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Influence of Tetrahydrouridine on the Pharmacokinetics of Intrathecally Administered 1-ß-D-arabinofuranosylcytosine

Pediatric Oncology Branch, Division of Cancer Treatment [R. R., D. L. G., D. G. P.], and Clinical Pharmacology Branch [B. C.], National Cancer Institute, Bethesda, Maryland 20205, and Division of Neurosurgery, Emory University Clinic, Atlanta, Georgia 30322 [J. W.]

Tetrahydrouridine (THU), a potent inhibitor of cytidine deaminase, has been shown to increase the antitumor activity of 1-ß-D-arabinofuranosylcytosine (ara-C) both in vitro and in vivo.

In initial studies, which examined the cerebrospinal fluid (CSF) pharmacokinetics of intrathecally (i.t.) administered THU, the drug was found to be slowly cleared from the CSF with and ß half-lives of 1 and 8 hr, respectively. In subsequent experiments, both i.v. pretreatment with THU and concomitant i.t. injection of THU were found to retard the disappearance of i.t. ara-C from the CSF, although the effect of i.t. THU was more profound.

ara-C given alone was cleared from CSF with and ß half-lives of 27.5 ± 6.7 and 115.6 ± 0.4 (S.D.) min, respectively. Pretreatment with i.v. THU resulted in and ß half-lives of 10.4 ± 1.5 and 85.7 ± 11.1, respectively, whereas concomitant administration of i.t. THU resulted in a single half-life of 96 ± 0.7. The mean calculated clearance rates for ara-C alone, ara-C plus i.v. THU, and ara-C plus i.t. THU were 7.5, 6.2, and 4.2 ml/hr, respectively. This effect appeared to be primarily due to THU inhibition of ara-C deamination, since a decrease in formation of 1-ß-D-arabinofuranosyluracil in the CSF was observed when ara-C was given in the presence of THU (either i.t. or i.v.). No acute neurotoxicity was noted after administration of either i.t. THU alone or i.t. THU with ara-C. The ability of THU to alter CSF ara-C pharmacokinetics may have potential therapeutic value.

¹ Present address: Department of Pediatrics, Catholic University of Rome, Largo A. Gemelli 8, Rome Italy.

² To whom requests for reprints should be addressed, at Building 10, Room (ACRF) 13C-103, NIH, Bethesda, Md. 20205.

Received 6/24/81. Accepted 12/31/81.