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Stereoselective metabolism and pharm...

University of Southern California.

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Stereoselective metabolism and pharmacokinetics of ifosfamide in the rat.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Stereoselective metabolism and pharmacokinetics of ifosfamide in the rat./
Author:	Wang, Jinghua.
Description:	300 p.
Notes:	Adviser: Eric J. Lien.
Contained By:	Dissertation Abstracts International57-03B.
Subject:	Chemistry, Pharmaceutical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9621731

Stereoselective metabolism and pharmacokinetics of ifosfamide in the rat.
Wang, Jinghua.

Stereoselective metabolism and pharmacokinetics of ifosfamide in the rat. - 300 p.

Adviser: Eric J. Lien.

Thesis (Ph.D.)--University of Southern California, 1995.

The stereoselective metabolism and pharmacokinetics of ifosfamide (IF) was investigated in Sprague-Dawley rats using pseudoracemate and gas chromatography-mass spectrometry (GC/MS) methodology. The enantiomers of unlabeled IF and strategically deuterium labeled IF were obtained by asymmetric synthesis. Along with four known metabolites, namely, N2-dechloroethyl ifosfamide (N2D), N3-dechloroethyl ifosfamide (N3D), alcoifosfamide (alcolF), and iphosphoramide mustard (IPM), four new metabolites (4-hydroxy N2D, 4-hydroxy N3D, N-dechloroethyl IPM, and N2,N3-didechloroethyl Ifosfamide) were identified in rat urine using combined techniques of chemical modification, ion cluster analysis, and chemical synthesis. In addition, the key metabolite 4-hydroxy ifosfamide (4-OHIF) was characterized as a cyanohydrin adduct for the first time.Subjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Stereoselective metabolism and pharmacokinetics of ifosfamide in the rat.
LDR:03409nmm 2200289 a 45 001 886458
005 20101007
008 101007s1995 ||||||||||||||||| ||eng d
035 $a (UMI)AAI9621731
035 $a AAI9621731
040 $a UMI $c UMI
100 1 $a Wang, Jinghua. $3 1058155
245 1 0 $a Stereoselective metabolism and pharmacokinetics of ifosfamide in the rat.
300 $a 300 p.
500 $a Adviser: Eric J. Lien.
500 $a Source: Dissertation Abstracts International, Volume: 57-03, Section: B, page: 1736.
502 $a Thesis (Ph.D.)--University of Southern California, 1995.
520 $a The stereoselective metabolism and pharmacokinetics of ifosfamide (IF) was investigated in Sprague-Dawley rats using pseudoracemate and gas chromatography-mass spectrometry (GC/MS) methodology. The enantiomers of unlabeled IF and strategically deuterium labeled IF were obtained by asymmetric synthesis. Along with four known metabolites, namely, N2-dechloroethyl ifosfamide (N2D), N3-dechloroethyl ifosfamide (N3D), alcoifosfamide (alcolF), and iphosphoramide mustard (IPM), four new metabolites (4-hydroxy N2D, 4-hydroxy N3D, N-dechloroethyl IPM, and N2,N3-didechloroethyl Ifosfamide) were identified in rat urine using combined techniques of chemical modification, ion cluster analysis, and chemical synthesis. In addition, the key metabolite 4-hydroxy ifosfamide (4-OHIF) was characterized as a cyanohydrin adduct for the first time.
520 $a Stereoselectivity on the metabolism of IF was studied by measuring the enantiomeric ratios of unchanged IF and the metabolites in rat urine following administration of pseudoracemates. The data revealed that all three major metabolic pathways displayed stereoselectivity. The activation pathway of IF leading to the formation of 4-OHIF preferred the R configuration (R/S ratio $1 .53\pm0.04).$ This preference was preserved in two subsequent steps, the cleavage to IPM (R/S ratio $1 .51\pm0.03)$ and the reduction to alcolF (R/S ratio $1 .57\pm0.01).$ N2-Dealkylation only showed a small preference for R-IF (R/S ratio $1 .13\pm0.10),$ however, N3-dealkylation displayed a pronounce preference for S-IF (R/S ratio $0 .33\pm0.02).$
520 $a Pseudoracemates were given to six rats at 40 mg/kg iv and the plasma levels of enantiomeric IFs and their metabolites were analyzed using a specific GC/MS method with deuterium labeled analogs as the internal standards. The results showed R-IF was eliminated from blood stream slightly faster than S-IF, with a lower AUC value (R/S ratio $0 .86\pm0.04).$ The AUC values of 4-OHIF and IPM generated from R-IF were significantly higher than those from S-IF (R/S ratio $1 .62\pm0.27$ and $1 .46\pm0.27,$ respectively). The AUC value of N2D generated from R-IF was significantly lower than that from S-IF (R/S ratio $0 .29\pm0.04).$ The enantiomeric selectivity for N3-dealkylation was not significant. Since N-dealkylation of IF generates a potentially neurotoxic product (CAA) while 4-hydroxylation is considered the necessary activation process, the observed enantioselective metabolism and pharmacokinetic disposition suggests the clinical use of the eutomer--R-IF.
590 $a School code: 0208.
650 4 $a Chemistry, Pharmaceutical. $3 550957
650 4 $a Health Sciences, Pharmacy. $3 1017737
690 $a 0491
690 $a 0572
710 2 $a University of Southern California. $3 700129
773 0 $t Dissertation Abstracts International $g 57-03B.
790 $a 0208
790 1 0 $a Lien, Eric J., $e advisor
791 $a Ph.D.
792 $a 1995
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9621731