CLINICAL PHARMACOLOGY
General Pharmacology And Mechanism Of Action
Vitamin B12 is essential to growth, cell reproduction, hematopoiesis,
and nucleoprotein and myelin synthesis. Cells characterized by rapid division
(e.g., epithelial cells, bone marrow, myeloid cells) appear to have the greatest
requirement for vitamin B12. Vitamin
B12 can be converted to coenzyme B12 in tissues, and
as such is essential for conversion of methylmalonate to succinate and synthesis
of methionine from homocysteine, a reaction which also requires folate. In the
absence of coenzyme B12, tetrahydrofolate cannot be regenerated from
its inactive storage form, 5- methyltetrahydrofolate, and a functional folate
deficiency occurs. Vitamin B12 also may be involved in maintaining
sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme
systems. Through these reactions, vitamin B12 is associated with
fat and carbohydrate metabolism and protein synthesis. Vitamin B12
deficiency results in megaloblastic anemia, GI lesions, and neurologic damage
that begins with an inability to produce myelin and is followed by gradual degeneration
of the axon and nerve head.
Cyanocobalamin is the most stable and widely used form of vitamin B12,
and has hematopoietic activity apparently identical to that of the antianemia
factor in purified liver extract. The information below, describing the clinical
pharmacology of cyanocobalamin, has been derived from studies with injectable
vitamin B12.
Vitamin B12 is quantitatively and rapidly absorbed from intramuscular
and subcutaneous sites of injection. It is bound to plasma proteins and stored
in the liver. Vitamin B12 is excreted in the bile and undergoes some
enterohepatic recycling. Absorbed vitamin B12 is transported via
specific B12 binding proteins, transcobalamin I and II, to the various
tissues. The liver is the main organ for vitamin B12 storage.
Parenteral (intramuscular) administration of vitamin B12 completely
reverses the megaloblastic anemia and GI symptoms of vitamin B12
deficiency; the degree of improvement in neurologic symptoms depends on the
duration and severity of the lesions, although progression of the lesions is
immediately arrested.
Gastrointestinal absorption of vitamin B12 depends on the presence
of sufficient intrinsic factor and calcium ions. Intrinsic factor deficiency
causes pernicious anemia, which may be associated with subacute combined degeneration
of the spinal cord. Prompt parenteral administration of vitamin B12
prevents progression of neurologic damage.
The average diet supplies about 4 to 15 mcg/day of vitamin B12 in
a protein-bound form that is available for absorption after normal digestion.
Vitamin B12 is not present in foods of plant origin, but is abundant
in foods of animal origin. In people with normal absorption, deficiencies have
been reported only in strict vegetarians who consume no products of animal origin
(including no milk products or eggs).
Vitamin B12 is bound to intrinsic factor during transit through
the stomach; separation occurs in the terminal ileum in the presence of calcium,
and vitamin B12 enters the mucosal cell for absorption. It is then
transported by the transcobalamin binding proteins. A small amount (approximately
1% of the total amount ingested) is absorbed by simple diffusion, but this mechanism
is adequate only with very large doses. Oral absorption is considered too undependable
to rely on in patients with pernicious anemia or other conditions resulting
in malabsorption of vitamin B12.
Colchicine, para-aminosalicylic acid, and heavy alcohol intake for longer than
2 weeks may produce malabsorption of vitamin B12.
Pharmacokinetics
Absorption
A three way crossover study in 25 fasting healthy subjects was conducted to
compare the bioavailability of the B12 nasal spray to the B12
nasal gel and to evaluate the relative bioavailability of the nasal formulations
as compared to the intramuscular injection. The peak concentrations after administration
of intranasal spray were reached in 1.25 +/- 1.9 hours. The average peak concentration
of B12 obtained after baseline correction following administration
of intranasal spray was 757.96 +/- 532.17 pg/mL. The bioavailability of the
nasal spray relative to the intramuscular injection was found to be 6.1%. The
bioavailability of the B12 nasal spray was found to be 10% less than
the B12 nasal gel. The 90% confidence intervals for the loge-transformed
AUC(0-t) and Cmax was 71.71% - 114.19% and 71.6% - 118.66% respectively.
In pernicious anemia patients, once weekly intranasal dosing with 500 mcg B12
gel resulted in a consistent increase in pre-dose serum B12 levels
during one month of treatment (p < 0.003) above that seen one month after
100 mcg intramuscular dose (Figure).
Distribution
In the blood, B12 is bound to transcobalamin II, a specific B-globulin
carrier protein, and is distributed and stored primarily in the liver and bone
marrow.
Elimination
About 3-8 mcg of B12 is secreted into the GI tract daily via the
bile; in normal subjects with sufficient intrinsic factor, all but about 1 mcg
is reabsorbed. When B12 is administered in doses which saturate the
binding capacity of plasma proteins and the liver, the unbound B12
is rapidly eliminated in the urine. Retention of B12 in the body
is dose-dependent. About 80-90% of an intramuscular dose up to 50 mcg is retained
in the body; this percentage drops to 55% for a 100 mcg dose, and decreases
to 15% when a 1000 mcg dose is given.
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Figure. Vitamin B12 Serum Trough Levels After Intramuscular Solution (IM) of 100 mcg and Nasal Gel (IN) Administration of 500 mcg Cyanocobalamin After Weekly Doses. |
Figure. Vitamin B12 Serum Trough Levels After Intramuscular Solution (IM) of 100 mcg and Nasal Gel (IN) Administration of 500 mcg Cyanocobalamin After Weekly Doses.