Noteworthy idiosyncrasies of 1α,25‐dihydroxyvitamin D₃ kinetics for extrapolation from mouse to man: Commentary

Abstract

Calcitriol or 1,25-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. The degradation of both metabolites is mostly carried out by the more ubiquitous mitochondrial enzyme, CYP24A1. Despite the fact that calcitriol inhibits its formation and degradation, allometric scaling revealed strong interspecies correlation of the net calcitriol clearance (CL estimated from dose/AUC ∞ ), production rate (PR), and basal, plasma calcitriol concentration with body weight (BW). PBPK-PD (physiologically based pharmacokinetic-pharmacodynamic) modeling confirmed the dynamic interactions between calcitriol and Cyp27b1/Cyp24a1 on the decrease in the PR and increase in CL in mice. Close scrutiny of the literature revealed that basal levels of calcitriol had not been taken into consideration for estimating the correct AUC ∞ and CL after exogenous calcitriol dosing in both animals and humans, leading to an overestimation of AUC ∞ and underestimation of the plasma CL. In humans, CL was decreased in chronic kidney disease but increased in cancer. Collectively, careful pharmacokinetic data analysis and improved definition are achieved with PBPK-PD modeling, which embellishes the complexity of dose, enzyme regulation, and disease conditions. Allometric scaling and PBPK-PD modeling were applied successfully to extend the PBPK model to predict calcitriol kinetics in cancer patients. K E Y W O R D Sallometric scaling, calcitriol or 1,25(OH) 2 D 3 , CYP24A1, CYP27B1, pharmacokinetics

Effects of Simulated Weightlessness on Metabolizing Enzymes and Pharmacokinetics of Folic Acid in SD Rats

“…Application of PBPK modeling used in conjunction with in-vitro in-vivo extrapolation (IVIVE) of ADME data can provide a useful starting point to understand and extrapolate PK and dose across different species, populations, and disease states. 21) PBPK model had been extended to predict calcitriol kinetics in cancer patients 22) and explore the response of the human body on low-concentration supplementation of vitamin D under sunlight-restrictive conditions. 23) As a result of these studies,we observed the PK changes of FA under simulated microgravity, it is possible to make some dosing recommendations of FA during spaceflight, but more information is necessary to predict with precision all of the human pharmacokinetic variations occurring in spaceflight via PBPK modeling.…”

Significance of the Vitamin D Receptor on Crosstalk with Nuclear Receptors and Regulation of Enzymes and Transporters

“…It is usually considered that a patient is vitamin D deficient when plasma 25(OH)D 3 levels fall below 20 ng/ml or 50 nM (103,104), and vitamin D insufficient when the 25(OH)D 3 plasma level is between 20 and 30 ng/ml (105)(106)(107)(108). Due to the tight regulation of calcitriol on its production and degradation, excess 1,25(OH) 2 D 3 in plasma inhibits renal Cyp27B1 to curtail calcitrol production and enhance CYP24A1-mediated degradation (88). At low doses of calcitriol, when CYP24A1 is not induced, the half-life is the longest, whereas at high levels or with escalating calcitriol doses, CYP24A1 is greatly induced and CYP27B1 completley inhibited, reducing the half-life and increasing calcitriol clearance (88).…”

“…Due to the tight regulation of calcitriol on its production and degradation, excess 1,25(OH) 2 D 3 in plasma inhibits renal Cyp27B1 to curtail calcitrol production and enhance CYP24A1-mediated degradation (88). At low doses of calcitriol, when CYP24A1 is not induced, the half-life is the longest, whereas at high levels or with escalating calcitriol doses, CYP24A1 is greatly induced and CYP27B1 completley inhibited, reducing the half-life and increasing calcitriol clearance (88).…”

“…Pursuant to dose administration, we were able to identify the pharmacokinetics and pharmacodynamics of calcitriol. Upon continued administration of calcitriol to mice, the half-lives of calcitriol become shortened due to induction of Cyp24a1 and inhibition of synthesis via Cyp27b1 in the mouse (15,17,51,88).…”

Physiologically Based Pharmacokinetic Modeling of Vitamin D3 and Metabolites in Vitamin D–Insufficient Patients

“…where E max,T is the maximum stimulatory effect in tissue T, EC 50,T is the total plasma concentration of 1,25D 3 in the tissue to achieve 50% of E max , γ 1,T is the Hill coefficient for CYP24A1 in the tissue, and [1,25D T ] is the total concentration of 1,25D 3 in the tissue [Ramakrishnan et al, 2016]. Following the methods of [Noh et al, 2020, Ramakrishnan et al, 2016, k in,[] and k out,[] are presumed to have the same value but different (appropriate) units for the differential equation.…”