Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration

We evaluated the delivery of C-14-cytosine arabinoside (AraC) to rat brain by: 1) intravenous (IV) bolus, by 2) intrathecal (IT) and 3) intraventricul ar (NT) infusion, and by 4) convection-enhanced delivery (CED) into the cau date nucleus. Plasma and brain AraC metabolites were measured with HPLC, an d distribution and concentration of C-14-AraC in brain sections were measur ed by quantitative autoradiography. After IV administration, the alpha and beta plasma half-lives were 1.9 and 46.5 min, respectively. The blood-to-br ain transfer constant of AraC was 2.5 +/- 1.4 mu l g(-1) min(-1), compatibl e with high water solubility. After IT and IVT administration, tissue level s were high at the brain and ventricular surfaces, but declined exponential ly into brain. After CED, maximum brain levels were up to 10,000 times high er than the IV group, and the distribution pattern was one of high C-14-Ara C concentration in the convective component, with exponentially declining c oncentrations outside this region. The rate loss constant from brain was 0. 002 +/- 0.0004 min(-1), suggesting that AraC was accumulating in brain cell s. AraC was metabolized into uracil arabinoside within the brain. C-14-AraC was infused into 1 dog and distributed widely in the ipsilateral hemispher e. These studies suggest that delivery of AraC to brain parenchyma by the I V, IT or IVT routes will be subtherapeutic. Delivery by CED can achieve, an d maintain, therapeutic levels of AraC in the brain, and should be further evaluated as a potential method of drug delivery. (C) 2000 Published by Els evier Science B.V. All rights reserved.