National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Cytarabine
• 4-AMINO-1-BETA-D-ARABINOFURANOSYL-2(1H)-PYRIMIDINONE (9CI)
• CYTOSINE ARABINOSIDE

Human Toxicity Excerpts

• HUMAN EXPOSURE STUDIES: Limited information is available on the acute toxicity of conventional cytarabine. IV doses of cytarabine 4.5 g/sq m administered over 1 hr every 12 hours for 12 doses caused excessive toxicity, including irreversible CNS toxicity and death. single doses of cytarabine up to 3 g/sq m iv have been administered by rapid iv infusion without apparent toxicity. There is no known antidote for overdosage of conventional cytarabine. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 993]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: Cytarabine ... has been tested for toxicity to the cornea in ... human beings. A solution of 0.1% cytarabine hydrochloride applied six times a day for six to ten days was not injurious, but concn of 0.5% or more, caused reversible changes in the corneal epithelium. Some patients with normal corneas treated in this way for seven days developed glittering opacities in the lower layers of the epithelium, usually without stainability by fluorescein. Some had pain and developed signs of iritis. The severity was related to the concentration used and the time of exposure. After the applications were discontinued, all corneas cleared gradually during three weeks. A number of patients who have been treated systemically for leukemia or lymphoma with high doses have developed similar signs and symptoms, with punctate epithelial keratitis and photophobia in up to 46% of those treated with the drug intravenously. ... Topical corticosteroid treatment has been disappointing. The keratitis has usually cleared in 1 to 2 weeks without this treatment. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 301]**PEER REVIEWED**
  
• HUMAN EXPOSURE STUDIES: The occurrence of fatal or nearly fatal pulmonary insufficiency in 5/22 pediatric patients with relapsed acute myelogenous leukemia (AML) treated with high dose cytosine arabinoside (Ara-C) is reported. Ara-C (1.0-1.5 g/sq m/day) was given as a 5 day continuous infusion to all patients. Four patients with persistent leukemia received a second 3- or 5-day course. The POG protocol included the admin of granulocyte colony stimulating factor for the priming of myeloblasts. Diagnostic criteria for pulmonary insufficiency included noncardiogenic pulmonary edema with exclusion of underlying cardiorespiratory, infectious, or metabolic conditions. autopsy material also was reviewed. Of the 22 patients, 5 died (23%), including 2 who received a second course of Ara-C as a results of pulmonary insufficiency that developed at a median of 8 days (range, 3-38 days) after the first course. Three patients died despite intubation and pressor support. Two patients were managed successfully with colloids, diuresis, and oxygen by face mask; remission was achieved in both. The postmortem exam of one patient disclosed airless lungs, profound pulmonary edema, and subpleural nodules, but no evidence of leukemia. Pulmonary insufficiency from high dose Ara-C varies in severity and may be fatal. It may occur during or after treatment. Awareness of this potential complication, careful attention to fluid status, and aggressive supportive care may optimize outcome. [Shearer P et al; Cancer 74 (7): 1953-8 (1994) ]**PEER REVIEWED**
  
• SIGNS AND SYMPTOMS: A number of patients who have been treated systemically for leukemia or lymphoma with high doses have developed similar signs and symptoms, with punctate epithelial keratitis and photophobia in up to 46% of those treated with the drug intravenously. ... Topical corticosteroid treatment has been disappointing. The keratitis has usually cleared in 1 to 2 weeks without this treatment. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 302]**PEER REVIEWED**
  
• CASE REPORTS: This report describes a patient who developed symptoms, signs, and EKG evidence of pericarditis following treatment with high dose cytarabine. The patient had no clinical or echocardiographic evidence of infection or leukemic involvement of the pericardium. Isolated pericarditis assoc with high dose cytarabine has been rarely reported. This therapy is frequently used and, therefore, it seems prudent to alert physicians to this potential complication of cytarabine. [Reykdal S et al; Leuk Res 19 (2): 141-4 (1995) ]**PEER REVIEWED**
  
• CASE REPORTS: 2 deaths related to DepoCyt were reported. One patient died after developing encephalopathy 36 hours after an intraventricular dose of DepoCyt, 125 mg. This patient was receiving concurrent whole-brain irradiation and had previously received systemic chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil, as well as intraventricular methotrexate. The other patient received DepoCyt, 50 mg by the intraventricular route and developed focal seizures progressing to status epilepticus. This patient died approximately 8 weeks after the last dose of study medication. /Cytarabine liposome injection/ [Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 1143]**PEER REVIEWED**
  
