Summary
Cytosine arabinoside (ara-C) is a component of many protocols for the treatment of CNS (central nervous system) leukemia and lymphoma in humans and dogs. It is also used for the prophylaxis of CNS metastasis in acute lymphoblastic leukemia. Although ara-C enters the cerebrospinal fluid (CSF) of human cancer patients after i.v. administration, it is unclear whether a similar CNS distribution occurs in humans whose blood-brain barrier has not been compromised by invasive disease. No information on the penetration of ara-C into the CSF in dogs is available. We studied the plasma and CSF pharmacokinetics of 600 mg/m2 ara-C in ten healthy male dogs after its administration as a rapid i.v. bolus (six dogs) or as a 12-h i.v. infusion (four dogs). Ara-C concentration in blood and CSF samples was determined by high-performance liquid chromatography (HPLC). After an i.v. bolus of ara-C, the mean plasma distribution half-life was 7.1±4.5 min and the mean elimination half-life was 69±28 min. The mean plasma clearance was 227±125 ml min−1 m−2. The peak concentration of ara-C in the CSF was 29±11 μm, which occurred at 57±13 min after the ara-C bolus. The CSF elimination half-life was 113±26 min. During a 12-h infusion of ara-C (50 mg m−2 h−1), the plasma steady-state concentration was 14.1±4.2 μm, the CSF steady-state concentration was 8.3±1.1 μm, and the CSF: plasma ratio was 0.62±0.14. The plasma eleimination half-life was 64±19 min and the plasma clearance was 214±69 ml min−1 m−2. The CSF elimination half-life was 165±28 min. No clinically significant toxicity was observed over a 21-day period following drug administration in either of the treatment groups. Our data indicate that ara-C crosses the blood-brain barrier in normal dogs and that i.v. administration of this drug has potential as a treatment modality for neoplasia involving the CNS.
Similar content being viewed by others
References
Avramis VI, Weinberg KI, Sato JK, Lenarsky C, Willoughby ML, Coates TD, Ozkaynak MF, Parkman R (1989) Pharmacology studies of 1β-d-arabinofuranosylcytosine in pediatric patients with leukemia and lymphoma after a biochemically optimal regimen of loading bolus plus continuous infusion of the drug. Cancer Res 49: 241–247
Band PR, Holland JF, Bernard J, Weil M, Walker M, Rall D (1973) Treatment of central nervous system leukemia with intrathecal cytosine arabinoside. Cancer 32: 744–748
Breithaupt H, Pralle H, Eckhardt T, Von Hattingberg M, Schick J, Loffler H (1982) Clinical results and pharmacokinetics of high-dose cytosine arabinoside (HD ARA-C). Cancer 50: 1248–1257
Capizzi RL, Yang JL, Cheng E, Bjornsson T, Sahasrabudhe D, Tan RS, Cheng Y-C (1983) Alteration of the pharmacokinetics of high-dose ara-C by its metabolite ara-U in patients with acute leukemia. J Clin Oncol 1: 763–771
Champlin R, Ho W, Winston D, Decker R, Greenberg P, Burnison M, Holly FE, Gale RP (1987) Treatment of adults with acute myelogenous leukemia: prospective evaluation of high-dose cytarabine in consolidation chemotherapy and with bone marrow transplantation. Semin Oncol 14: 1–6
Couto CG, Cullen J, Pedroia V, Turrel JM (1984) Central nervous system lymphosarcoma in the dog. J Am Vet Med Assoc 184: 809–813
Crow SE (1982) Lymphosarcoma (malignant lymphoma) in the dog: diagnosis and treatment. Compend Cont Educ Pract 4: 283–289
Damon LE, Linker CA (1989) Comparison of plasma and cerebrospinal fluid pharmacokinetics of high-dose versus intermediatedose cytosine arabinoside (abstract). Proceedings, Annual Meeting of the American Society of Clinical Oncologists, 8, p 267
DeLoach JR, Barton C (1982) Circulating carrier erythrocytes: slow-release vehicle for an antileukemic drug, cytosine arabinoside. Am J Vet Res 43: 2210–2212
Early AP, Preisler HD, Slocum H, Rustum YM (1982) A pilot study of high-dose 1-β-d-arabinofuranosylcytosine for acute leukemia and refractory lymphoma: clinical response and pharmacology. Cancer Res 42: 1587–1594
Ellens H, Rustum Y, Mayhew E, Ledesma E (1982) Distribution and metabolism of liposome-encapsulated and free 1-β-d-arabinofuranosylcytosine (ara-C) in dog and mouse tissues. J Pharmacol Exp Ther 222: 324–330
Frick J, Ritch PS, Hansen RM, Anderson T (1984) Successful treatment of meningeal leukemia using systemic high-dose cytosine arabinoside. J Clin Oncol 2: 365–368
