In Silico Identification of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Derivatives

Publication: FASEB J
Software: ADMET Predictor®


Vitamin D3 is an endogenous substance either biosynthesized in humans or absorbed from diet and health supplements. Although calcitriol, the most active form of vitamin D3, is primarily responsible for the health benefits of vitamin D3 including bone and anticancer functions, there are several derivatives in the metabolic pathways of vitamin D3. Calcitriol has largely been the focus of the disposition experimental studies but not the other vitamin D3 derivatives. The objective of this study was to identify the physicochemical and pharmacokinetic properties of vitamin D3 derivatives in silico.

Thirteen chemical structures of vitamin D3 derivatives were obtained from the PubChem and PubMed databases. The structures were imported to the GastroPlus software and simulations were run using the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor module. The ADMET Predictor data were used to simulate the pharmacokinetic properties using physiologically-based pharmacokinetic (PBPKPlus) modeling. The ADMET Predictor module provided the structure-based physicochemical properties, cytochrome P450-based metabolism and the ability to cross blood-brain barrier by vitamin D3 derivatives. In comparison, the PBPKPlus module predicted the pharmacokinetic properties (e.g., bioavailability, half-life, clearance) based on the physicochemical parameters. It also developed pharmacokinetic curves for the vitamin D3 derivatives and simulated concentration versus time plots. Microsoft Excel module was used to compile the data obtained and run lipophilicity (Log P) versus fraction absorbed (Fa) correlation analyses.

The predicted hydrogen ion (pH) values ranged from 3.0 to 9.0 with calcitriol having a lipophilicity of 5.5 units. The structures with more hydroxyl groups have better solubility values than the structures with fewer hydroxyl groups. The fraction absorbed values for the vitamin D3 derivatives were low except for calcitroic acid, 1,23,25-trihydroxy-24-oxo-vitamin D3, and 1,25-dihydroxyvitamin D3-26,23-lactone each being greater than 90% fraction absorbed. The half-lives ranged from 1.2 to 8.0 hours with 1,23,25-trihydroxyvitamin D3 having the lowest half-life of 1.2 hours. Most of the vitamin D3 derivatives have high blood-brain barrier penetration ability except for calcitetrol, 1,23,25 trihydroxyvitamin D3, and 1,23,25-trihydroxy-24-oxo-vitamin D3. The lipophilicity (Log P) versus fraction absorbed (Fa) of all the vitamin D3 derivatives studied yielded a correlation (r2) of 0.66.

Simulation data from GastroPlus indicate that vitamin D3 pathway has several structurally-related compounds with differential physicochemical and pharmacokinetic properties that ranged from being hydrophilic to lipophilic and thus influencing their plasma concentration. The hydrophilic derivatives of vitamin D3 have higher fraction absorbed over the lipophilic ones. Understanding the ADME properties of vitamin D3 derivatives with the knowledge of pharmacological potency could influence the identification of pharmacokinetically most acceptable vitamin D3 derivative for routine supplementation.