• CASE REPORTS: A 43-yr old man was treated for refractory acute promyelocytic leukemia with a regimen of high dose cytosine arabinoside (Ara-C). He died after dysarthria, ophthalmoplegia, and severe cerebellar neurotoxicity developed. The postmortem exam revealed a peculiar subacute neuronopathy that involved preponderantly brain stem tegmental and spinal motor neurons. The neuronopathy was characterized by hypereosinophilic perikarya and karyolytic nuclei. The perikaryal changes resulted from accumulations of argyrophilic masses of filaments that stained positively with neurofilament antibodies and ultrastructurally were shown to be composed of bundles of intermediate filaments. This report indicated that Ara-C neurotoxicity, possibly aggravated in our patient by oliguric renal failure, is not confined to the cerebellum but involves cranial nerve and spinal motor neurons, which in turn may explain the cranial neuropathies that sometimes complicate the use of high-dose Ara-C therapy. [Vogel H, Horoupian D; Cancer 71 (4): 1303-8 (1993) ]**PEER REVIEWED**
  
• CASE REPORTS: A 51-year-old woman who was in complete remission from non-Hodgkin's lymphoma, developed a rapidly progressive dementia. Progressive multifocal leukoencephalopathy (PML) was diagnosed on the basis of a rising antibody titre to JC polyomavirus in cerebro-spinal fluid and serum and the presence of diffuse white matter changes on magnetic resonance imaging. She was treated initially with intravenous cytarabine and showed minimal improvement. Rapid improvement occurred when intrathecal cytarabine was added and the patient is in complete remission from both lymphoma and PML 20 months later. [O'Riordan T et al; J Infect 20 (1): 51-4 (1990) ]**PEER REVIEWED** PubMed Abstract
  
• CASE REPORTS: Dermatologic side effects of cytosine arabinoside (ara-C) are rare and most commonly occur after high-dose (more than 100 to 200 mg/sq m per day) therapy has been administered for several days. Although vascular reactions after combination chemotherapeutic regimens with ara-C have been anecdotally described, they have not been previously reported after single-agent chemotherapy with ara-C. Herein /the authors/ describe two patients with acute nonlymphoblastic leukemia in whom cutaneous small vessel necrotizing vasculitis developed after high-dose single-agent chemotherapy with ara-C. Cutaneous lesions developed 3 to 5 days after initiation of therapy and resolved spontaneously within a week after the chemotherapeutic regimen was completed. No evidence of systemic vasculitis was present in either patient. Prior experimental data have demonstrated a direct toxic effect of ara-C on endothelial cells, and this outcome may represent the underlying mechanism of vascular injury. [Ahmed I et al; Mayo Clin Proc 73 (3): 239-42 (1998) ]**PEER REVIEWED** PubMed Abstract
  
• CASE REPORTS: An 11-year-old Hispanic boy with acute myeloblastic leukemia developed symptoms of pseudotumor cerebri (headache, diplopia, photophobia, nausea, vomiting) after receiving chemotherapy including cytarabine. The patient improved after a lumbar puncture and treatment with prednisone and acetazolamide, and is now asymptomatic. Pseudotumor cerebri is a condition usually associated with obese women of child-bearing age. Case reports in pediatric patients are unusual. ... Most of the information on medication-induced pseudotumor cerebri is in the form of case reports. Different mechanisms for causing this condition have been offered for individual medications. Most of these explanations involve fluid imbalance or interference with the Na+/K+ adenosine triphosphatase pump. Controlled studies are difficult because this condition is an unpredictable and rare occurrence. Cytarabine has frequently been associated with neurologic toxicities, but few reports of pseudotumor cerebri can be found. The exact cause of pseudotumor cerebri in this patient is unknown, but cytarabine seems a likely cause. The mechanism by which cytarabine could cause this reaction is unclear. [Fort J, Smith L; Ann Pharmacother 33 (5): 576-8 (1999) ]**PEER REVIEWED** PubMed Abstract
  
