Pharmacokinetics of XXXX in intralipid following hepatic regional administration in rabbits.

@entity432 @entity11558 @entity28042
@entity11558 ( @entity28042 ) is a cytotoxic agent demonstrated to have broad antitumor activity. Poor solubility in aqueous media has precluded significant evaluation of parenteral administration of this drug. A formulation of @entity28042 dissolved in Intralipid has demonstrated excellent tolerance following parenteral administration. The goal of this study was to evaluate the pharmacology of @entity28042 in Intralipid following hepatic regional administration. The routes of administration were intraarterial via the hepatic artery with and without @entity432 , i.v. via the portal and jugular veins, and i.p. All animals received a total dose of 10 mg @entity28042 /kg of body weight. Hepatic extraction of @entity28042 was most evident via the portal vein (PV) route [AUC(PV)/AUC(i.v.) = 0.5; P less than 0.05]. Lower plasma levels and areas under the curve (AUCs) were observed for the hepatic artery and hepatic artery-stop flow groups when compared to i.v., but the difference was not significant. Administration i.p. yielded low plasma levels but a very long half-life (88 min). Hepatic tissue levels were highest in the group receiving @entity28042 by the hepatic artery-stop flow route. We conclude that the @entity28042 -Intralipid mixture is well tolerated, that @entity28042 is extracted to a significant degree by the liver following PV administration, and that an i.p. installation of @entity28042 -Intralipid results in prolonged plasma drug levels. This preclinical study supports further efforts at evaluation of parenteral administration of the @entity28042 -intralipid mixture.
