Physiologically Based Pharmacokinetic Modeling of Vitamin B-12 Incorporating Mechanistic Absorption: An Example...

Vitamin B-12 (cobalamin) is an essential micronutrient required for neurologic function, hematopoiesis, and DNA synthesis. Oral absorption of vitamin B-12 occurs through an intrinsic factor (IF)-dependent pathway at physiological intake amounts supplemented by passive diffusion at pharmacologic doses. Vitamin B-12 deficiency is a global public health concern, with certain populations such as older adults and pregnant women at higher risk. Despite adherence to intake recommendations, a substantial proportion of pregnant women exhibit suboptimal vitamin B-12 status. A pharmacokinetic model may improve the evaluation of intake requirements across different populations.

This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of vitamin B-12 absorption and apply it to evaluate intake requirements under altered physiological conditions.

A PBPK model incorporated key absorption mechanisms, including vitamin B-12-IF binding, cubilin-mediated uptake, and passive diffusion. The model was applied to simulate vitamin B-12 absorption across a range of intake doses and to predict plasma vitamin B-12 concentrations under reduced IF secretion and increased systemic clearance reflective of pregnancy-related changes.

The model successfully reproduced the nonlinear absorption behavior of vitamin B-12 and its dependence on IF and cubilin. Simulated absorption percentages following single oral doses of 1, 2, and 1000 μg (83%, 63%, and 1%, respectively) were within the expected range. Simulations with unlimited cubilin availability indicated that cubilin-mediated uptake is the rate-limiting step in IF-dependent absorption. In pregnancy simulations, a daily intake of 150 μg, divided into three 50-μg doses at 6-h intervals, was required to restore plasma vitamin B-12 concentrations depleted by pregnancy to an adequate concentration of >300 pmol/L, whereas the same amount given as a single daily dose did not achieve this concentration.

This study demonstrates the utility of PBPK modeling in providing mechanistic understanding of vitamin B-12 absorption and supporting intake recommendations for populations with altered physiological states.