Abstract
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.
Footnotes
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Send reprint requests to: Kenneth K. Chan, Room 308, Comprehensive Cancer Center, The Ohio State University, 410 W. 12th Ave., Columbus, OH 43210.
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This study was supported in part by grant P30 CA16058 by The National Cancer Institute.
- Abbreviations used are::
- IF
- ifosfamide
- CP
- cyclophosphamide
- HOIF
- 4-hydroxyifosfamide
- N2D
- N2-dechloroethylifosfamide
- N3D
- N3-dechloroethylifosfamide
- PB
- phenobarbital
- IPM
- isophosphoramide mustard
- CYP or P450
- cytochrome P450
- Received December 23, 1996.
- Accepted December 11, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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