senior authors.

  • ↵2 Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599.

  • This work was supported by the Canadian Institutes of Health Research (to K.S.P.), the National Sciences and Engineering Research Council of Canada (to H.P.Q. and E.C.Y.C.), and the Ontario Graduate Scholarship Program (to H.P.Q. and Q.J.Y.).

  • dx.doi.org/10.1124/dmd.115.067033.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (2)
Drug Metabolism and Disposition
Vol. 44, Issue 2
1 Feb 2016
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Research ArticleArticle

PBPK-PD Modeling of 1,25(OH)2D3 in Mice

Vidya Ramakrishnan, Qi Joy Yang, Holly P. Quach, Yanguang Cao, Edwin C. Y. Chow, Donald E. Mager and K. Sandy Pang
Drug Metabolism and Disposition February 1, 2016, 44 (2) 189-208; DOI: https://doi.org/10.1124/dmd.115.067033

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Research ArticleArticle

PBPK-PD Modeling of 1,25(OH)2D3 in Mice

Vidya Ramakrishnan, Qi Joy Yang, Holly P. Quach, Yanguang Cao, Edwin C. Y. Chow, Donald E. Mager and K. Sandy Pang
Drug Metabolism and Disposition February 1, 2016, 44 (2) 189-208; DOI: https://doi.org/10.1124/dmd.115.067033
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