Toprelin Mechanism of Action



T. O. Chemicals


T. O. Chemicals
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Pharmacology: Pharmacodynamics: Pregabalin binds with high affinity to the α2-δ site (an auxiliary subunit of voltage-gated calcium channels) in CNS tissues. Although the exact mechanism of action of pregabalin is unknown, binding to the α2-δ site may be related to pregabalin's analgesic and anticonvulsant effects. In vitro, pregabalin reduces the calcium-dependent release of various neurotransmitters, including glutamate, norepinephrine, calcitonin gene-related peptide, and substance P, possibly by modulation of calcium channel function.
Pregabalin is a structural derivative of the inhibitory CNS neurotransmitter gamma-aminobutyric acid (GABA). Although pregabalin was developed as a structural analog of GABA, the drug dose not bind directly to GABAA, GABAB or benzodiazepine receptors; dose not augment GABAA responses in cultured neuron; and does not alter brain concentrations of GABA in rats or affect GABA uptake or degradation. However, in cultured neurons, prolonged application of pregabalin increases the density of GABA transport protein and increase the rate of functional GABA transport.
Pharmacokinetics: Absorption: Pregabalin is well absorbed after oral administration. Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is 90% or more and is independent of dose. Following single-dose (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (Cmax) and area under the 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 Cmax of approximately 25% to 30% and an increase in time of maximal concentration (Tmax) 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.
Distribution: 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 system L transporter, which is responsible for the transport for the large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin crossed the blood brain barrier in mice, rats, and monkeys. In addition, pregabalin crossed the placenta in rats and was present in the milk of lactating rats.
Metabolism: 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. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantionmer in mice, rats, rabbits, or monkeys.
Excretion: 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 healthy renal function. Mean renal clearance was estimated to be 67 to 80.9 mL/min in young, healthy subjects. Pregabalin elimination is nearly proportional to CrCl.
Special Populations: Renal function impairment: Pregabalin clearance is nearly proportion to CrCl. Dosage reduction in patients with renal impairment is necessary. Pregabalin is effectively removed from plasma be hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced approximately 50%. For patients on hemodialysis, dosing must be modified. (See Dosage & Administration.)
Elderly: Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CrCl. Reduction of the pregabalin dose may be required in patients who have age-related compromised renal reduction. (See Dosage & Administration.)
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