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Noteworthy Idiosyncrasies of 1α,25‐Dihydroxyvitamin D 3 Kinetics for Extrapolation from Mouse to Man
Author(s) -
Pang K. Sandy,
Noh Keumhan,
Yang Qi Joy,
Sekhon Lavtej,
Quach Holly P.,
chow Edwin C.Y.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02039
Subject(s) - calcitriol , cyp27a1 , endocrinology , calcitriol receptor , medicine , vitamin d and neurology , metabolite , cyp24a1 , chemistry , cholecalciferol , biology , metabolism
Calcitriol or 1α,25‐dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] is the active ligand of the vitamin D receptor (VDR) that plays a vital role in health and disease. Vitamin D is converted to the relatively inactive metabolite, 25‐hydroxyvitamin D 3 [25(OH)D 3 ] by CYP27A1 and CYP2R1 in the liver, then to 1,25(OH) 2 D 3 by a specific, mitochondrial enzyme, CYP27B1 (1α‐hydroxylase) that is present primarily in the kidney. Degradation of both metabolites is mostly carried out by the more ubiquitous mitochondrial enzyme, CYP24A1. Despite that calcitriol inhibits its formation and degradation, allometric scaling revealed strong interspecies (mouse, rat, dog and human) correlations of the net calcitriol clearance (CL from dose/AUC ∞ ), production rate (PR), and basal, plasma calcitriol concentration (C BL ) with body weight (BW). A closer scrutiny of the collated literature data revealed that the basal plasma concentration of calcitriol was not taken into consideration in the estimation of AUC ∞ (with subtraction of C BL ) and CL after exogenous calcitriol dosing in both animals and humans. This led to an overestimation of AUC ∞ and underestimation of CL. After correction, the allometric equations [plots of log(CL) or log(PR) versus log(body weight) or log(BW)] were: CL=0.654xBW 0.807 and PR=36.6xBW 0.718 . The CL of calcitriol was further influenced by diseased states, and was found to be reduced in chronic kidney disease but increased in cancer when compared to healthy humans. These changes, however, were not discerned with allometric scaling since all clinical data appeared as a cluster of closely similar values on the allometric plot. PBPK‐PD (physiologically‐based pharmacokinetic‐pharmacodynamic) modeling (Ramakrishnan et al 2016), however, confirmed the dynamic interactions between calcitriol and Cyp27b1/Cyp24a1, showing the increase in CL as well as decrease in PR in a dose‐dependent fashion for the intravenous, murine data of Quach et al (2015). The PBPK model was successful in predicting data from the escalating oral and intravenous doses of calcitriol given to cancer patients upon scale‐up.