Effects of phenobarbital on stereoselective metabolism of ifosfamide in rats.
Plasma and urinary levels of ifosfamide (IF) enantiomers and their metabolites 2-dechloroethylifosfamide, 3-dechloroethylifosfamide, 4-hydroxyifosfamide, and isophosphoramide mustard were determined for control and phenobarbital-treated male Sprague-Dawley rats by using pseudoracemates and GC/MS and stable-isotope dilution analytical methods. For the control rats, the mean AUC for (S)-IF in plasma was greater than that for (R)-IF (R/S AUC ratio, 0.78) and the mean half-life of 41.8 min for (S)-IF was slightly longer than that of 34.3 min for (R)-IF. Phenobarbital pretreatment significantly decreased the AUC values for (R)-IF and (S)-IF, to 21 and 30% of the control values, respectively, and shortened plasma half-lives for both enantiomers [half-life for (R)-IF, 19.8 min; half-life for (S)-IF, 19.4 min]. The urinary excretion values for (R)-IF and (S)-IF were decreased to 41 and 30% of the control values, respectively. The overall amounts of the metabolites in urine were concomitantly increased. Additionally, there were significant reversals in both the R/S AUC ratio and the urinary excretion of 3-dechloroethylifosfamide. Moreover, the enantioselectivity for the generation of 4-hydroxyifosfamide and isophosphoramide mustard disappeared after phenobarbital treatment. These results strongly suggested that the 4-hydroxylation and dechloroethylation of IF enantiomers were mediated by different P450 isozymes or the same isozyme with different stereochemical selectivities.
Lu
H
H
College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Wang
J J
JJ
Chan
K K
KK
Young
D
D
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007069:Ifosfamide / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
D000927:Anticonvulsants; D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide; D010634:Phenobarbital