Fulton DS, Levin VA, Gutin PH, Edwards MSB, Seager ML, Stewart J, Wilson CB (1982) Intrathecal cytosine arabinoside for the treatment of meningeal metastases from malignant brain tumors and systemic tumors. Cancer Chemother Pharmacol 8: 285–291
Gale RP (1979) Advances in the treatment of acute myelogenous leukemia. N Engl J Med 300: 1189–1199
Hande KR, Stein RS, McDonough DA, Greco FA, Wolff SN (1982) Effects of high-dose cytarabine. Clin Pharmacol Ther 31: 669–674
Harris AL, Potter C, Bunch C, Boutagy J, Harvey DJ, Grahame-Smith DG (1979) Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia. Br J Clin Pharmacol 8: 219–227
Herman TS, Hammond N, Jones SE, Butler JJ, Byrne GE, McKelvey EM (1979) Involvement of the central nervous system by non-Hodgkin's lymphoma. Cancer 43: 390–397
Ho DHW, Frei E III (1971) Clinical pharmacology of 1-β-d-arabinofuranosylcytosine. Clin Pharmacol Ther 12: 944–954
Ho DHW, Carter CJK, Loo TL, Abbott RL, McBride CM (1975) Pharmacologic studies of cyclocytidine and arabinosylcytosine in dogs. Drug Metab Dispos 3: 309–313
Hoff HE, Deavers S, Huggins RA (1966) Effects of hypertonic glucose and mannitol on plasma volume. Proc Soc Exp Biol Med 122: 630–634
Law IP, Blom J (1977) Adult acute leukemia. Frequency of central nervous system involvement in long term survivors. Cancer 40: 1304–1306
Perlow L, Ohnuma T, Andrejczuk A, Shafir M, Strauchen J, Holland JF (1985) Pharmacology and toxicology of a seven-day infusion of 1-β-d-arabinofuranosylcytosine plus uridine in dogs. Cancer Res 45: 2572–2577
Regazzi MB, Rondanelli R, Morra E, Lazzarino M, Alessandrino EP, Bernasconi C (1989) Ara-C pharmacokinetics in meningeal leukemia treatment (abstract). J Chemother Infect Dis Malig 1 [Suppl 1]: 279
Rohrig KE (1983) Acute myelomonocytic leukemia in a dog. J Am Vet Med Assoc 182: 137–141
Rustum YM, Riva C, Preisler HD (1987) Pharmacokinetic parameters of 1-β-d-arabinofuranosylcytosine (ara-C) and their relationship to intracellular metabolism of ara-C, toxicity, and response of patients with acute non-lymphocytic leukemia treated with conventional and high-dose ara-C. Semin Oncol 14 [Suppl 1]: 141–148
Slevin ML, Piall EM, Aherne GW, Johnston A, Lister TA (1982) The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high-dose therapy. Med Pediatr Oncol 10 [Suppl 1]: 157–168
Spriggs DR, Robbins G, Arthur K, Mayer RJ, Kufe D (1988) Prolonged high-dose ara-C infusions in acute leukemia. Leukemia 2: 304–306
Stewart DJ, Keating MJ, McCredie KB, Smith TL, Youness E, Murphy SG, Bodey GP, Freirich EJ (1981) Natural history of central nervous system acute leukemia in adults. Cancer 47: 184–196
Stewart DJ, Hugenholtz H, DaSilva V, Benoit B, Richard M, Russell N, Maroun J, Verma S (1987) Cytosine arabinoside plus cisplatin and other drugs as chemotherapy for gliomas. Semin Oncol 14: 110–115
Sullivan MP (1982) Use of cytosar in pediatric acute myelocytic leukemia and leukemic meningitis. Med Pediatr Oncol 10 [Suppl 1]: 193–200
Sweet DL, Golomb HM, Ultman JE, Miller JB, Stein RS, Lester EP, Mintz U, Bitran JD, Streuli RA, Daly K, Roth NO (1980) Cyclophosphamide, vincristine, methotrexate with leucoverin rescue and cytarabine (COMLA) combination sequential chemotherapy for advanced diffuse histiocytic lymphoma. Ann Intern Med 92: 785–790
Theilen GH, Worley M, Benjamini E (1977) Chemoimmunotherapy for canine lymphosarcoma. J Am Vet Med Assoc 170: 607–610
Van Prooijen R, Van der Kleijn E, Haanen C (1977) Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia. Clin Pharmacol Ther 21: 744–750
Wang JJ, Pratt CB (1970) Intrathecal arabinosyl cytosine in meningeal leukemia. Cancer 25: 531–534
Weller RE, Theilen GH, Madewell BR (1982) Chemotherapeutic responses in dogs with lymphosarcoma and hypercalcemia. J Am Vet Med Assoc 181: 891–893
Ziegler JL, Bluming AZ (1971) Intrathecal chemotherapy in Burkitt's lymphoma. BMJ 3: 508–512
Author information
Authors and Affiliations
Additional information
Supported by the Canine Disease Research Fund and in part by the Elsa U. Pardee Foundation
Rights and permissions
About this article
Cite this article
Scott-Moncrieff, J.C.R., Chan, T.C.K., Samuels, M.L. et al. Plasma and cerebrospinal fluid pharmacokinetics of cytosine arabinoside in dogs. Cancer Chemother. Pharmacol. 29, 13–18 (1991). https://doi.org/10.1007/BF00686329
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00686329