Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D(3) and Its Natural Derivatives

Vitamin D(3) is an endogenous fat-soluble secosteroid, either biosynthesized in human skin or absorbed from diet and health supplements. Multiple hydroxylation reactions in several tissues including liver and small intestine produce different forms of vitamin D(3). Low serum vitamin D levels is a global problem which may origin from differential absorption following supplementation. The objective of the present study was to estimate the physicochemical properties, metabolism, transport and pharmacokinetic behavior of vitamin D(3) derivatives following oral ingestion. GastroPlus software, which is an in silico mechanistically-constructed simulation tool, was used to simulate the physicochemical and pharmacokinetic behavior for twelve vitamin D(3) derivatives. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules were employed to derive the relevant parameters from the structural features of the compounds. The majority of the vitamin D(3) derivatives are lipophilic (log P values >5) with poor water solubility which are reflected in the poor predicted bioavailability. The fraction absorbed values for the vitamin D(3) derivatives were low except for calcitroic acid, 1,23S,25-trihydroxy-24-oxo-vitamin D(3), and (23S,25R)-1,25-dihydroxyvitamin D(3)-26,23-lactone each being greater than 90% fraction absorbed. Cytochrome P450 3A4 (CYP3A4) is the primary hepatic enzyme along with P-glycoprotein involved in the disposition of the vitamin D derivatives. Lipophilicity and solubility appear to be strongly associated with the oral absorption of the vitamin D(3) derivatives. Understanding the ADME properties of vitamin D(3) derivatives with the knowledge of pharmacological potency could influence the identification of pharmacokinetically most acceptable vitamin D(3) derivative for routine supplementation.