Pharmacokinetics of nefiracetam and three metabolites in humans and stereoselective hydroxylation of its pyrrolidine ring.
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 +/- 0.9 nmol/ml. Cmax values of the three metabolites were comparatively low (0.96-4.89 nmol/ml), and tmax and t1/2 values of the metabolites (4.1-9.6 h and 7.8-21.9 h, respectively) were longer than those of I (1.6 h and 3.9 h respectively). Urinary excretion of I in 24 h 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 x 200 mg 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.
Fujimaki
Y
Y
Drug Metabolism and Analytical Chemistry Research Center, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.
Sudo
K
K
Hakusui
H
H
D000328:Adult; D004334:Drug Administration Schedule; D006801:Humans; D006900:Hydroxylation; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011619:Psychotropic Drugs / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D011759:Pyrrolidines / Q000378:metabolism; D011760:Pyrrolidinones / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011619:Psychotropic Drugs; D011759:Pyrrolidines; D011760:Pyrrolidinones; C058876:nefiracetam; D006899:Mixed Function Oxygenases