Gablin Plus Mechanism of Action

Antiepileptic/Vitamin.
Pharmacology: Pharmacodynamics: Pregabalin: Pregabalin binds with high affinity to the alpha-2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues.
While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors, does not augment GABA_A responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.
Pregabalin does not block sodium channels, is not at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.
Methylcobalamin: Methylcobalamin (Mecobalamin, MeCbl), is one of the two biologically active vitamin B₁₂. Mecobalamin acts as an important cofactor in the reaction of one class of the B₁₂ enzymes, the methyltransferases. The B₁₂-dependent methyltransferases play an important role in amino acid metabolism in many organisms as well as in one-carbon metabolism and CO₂ fixation in anaerobic microbes. Among them, methionine synthase is the most extensively studied B₁₂-dependent methyltransferase in humans. As the cofactor of the enzyme methionine synthase, mecobalamin functions to catalyse the transfer of the methyl group from methylene tetrahydrofolate to homocysteine (Hcy) to form methionine and tetrahydrofolate.
Deficiency of vitamin B₁₂ results in the lack of mecobalamin and has been associated with significant neurological pathology, especially peripheral neuropathy.
Pharmacokinetics: Pregabalin: Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 6 hours.
Absorption and Distribution: Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is greater than or equal to 90% and is independent of dose. Following single- (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (C_max) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.
The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in C_max of approximately 25% to 30% and an increase in T_max to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.
Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for the system L transporter which is responsible for the transport of large amino acids across the blood-brain barrier.
Metabolism and Elimination: Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects.
Special populations: Age: Geriatrics: Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr_. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Renal impairment and haemodialysis: Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by haemodialysis. Following a 4-hour haemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on haemodialysis, dosing must be modified.
Methylcobalamin: Absorption: Evidence indicates methylcobalamin is utilized more efficiently than cyanocobalamin to increase levels of one of the coenzyme forms of vitamin B₁₂. Experiments have demonstrated similar absorption of methylcobalamin following oral administration. The quantity of cobalamin detected following a small oral dose of mecobalamin is similar to the amount detected following the administration of cyanocobalamin, but significantly more cobalamin accumulates in liver tissue, which is associated with mecobalamin intake.
Distribution and Metabolism: Cobalamin circulates in plasma bound to two carrier proteins: transcobalamin (TC) and haptocorrin. TC is a 43-kDa non-glycoprotein that transfers cobalamin from the intestine into the bloodstream and then into all the cells of the body. Cobalamin-saturated transcobalamin (holoTC) constitutes 6-20% of total plasma cobalamin. The unsaturated TC is called apotranscobalamin, which constitutes the major part of TC. Additionally, total homocysteine (Hcy) and methylmalonic acid are considered to be two functional markers of vitamin B₁₂ status in adults.
Excretion: Human urinary excretion of methylcobalamin is about one-third that of a similar dose of cyanocobalamin, indicating substantially greater tissue retention.