Stereoselective metabolism and pharmacokinetics of racemic methylphenobarbital in humans.
The stereoselectivity of the metabolism and pharmacokinetics of methylphenobarbital (MPB) was studied in six healthy adult male volunteers given single oral doses of the racemic drug. All of the volunteers were phenotypically extensive metabolizers of the drug. The R- and S-enantiomers of MPB were analyzed in plasma by an enantioselective HPLC method, and the enantiomers of the 4-hydroxy-MPB metabolite in urine by a similar procedure. The (R)-MPB was extensively hydroxylated, with an average of 49.56% of that enantiomer being recovered in urine as (R)-4-hydroxy-MPB. Only 7.16% of the (S)-MPB was converted to the corresponding hydroxy metabolite. The extensive hydroxylation of (R)-MPB resulted in rapid elimination of this enantiomer, with a terminal plasma half-life of 7.52 +/- 1.70 (SD) hr. The (S)-MPB, the only recognized metabolites of which were (S)-4-hydroxy-MPB and phenobarbital (PB), was eliminated very slowly [t1/2, 69.78 +/- 14.77 (SD) hr]. The oral clearance of (R)-MPB (0.470 +/- 0.184 (SD) liters/hr/kg) was much higher than that of (S)-MPB [0.017 +/- 0.001 (SD) liters/hr/kg]. The extreme differences in metabolic fate and pharmacokinetics of the enantiomers of MPB are interesting. Most of the circulating PB seemed to be derived from (S)-MPB. In other respects the pharmacodynamic implications of these pharmacokinetic differences are unclear, because the relative anticonvulsant potencies of the enantiomers of MPB are unknown.
Lim
W H
WH
Department of Medicine of Queensland University, Royal Brisbane Hospital.
Hooper
W D
WD
D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D008618:Mephobarbital / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010634:Phenobarbital / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013997:Time Factors
D008618:Mephobarbital; D010634:Phenobarbital