PHARMACOKINETICS OF DEXTROMETHORPHAN AND DEXTRORPHAN IN EPILEPTIC PATIENTS

The present report describes the pharmacokinetic characteristics of de xtromethorphan (DM) and its main active metabolite dextrorphan (DX) in a group of epileptic patients receiving comedication. Patients were s equentially dosed with DM 40 mg/6 h (8 weeks) and 50 mg/6 h (8 weeks) while concurrent antiepileptic drugs were kept stable. During baseline period, patients were phenotyped with regard to their drug metabolizi ng capacity. At the end of each treatment period, timed plasma DM and DX levels were determined post-dose by HPLC. Urine and cerebrospinal f luid (CSF) samples were also collected. The pharmacokinetic parameters of DM showed a wide intersubject variation. The genetic polymorphism of DM metabolism was identified as the possible cause of the observed variability. For both DM and DX mean values for Cmax and AUC increased in a linear fashion with dose, while the mean values of tmax and t1/2 were not dependent on dose. The mean values of CL/F and Vss/F for DM were also dose-dependent. 3-Methoxymorphinan, an N-demethylated metabo lite of DM was detected in plasma and CSF of some patients and warrant s further investigation as to its possible CNS effects. In conclusion, DM given in doses up to 50 mg/6 h can produce plasma and brain concen trations similar to the in vitro antiepileptic levels, without causing significant adverse effects.