Metabolism of Lyrica (Pregabalin)

Pregabalin undergoes negligible metabolism in humans and is primarily eliminated unchanged through renal excretion. 1

Pharmacokinetic Profile

Pregabalin is well absorbed after oral administration with bioavailability ≥90%, independent of dose 1
Peak plasma concentrations occur within 1.5 hours after oral administration in fasting conditions 1
Food decreases Cmax by 25-30% and delays Tmax to approximately 3 hours, but does not significantly affect total absorption 1, 2
Pregabalin does not bind to plasma proteins 1, 2
The apparent volume of distribution is approximately 0.5 L/kg 1

Approximately 90% of administered pregabalin is recovered in urine as unchanged drug 1, 3
Pregabalin undergoes negligible metabolism (<2%) in humans 1, 2
The N-methylated derivative is the major metabolite found in urine, accounting for only 0.9% of the dose 1
Pregabalin (S-enantiomer) does not undergo racemization to the R-enantiomer 1
Unlike many other CNS medications, pregabalin is not metabolized by the cytochrome P450 enzyme system 2, 4

Mean elimination half-life is approximately 6.3 hours in subjects with normal renal function 1, 2
Renal clearance ranges from 67.0 to 80.9 mL/min in young healthy subjects 1
Pregabalin elimination is nearly proportional to creatinine clearance (CLcr) 1, 3
Pregabalin is effectively removed by hemodialysis, with plasma concentrations reduced by approximately 50% after a 4-hour treatment 1, 3

Elderly patients may have decreased pregabalin clearance consistent with age-related decreases in creatinine clearance 1
Pediatric patients (3 months to <17 years) show weight-dependent clearance and volume of distribution 1
No dose adjustment is needed based on race or gender 1
Dose adjustment is necessary in patients with renal impairment 1, 3, 2

Due to minimal metabolism and lack of protein binding, pregabalin has a low potential for pharmacokinetic drug interactions 1, 2
No significant pharmacokinetic interactions have been observed between pregabalin and commonly used antiepileptic drugs (carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate) 1
While pharmacokinetic interactions are minimal, pharmacodynamic interactions (additive effects on cognitive and gross motor function) may occur when pregabalin is co-administered with oxycodone, lorazepam, or ethanol 1

The predictable pharmacokinetics and minimal metabolism make pregabalin dosing straightforward in patients with normal renal function 2
Dose adjustment is required in patients with renal impairment (CLcr <60 mL/min) 1, 3
Supplemental doses may be required after hemodialysis to maintain therapeutic levels 1, 3
The lack of hepatic metabolism and protein binding reduces the risk of drug-drug interactions compared to many other CNS medications 2, 5