title: The pharmacokinetics of reduced folates after intraperitoneal and intravenous administration of racemic [6S,R]-folinic acid.
abstract: We investigated the pharmacokinetics of tetrahydrofolates following the administration of [6S,R]-folinic acid and 5-flurouracil delivered i.v., i.p., and by a combination of both routes in patients with colon cancer. The concentrations of the biologically active tetrahydrofolates ([6S]-folinic acid and 5-methyltetrahydrofolate) and the relatively inert diastereomer [6R]-folinic acid were monitored using a selective on-line coupled achiral-chiral high-performance liquid chromatographic method. In plasma, a target concentration of 5 microM active tetrahydrofolates, which is considered necessary for an optimal synergistic effect, could be achieved after i.v. or combined i.v. and i.p. administration but was not reached in a patient receiving i.p. [6S,R]-folinic acid alone. In three patients receiving i.p. [6S,R]-folinic acid a high level of [6S]-folinic acid was observed in ascites, suggesting that the peritoneal cavity may act as a storage site for tetrahydrofolates after i.p. administration. In these patients, only a trace level of the active metabolite 5-methyltetrahydrofolate was detected in ascites, which may indicate that tetrahydrofolate derivatives penetrate only minimally, if at all, into the peritoneal cavity from the central compartment. These data would indicate that a combination of i.p. and i.v. administration may, from the pharmacological point of view, indeed contribute to an improved treatment of minimal residual disease persisting in the peritoneal cavity.
authors.affiliation: Department of Clinical Chemistry, Antoni van Leeuwenhoek Huis/The Netherlands Cancer Institute, Amsterdam.
authors.forename: J H
authors.initials: JH
authors.lastname: Sips
authors.forename: O
authors.initials: O
authors.lastname: van Tellingen
authors.forename: W J
authors.initials: WJ
authors.lastname: Nooijen
authors.forename: S
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: W J
authors.initials: WJ
authors.lastname: Ten Bokkel Huinink
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D001201:Ascites / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013237:Stereoisomerism
chemical_list: D002955:Leucovorin; D005472:Fluorouracil