Pharmacokinetics of nefiracetam and three metabolites in humans and stereoselective hydroxylation of its pyrrolidine ring

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Abstract
1. The kinetics of nefiracetam (I) and three metabolites (II-IV) were investigated in healthy volunteers. Compounds I-IV in serum and urine were measured by h.p.l.c. 2. After a single 200 mg dose of nefiracetam the drug was absorbed rapidly and showed peak serum levels of 16.3×0.9nmol/ml. Cmax values of the three metabolites were comparatively low (0.96–4.89nmol/ml), and tmax and t1/2 values of the metabolites (4.1–9.6h and 7.8–21.9h, respectively) were longer than those of I (1.6 h and 3.9 h respectively). Urinary excretion of I in 24h was about 5% of the dose. The major urinary metabolite, a pyrrolidine ring scission product (IV), had a mean total excretion of 17.8% dose. The total of all four compounds in urine amounted to 43.4% dose. 3. In a multiple-dose study (daily 3 × 200mg doses of nefiracetam for 7 days), the serum concentration profile of each compound indicated that the steady state was reached in 7 days. 4. Metabolite II existed as a racemate and III mainly as the (–)-enantiomer in human urine.