• CASE REPORTS: A patient with acute cerebellar toxicity following systemic high-dose cytosine arabinoside (ara-C) 3 g/sq m/12 hr for secondary acute nonlymphocytic leukemia is reported. Initial symptoms of ataxia and dysarthria emerged at 30 g/sq m cumulative dose and persisted without improvement over a ten-week period. Recurrence and worsening of cerebellar symptoms followed further consolidation treatment with high-dose ara-C. Subsequent autopsy showed extensive Purkinje's cell damage in the lateral cerebellar hemispheres. Persistent severe toxicity can occur at total doses less than those generally recognized. [Dworkin L et al; J Clin Oncol 3 (5): 613-6 (1985) ]**PEER REVIEWED** PubMed Abstract
  
• EPIDEMIOLOGY STUDIES: The frequency and significance of central nervous system (CNS), ocular, and dermatologic toxicities associated with high-dose cytosine arabinoside (HDARA-C) infusions was evaluated. Patients were selected from one of three Southeastern Cancer Study Group protocols using HDARA-C 2-3 g/sq m body surface area (BSA) and their medical records were reviewed to identify and document the frequency of the toxicities. Those exhibiting CNS toxicity were compared across age, sex, race, previous standard-dose ARA-C or HDARA-C therapy, and infusion rate for toxicity occurrence. Statistical analysis was performed using Fisher's exact test with p less than 0.05. Of the 53 patients evaluated, 37.7% exhibited CNS, 37.7% ocular, and 45.3% dermatologic toxicities. Of the risk factors evaluated, only increasing age and previous ARA-C therapy approached statistical significance. The CNS toxicities associated with HDARA-C are clinically significant since permanent damage may result. Ocular and dermatologic toxicities usually resolve without medical intervention when HDARA-C therapy is discontinued. Further study is necessary to determine appropriate prophylaxis for these toxicities. [Graves T, Hooks M; Pharmacotherapy 9 (1): 23-8 (1989) ]**PEER REVIEWED** PubMed Abstract
  
• Patients who receive myelosuppressive drugs experience an increased frequency of infections (e.g., viral, bacterial, fungal) as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs. ...Treatment with cytarabine should be initiated only with extreme caution in patients with preexisting drug-induced bone marrow suppression. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 992]**PEER REVIEWED**
  
• Severe, sometimes fatal, pulmonary toxicity has occurred in patients receiving high-dose regimens of conventional cytarabine. Pneumonia and shortness of breath have been reported in patients receiving conventional cytarabine. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 991]**PEER REVIEWED**
  
• Blindness occurred in 2 leukemic patients in remission who had received systemic combination chemotherapy, prophylactic CNS irradiation, and intrathecal cytarabine. Necrotizing leukoencephalopathy also occurred in 5 children who had received intrathecal cytarabine, methotrexate, and hydrocortisone sodium succinate and CNS irradiation. The manufacturer states that administration of cytarabine both IV and intrathecally within a period of a few days may be associated with an increased risk of neurotoxicity (i.e., spinal cord toxicity). Progressive ascending paralysis, resulting in death in one patient, occurred in 2 children 4-6 months after receiving intrathecal and IV cytarabine at conventional doses in combination with other drugs and CNS irradiation. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 991]**PEER REVIEWED**
  
• Anaphylaxis with acute cardiopulmonary arrest which required resuscitation occurred in one patient immediately after IV administration of the drug. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 922]**PEER REVIEWED**
  
• Severe and sometimes fatal CNS, GI, and pulmonary toxicity, which differs from that seen with usual dosages, has been associated with high-dose† cytarabine regimens for refractory or secondary acute leukemia or refractory non-Hodgkin's lymphomas. Adverse effects associated with these regimens include cerebral and cerebellar dysfunction (e.g., somnolence, coma, personality changes), which are usually reversible; hemorrhagic conjunctivitis and reversible corneal toxicity (e.g., keratitis), which may be minimized or prevented by prophylaxis with ophthalmic corticosteroid preparations; one case of syndrome of inappropriate secretion of antidiuretic hormone (SIADH); severe GI ulceration, including pneumatosis cystoides intestinalis leading to peritonitis; bowel necrosis; necrotizing colitis; sepsis and liver abscess; liver damage with increased hyperbilirubinemia; pericarditis with tamponade; and pulmonary edema. Reversible, acute aseptic meningitis, combined with cerebellar dysfunction, has been reported in at least 1 patient. Rarely, severe rash leading to desquamation has occurred. Complete alopecia occurs more commonly with high-dose regimens than with usual dosage regimens of the drug. A syndrome of sudden respiratory distress, rapidly progressing to pulmonary edema and radiographically pronounced cardiomegaly and which was sometimes fatal, has been reported in patients with refractory acute leukemia receiving high-dose therapy. Cases of cardiomyopathy with subsequent death also have been reported in patients receiving high-dose cytarabine in combination with cyclophosphamide in preparation for bone marrow transplantation; this cardiac toxicity may be schedule dependent. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 992]**PEER REVIEWED**
  
