Funxion Mechanism of Action

Pharmacology: Pharmacodynamics: Pregabalin is an anticonvulsant that is structurally related to the inhibitory central nervous system (CNS) neurotransmitter gamma aminobutyric acid (GABA). Although pregabalin was developed as a structural analog of GABA, the drug does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors; does not augment GABA_A responses in cultured neurons; 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 transporter protein and increases the rate of functional GABA transport.
Pregabalin binds with high affinity to the α₂-δ site (an auxillary subunit of voltage-gated calcium channels) in CNS tissues. Although the exact mechanism of action of pregabalin has not been elucidated, binding to the α₂-δ subunit may be involved in pregabalin's anticonvulsant effect. In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, including glutamate, norepinephrine, calcitonin gene-related peptide, and substance P, possibly by modulation of calcium channel function.
Pharmacokinetics: Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within one hour after both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose. Maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) values increase proportionality after single- and multiple-dose administration. After repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in C_max by approximately 25 to 30% and a delay in T_max to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin bioavailability.
At clinical doses of 150 to 600 mg per day, the average steady-state plasma pregabalin concentrations were approximately 1.5 and 6 g/mL, respectively. Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are predictable from single-dose data.
The apparent volume of distribution of pregabalin after oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. In animal models, pregabalin has been shown to cross the blood brain barrier. Pregabalin undergoes negligible metabolism in human. After a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was 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, there was no indication of racemization of pregabalin S-enantiomer to the R-enantiomer.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Renal clearance (CL_cr) derived from Phase I studies was 73 mL/min. Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance.
Special Population: Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by hemodialysis (after a four hour hemodialysis treatment plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dosage reduction in patients with renal impairment and dosage supplementation after hemodialysis is necessary.
Hepatic impairment: Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
Elderly (65 years and older): Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age related compromised renal function.