Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations

The systems involving folate and cobalamin have several features in common: 1) their dietary forms require luminal digestion for absorption; 2) intestinal bacteria in the upper intestine synthesize and utilize both vitamins, creating possible competition for the nutrients; 3) there is one major intestinal brush border protein essential for absorption; 4) both are subject to extensive entero-hepatic circulation. Finally, human mutations have confirmed the role of specific transporters and receptors in these processes. There are other features, however, that distinguish the metabolism of these vitamins: 1) upper intestinal bacteria tend to produce folate, while cobalamin (cbl) utilization is more common; 2) cbl absorption requires a luminal binding protein, but folate does not; 3) folate absorption can occur throughout the small bowel, but the cbl receptor, cubilin, is restricted to the distal half of the small bowel; 4) movement into cells uses transporters, exchangers, and symporters, whereas cbl is transferred by receptor-mediated endocytosis; 5) folate is carried in the blood mostly in red blood cells, whereas cbl is carried on specific binding-proteins; 6) folate can enter cells via multiple systems, but cbl uptake into all tissues use the transcobalamin receptor (TC-R), with the asialoglycoprotein receptor (ASGP-R) present in hepatocytes for uptake of haptocorrin-cbl (HC-cbl) complexes. In summary, the systems for absorption and distribution of folate and cobalamin are complex. These complexities help to explain the variable clinical responses after oral administration of the vitamins, especially when provided as supplements.