• Chemical arachnoiditis, a syndrome manifested primarily by nausea, vomiting, headache, and fever has been a common adverse event in all studies. If left untreated, chemical arachnoiditis may be fatal. The incidence and severity of chemical arachnoiditis can be reduced by coadministration of dexamethasone. Patients receiving DepoCyt should be treated concurrently with dexamethasone to mitigate the symptoms of chemical arachnoiditis. Infectious meningits may be associated with intrathecal drug administration. Hydrocephalus has also been reported, possibly precipitated by arachnoiditis. /Cytarabine liposome injection/ [Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 1143]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• LABORATORY ANIMALS: Acute Exposure: Single subconjunctival injections of 37.5 mg/kg in rabbits have caused an inflammatory response in the conjunctiva lasting less than 24 hours, without disturbance of other parts of the eye. [Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 302]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Ara-c ip admin in pregnant rats on day 11 produced preaxial polydactyly (87.9%) and on day 12 or 13 led to oligodactyly formation (day 12, 57.3%; day 13, 86.8%) in the hindlimb. However, the repeated treatments on 2 days 11 and 12 or 11 and 13 not only converted the polydactyly-inducing effect into the oligodactyly-inducing effect, but also reduced (49.2%, on days 11 and 12) or incr (100%, on days 11 and 13) the incidence of total digital malformations compared with that of single treatment on day 11, 12, or 13. This might be due to the different susceptibility of the ectodermal and mesodermal cells to the teratogen, because the stage of cellular differentiation was different between the ectoderm and the mesoderm of the hindlimb bud. [OKAGAWA T ET AL; SENTEN IJO 22 (2): 161 (1982) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Correlations were observed between the necrotic patterns induced by cytosine arabinoside in fetal mouse limb buds (when the drug was given ip to the pregnant mothers and the results observed 6-54 hr later) and the skeletal defects observed in full-term fetuses submitted to the same treatments. The drug exerted its deleterious effect on limb morphogenesis by causing abnormal cell death within the undifferentiated limb bud mesoderm. Observations after the teratogenic treatment suggested the final skeletal pattern observed in full-term fetuses was the result of a compromise between the number of dead mesodermal cells and the regulatory capacities of the remaining healthy mesoderm. [ROOZE M; PROG CLIN BIOL RES 110 (LIMB DEV REGENER, PT A): 365 (1983) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Pregnant Jcl:ICR mice were given a single ip dose of 2.5, 5, or 10 mg/kg cytosine arabinoside (Ara-C) on day 9.5 or 10.5 of gestation (gd). The treatment groups consisted of over 20 animals per group. The dams were killed on gd 18 and live fetuses were examined for digit anomalies. Oligodactyly of the hindlimbs was most frequent in male fetuses at the 10 mg/kg Ara-C dose on gd 9.5. In the 5 mg/kg Ara-C group treated on gd 10.5, oligodactyly of the forelimbs were observed more frequently in male fetuses, while polydactyly occurred more frequently in female fetuses. [Goto T, Endo A; Teratology 35:35-40 (1987) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Slc:SD rats on day 10.5 of gestation were explanted and cultured in rat serum containing Ara-C /1-beta-D-arabinofuranosylcytosine/ (5-10 ug/mL) for 48 hr. Rabbit embryos of the Japanese White strain on day 9 or 10 of gestation were explanted and cultured in rabbit serum containing Ara-C (0.03-1.0 or 3-30 ug/mL) or Ara-U /1-beta-D-arabinofuranosyluracil/ (1.0 or 30 ug/mL) for 48 or 24 hr. Cultured rat embryos exposed to Ara-C showed abnormalities of the head (malformations of the telencephalon, mesencephalon and rhombencephalon), mandible and limb bud, and short tail. Growth parameters, such as crown-rump length, head length, protein content and somite number, were reduced with increasing conc of Ara-C. In the rabbit, embryos cultured from day 9 of gestation for 48 hr showed abnormalities of the head (telencephalon, rhombencephalon), mandible and limb bud with Ara-C at 0.1 ug/mL and higher conc. Conc-dependent decreases in crown-rump length, head length and protein content were observed. the findings in embryos cultured from day 10 of gestation were similar to those in embryos cultured from day 9. Ara-U produced no detectable abnormalities in embryos ... These results indicate that Ara-C has teratogenicity in vitro that is similar in both rat and rabbit embryos. [Ninomiya H et al; Toxicology In Vitro 8 (1): 109-16 (1994) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: Pregnant mice of the Jcl:ICR strain were injected ip with a single dose of 5 mg/kg of cytosine arabinoside (Ara-C) on gestation day 10.5. Skeletal changes of the forepaw and hindpaw were evaluated in the offspring on the 15th or 24th postnatal day. Various anomalies of carpal and tarsal bones such as fusion, absence, and deformation occurred at high incidence at a dose that produced digital anomalies. Almost all newborns with Ara-C-induced digital anomalies (oligodactyly or polydactyly) had anomalies of carpal or tarsal bones could occur in the presence or absence of digital anomalies. Carpal and tarsal bone anomalies may become a sensitive and novel parameter of limb development in the postnatal teratogen testing system. [Rahman M et al; Reprod Toxicol 8 (1): 41-7 (1994) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: ICR female mice were housed under a controlled light/dark cycle of 12 hr ... Females were paired with a male for 1 hr from 0200 to 0300. The pregnant mice were injected ip with a single dose of 5 mg/kg of Ara-C on gestation day (dg) 10 at either 0800, 1100, 1400, or 1700 ... All mice were killed at 1000 on dg 17. After laparotomy, implantation sites were counted and live fetuses were removed, sexed, weighed, and examined for digit malformations. During the 9-hr period studied, the incidence of oligodactyly of both the forelimbs and the hindlimbs incr gradually, while the incidence of polydactyly in hindlimbs decreased gradually, when the time of the treatment grew later. At dg 10, development of digits in mouse embryos was very stage-specific, and the sensitivity of digit formation to Ara-C seemed to change even hourly. Conversely, the patterns of Ara-C-induced digit malformation can be used as sensible markers to speculate on the developmental stage of the embryos. [Ishikawa H et al; Teratology 44 (6): 10B (1991) ]**PEER REVIEWED**
  
