Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Natural Derivatives

Abstract

Vitamin D₃ 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 D₃. 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 D₃ 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 D₃ 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 D₃ 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 D₃ derivatives were low except for calcitroic acid, 1,23S,25-trihydroxy-24-oxo-vitamin D₃, and (23S,25R)-1,25-dihydroxyvitamin D₃-26,23-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 D₃ derivatives. 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.

Keywords: cytochrome P450; lipophilicity; pharmacokinetics; physicochemical; solubility; transporter; vitamin D3.

Figure 1

Chemical structures of provitamin D₃ and vitamin D₃ derivatives. 1. Provitamin D₃ (7-dehydrocholesterol) 2. Vitamin D₃ (Cholecalciferol) 3. 25-hydroxyvitamin D₃ (Calcifediol) 4. 1,25-dihydroxyvitamin D₃ (Calcitriol) 5. 1-hydroxyvitamin D₃ (Alfacalcidol) 6. 24R,25-dihydroxyvitamin D₃ 7. 25S,26-dihydroxyvitamin D₃ 8. 1-hydroxy-23-carboxytetranorvitamin D₃ (Calcitroic acid) 9. (23S,25R)-1,25-dihydroxyvitamin D₃-26,23-lactone 10. 1,24R,25-trihydroxyvitamin D₃ (Calcitetrol) 11. 1,23S,25-trihydroxyvitamin D₃ 12. 1,23-dihydroxy-24,25,26,27-tetranorvitamin D₃ (Tetranorcholecalciferol) 13. 1,23S,25-trihydroxy-24-oxo-vitamin D₃. Red letters on structures indicate presence of oxygen-containing functional group(s).