Methycobal Mechanism of Action

Pharmacology: Pharmacodynamics: Mecobalamin is a kind of endogenous coenzyme B₁₂: Mecobalamin plays an important role in transmethylation as a coenzyme of methionine synthetase in the synthesis of methionine from homocysteine.
Mecobalamin is well transported to nerve cell organelles, and promotes nucleic acid and protein synthesis: Mecobalamin is better transported to nerve cells organelles than cyanocobalamin in rats. It has been shown in experiments with cells from the brain origin and spinal nerve cells in rats to be involved in the synthesis of thymidine from deoxyuridine, promotion of deposited folic acid utilization and metabolism of nucleic acid. Also, mecobalamin promotes nucleic acid and protein synthesis in rats more than cobamamide does.
Mecobalamin promotes axonal transport and axonal regeneration: Mecobalamin normalizes axonal skeletal protein transport in sciatic nerve cells from rat models with streptozotocin-induced diabetes mellitus. It exhibits neuropathologically and electrophysiologically inhibitory effects on nerve degeneration in neuropathies induced by drugs, such as adriamycin, acrylamide, and vincristine (in rats and rabbits), models of axonal degeneration in mice and neuropathies in rats with spontaneous diabetes mellitus.
Mecobalamin promotes myelination (phospholipid synthesis): Mecobalamin promotes the synthesis of lecithin, the main constituent of medullary sheath lipids, and increases myelination of neurons in rat tissue culture more than cobamamide does.
Mecobalamin restores delayed synaptic transmission and diminished neurotransmitters to normal: Mecobalamin restores end-plate potential induction early by increasing nerve fiber excitability in the crushed sciatic nerve in rats. In addition, mecobalamin normalizes diminished brain tissue levels of acetylcholine in rats fed a choline-deficient diet.
Injection: Mecobalamin promotes the maturation and division of erythroblasts, thereby alleviating anemia: It is well known that vitamin B₁₂-deficiency may cause specific megaloblastic anemia. Mecobalamin promotes nucleic acid synthesis in bone marrow and promotes the maturation and division of erythroblasts, thereby increasing erythrocyte production. Mecobalamin brings about a rapid recovery of diminished red blood cell, hemoglobin, and hematocrit in vitamin B₁₂-deficient rats.
Clinical Studies: Clinical efficacy: Tablet: Mecobalamin was administered orally to patients with peripheral neuropathies at doses of 1,500 mcg and 120 mcg (low-dose group) daily divided into three doses for 4 consecutive weeks in a double-blind clinical trial. In the chronic stage and fixed stage in peripheral neuropathies, the improvement rate for moderately to remarkably improved was 17.6% (6/34) in 1,500 mcg group and 9.7% (3/31) in 120 mcg group. The improvement rate for fairly to remarkably improved was 64.7% (22/34) in the 1,500 mcg group and 41.9% (13/31) in the 120 mcg group. The dose of 1,500 mcg/day was thus demonstrated to be useful.
In a placebo-controlled double-blind clinical trial, mecobalamin and cobamamide were administered orally to patients with peripheral neuropathies at doses of 1,500 mcg daily for 4 consecutive weeks. The rates for moderately to remarkably improved for peripheral neuropathies were 38.6% (17/44) for mecobalamin, 22.2% (10/45) for cobamamide and 26.7% (12/45) for placebo. Mecobalamin was thus demonstrated to be useful.
Injection: Mecobalamin was administered intramuscularly to patients with peripheral neuropathies in single doses of 500 mcg and 100 mcg (low-dose group) daily 3 times a week for 4 consecutive weeks in a double-blind clinical trial. In the chronic stage and fixed stage of peripheral neuropathies in the 500 mcg group aggravation of symptoms was significantly suppressed compared to the low-dose group and this dose was thus demonstrated to be useful.
In a placebo-controlled double-blind clinical trial, mecobalamin was administered intravenously or intramuscularly to patients with peripheral neuropathies at a single dose of 500 mcg daily 3 times a week for 4 consecutive weeks. The improvement rate for intravenous administration was 38.7% (24/62) for moderately to remarkably improved and 74.2% (46/62) for fairly to remarkably improved. The improvement rate for intramuscular administration was 46.3% (25/54) for moderately to remarkably improved and 81.5% (44.54) for fairly to remarkably improved.
The equivalence of mecobalamin efficacy for both administration routes was thus demonstrated. The diseases of subjects in the trial were diabetic neuropathy, polyneuritis, cervical spondylosis, sciatica, alcoholic neuropathy, facial paralysis and mononeuritis, etc.
When mecobalamin was administered to patients with megaloblastic anemia due to vitamin B₁₂ deficiency, their hemograms and symptoms improved in 3 weeks to 2 months after starting administration.
Pharmacokinetics: Single-dose administration: Tablet: When Mecobalamin (METHYCOBAL) was administered orally to healthy adult male volunteers at single doses of 120 mcg and 1,500 mcg^note), the peak serum total vitamin B₁₂ (abbreviated to B₁₂) concentration was reached after 3 hrs. for both doses, and this was dose-dependent. The half-life, increment in the serum total B₁₂ concentration and △AUC₀¹² by 12 hrs. after administration are shown in the following figure and table. 40 to 90 percent of the cumulative amount of total B₁₂ excreted in the urine by 24 hrs. after administration was excreted within the first 8 hrs.
(Note) The approved dosage and administration of mecobalamin are as follows: The usual adult dosage for oral use is 1,500 mcg of mecobalamin daily divided into three doses. The dosage may be adjusted depending on the patient's age and symptoms. (See Figure 1 and Table 3.)

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Injection: Mecobalamin was administered intramuscularly or intravenously to 12 healthy adult male volunteers at a single dose of 500 mcg. The time to reach peak serum total vitamin B₁₂ (abbreviated to B₁₂) concentration (tmax) was 0.9 hr after intramuscular administration and immediately to 3 mins. after intravenous administration, and the increment (except endogenous serum total B₁₂) in peak serum total vitamin B₁₂ concentration (△Cmax) was 22.4 ng/mL after intramuscular administration and 85.0 ng/mL after intravenous administration.
The area under the serum total B₁₂ concentration-time curve (△AUC) calculated by increment of the actual values at 144 hr. after administration was 204.1 ng · hr/mL after intramuscular administration and 358.6 ng · hr/mL after intravenous administration.
On the other hand, the rate of binding saturation showed a similar increase in both groups of subjects for 144 hr. after administration. (See Figure 2 and Table 4.)

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Repeated-dose administration: Tablet: Mecobalamin (METHYCOBAL) was administered orally to healthy adult male volunteers at a dose of 1,500 mcg daily for 12 consecutive weeks and changes in the serum total B₁₂ concentration were determined until 4 weeks after the last administration. The serum concentration increased for the first 4 weeks after administration, rising to about twice as high as the initial value. Thereafter, there was a gradual increase which peaked at about 2.8 times the initial value at the 12th week of dosing. The serum concentration declined after the last administration (12 weeks), but was still about 1.8 times the initial value 4 weeks after the last administration. (See Figure 3.)

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Injection: Mecobalamin was administered intravenously to 6 healthy adult male volunteers at a single dose of 500 mcg daily for 10 consecutive days. Serum total B₁₂ concentration determined before each administration increased from day to day. After 2 days of administration, the serum total B₁₂ concentration was 5.3±1.8 ng/mL, about 1.4 times the 24 hr value (3.9±1.2 ng/mL) after administration. At 3 days of administration it had increased to 6.8±1.5 ng/mL, about 1.7 times the 24 hr value, and this concentration was maintained until the last dosing.