Drug-drug interaction between pramipexole and cimetidine, an OCT2 inhibitor

Purpose: Pramipexole, a non-ergoline dopamine agonist, is approved for the treatment of Parkinson’s disease and restless legs syndrome (RLS). Pramipexole is well absorbed and undergoes little presystemic biotransformation. Approximately 90% was excreted in the urine as unchanged drug, with possible involvement with organic cation transporters (OCTs) in the renal tubules. We investigated the effects of cimetidine, known as an OCT2 inhibitor, on the pharmacokinetics of pramipexole.

Methods: Eighteen healthy male subjects were recruited for the study. In the control phase, each subject received a single oral dose of 0.25 mg pramipexole after overnight fasting. In the cimetidine phase, the subjects were administered an oral dose of 400 mg cimetidine twice daily for five days. On the morning of day 6, they received a single oral dose of 0.25 mg pramipexole two hours later the administration of a 400 mg oral dose of cimetidine. Blood samples were collected up to 48 hr after drug intake, and the plasma concentrations of pramipexole were determined by using LC-MS/MS system.

Results: In the cimetidine phase, C_max and AUC_inf of pramipexole was 1.2- and 1.4-fold higher than in the control phase (P<0.001 and P<0.0001, respectively). Apparent ral clearance (CL/F) of pramipexole in the cimetidine phase was 30% lower than in the control phase (P<0.0001). Elimination half-life (t_1/2) of pramipexole between two phase were not significantly different.

Conclusion: OCT2 is found to be associated with the renal excretion of pramipexole in vivo. Further studies on the effects of OCT2 genetic variants on the pharmacokinetics of pramipexole will be meaningful.