RT Journal Article
SR Electronic
T1 Chiral Pharmacokinetics and Inversion of Enantiomers of a New Quinoxaline Topoisomerase IIβ Poison in the Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 344
OP 348
DO 10.1124/dmd.30.3.344
VO 30
IS 3
A1 Zheng, Hui
A1 Jiang, Chun
A1 Chiu, Ming H.
A1 Covey, Joseph M.
A1 Chan, Kenneth K.
YR 2002
UL http://dmd.aspetjournals.org/content/30/3/344.abstract
AB XK469 (NSC 697887; (±)-2-[4-(7-chloro-2-quinoxaliny)oxy]phenoxy propionic acid), an analog of the herbicide Assure, which possesses antitumor activity, especially against murine solid tumors and human xenografts, has recently been found to be the first topoisomerase IIβ poison. BothR(+) and S(−) isomers are cytotoxic, although the R-isomer is more potent. Using a chiral high-performance liquid chromatography assay, pharmacokinetics of R(+)-, S(−)-, and (±)-XK469 in Fischer-344 rats were investigated following their separate i.v. administrations. S(−)-XK469 was found to be predominantly converted to the R-isomer in circulation when the S-isomer was administered either alone or as a racemic mixture. No trace of the S-isomer was found in circulation or in urine or feces, following the R-isomer administration, up to 72 h. In the rat, the plasma concentration-time profiles for both isomers follow a two-compartment pharmacokinetics with the mean t1/2β for the R-isomer of 24.7 h being significantly longer than 4.2 h, the mean t1/2β for theS-isomer. The mean total clearance of theS-isomer was over 200-fold more rapid than that of theR-isomer, and the major clearance route of theS-enantiomer was inversion to its antipode, as estimated by the fractional formation clearance of R(+)-XK469 of 0.93. Protein binding for both enantiomers was in the range of 95 to 98%. Urinary and fecal elimination in 72 h as the intact drug were 7 to 10% and 8% of the administered dose, respectively, either administered as the individual enantiomers or as a racemate. Cumulative biliary elimination in 7 h was about 3% of the dose. No evidence of enantiomeric interaction at the pharmacokinetic level was detected. The American Society for Pharmacology and Experimental Therapeutics