Chiral pharmacokinetics and inversion of enantiomers of a new quinoxaline topoisomerase IIbeta poison in the rat.
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 IIbeta poison. Both R(+) 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 t(1/2beta) for the R-isomer of 24.7 h being significantly longer than 4.2 h, the mean t(1/2beta) for the S-isomer. The mean total clearance of the S-isomer was over 200-fold more rapid than that of the R-isomer, and the major clearance route of the S-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.
Zheng
Hui
H
College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.
Jiang
Chun
C
Chiu
Ming H
MH
Covey
Joseph M
JM
Chan
Kenneth K
KK
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000737:chemistry; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D001798:Blood Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011810:Quinoxalines; D059005:Topoisomerase II Inhibitors; C118180:XK 469; D004250:DNA Topoisomerases, Type II