Methycobal Mechanism of Action

Methycobal is a mecobalamin preparation, coenzyme-type vitamin B₁₂ occurring in the blood and cerebrospinal fluid. Mecobalamin is transported to nerve tissues better than other types of vitamin B₁₂. Biochemically, mecobalamin promotes nucleic acid, protein and lipid metabolism through transmethylation reactions. Mecobalamin repairs injured nerve tissues and inhibits abnormal impulse conduction. Mecobalamin promotes the maturation and division of erythroblast and heme synthesis, thereby improving the blood picture in anemia. Clinically, mecobalamin has been shown to benefit megaloblastic anemia and peripheral neuropathies eg, diabetic neuropathy and polyneuritis. Methycobal is the 1st vitamin B₁₂ preparation clinically proven to be effective by double-blind studies.
Pharmacology: 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 cell 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. Mecobalamin also 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 eg, 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.
Pharmacokinetics: Tablet: Single-Dose Administration: When Methycobal was administered orally to healthy adult male volunteers at single doses of 120 mcg and 1500 mcg during fasting, the peak serum total vitamin B₁₂ concentration was reached after 3 hrs for both doses, and this was dose-dependent. The t_½, increment in the serum total B₁₂ concentration and AUC¹²₀ by 12 hr after administration are shown in the table. Forty (40) to 80% of the cumulative amount of total B₁₂ excreted in the urine by 24 hrs after administration was excreted within the first 8 hrs. A single dose of 1500 mcg in unapproved. (See Figure 1 and table.)

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Repeated-Dose Administration: Methycobal was administered orally to healthy adult male volunteers at dose of 1500 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 2.)

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Clinical Studies: Clinical Efficacy: Mecobalamin was administered orally to patients with peripheral neuropathies at doses of 1500 mcg and 120 mcg (low-dose group) daily divided into 3 doses for 4 consecutive weeks in a double-blind clinical trial. In the chronic and fixed stage in peripheral neuropathies, the improvement rate for moderately to remarkably improved was 17.6% (6/34) in 1500 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 1500 mcg group and 41.9% (13/31) in the 120 mcg group. The dose of 1500 mcg/day was thus demonstrated to be useful.
In placebo-controlled double-blind clinical trial, mecobalamin and cobamamide were administered orally to patients with peripheral neuropathies at doses of 1500 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.
Ampoule: Single-Dose Administration: When a single IM or IV of 500 mcg of CH₃-B₁₂ was administered to healthy adults, the time required for the serum total vitamin B₁₂ level to reach a peak (T_max) was 0.9±0.1 hr after IM administration and immediately to 3 min after IV administration, and the increment in peak serum total vitamin B₁₂ level (C_max) was 22.4±1.1 ng/mL after IM administration and 85±8.9 ng/mL after IV administration.
The area under the blood concentration-time curve (AUC) 204.1±12.9 hr·ng/mL after IM administration and 358.6±34.4 hr·ng/mL after IV administration. (See Figure 3.)

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On the other hand, the rate of binding saturation showed a similar increase in both groups of subjects for 144 hrs after administration.
Repeated-Dose Administration: 500 mcg/day of CH₃-B₁₂ was administered IV to healthy adults for 10 consecutive days. Serum total vitamin B₁₂ levels measured before each administration (C_min) increased from day to day. At 2 days of administration, the serum level of total vitamin B₁₂ was 5.3±1.8 ng/mL, about 1.4 times the 24-hr value (3.9±1.2 ng/mL). At 3 days of administration, it was increased to 6.8±1.5 ng/mL, about 1.7 times the 24-hr value, and this level was maintained until the last dosing.
Clinical Studies: Clinical Efficacy: It has been shown in double-blind studies that CH₃-B₁₂ benefits peripheral neuropathies when the general improvement of symptoms is evaluated.
Equivalency in effect between the IV and IM routes has been demonstrated in double-blind clinical studies.
Adverse Reactions and Influences on Laboratory Values: Adverse reactions to Methycobal have been reported in 5 (0.27%) of 1864 cases. The main adverse reactions were eruptions in 2 cases (0.11%). No changes in laboratory values have been associated with Methycobal treatment.
Others: Methycobal should not be used over a period of months if there is lack of satisfactory clinical response in patients with megaloblastic anemia probably due to vitamin B₁₂ deficiency or with peripheral neuropathies.