• LABORATORY ANIMALS: Developmental or Reproductive Toxicity: 1-beta-D-Arabinofuranosylcytosine (Ara-C) ... was evaluated for developmental toxicity in pregnant Swiss mice. Ara-C was admin by ip inj on gestational days 6-15 at doses of 0, 0.5, 2, and 8 mg/kg/day. Maternal observations incl clinical signs, body weight change, food consumption, and gross evaluation of organs and uterine contents at necropsy (day 18). Live fetuses were examined for external, visceral, and skeletal alterations. Maternal toxicity was observed at 2 and 8 mg/kg/day, as evidenced by a significant decr in body weight gain and food consumption during the treatment period. Significantly incr early and late resorptions and reduced number of live fetuses per liter as well as decr fetal body weight were observed at 8 mg/kg/day. At 2 mg/kg/day, the incidence of cleft palate, renoureteral agenesis or hypoplasia, and poly- or oligodactyly was significantly incr, whereas fetal weight was reduced at 0.5 mg/kg/day. Thus, the developmental NOAEL of Ara-C in the pregnant mouse is lower than 0.5 mg/kg/day, while the NOAEL for maternal toxicity is 0.5 mg/kg/day. We believe that exposure to this agent ought to be avoided during organogenesis. [Ortega, A et al; Teratology 44 (4): 379-84 (1991) ]**PEER REVIEWED**
  
• GENOTOXICITY: No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with DepoCyt. The active ingredient of DepoCyt, cytarabine, was mutagenic in in vitro tests and was clastogenic in vitro (chromosome aberrations and SCE in human leukocytes) and in vivo (chromosome aberrations and SCE assay in rodent bone marrow, mouse micronucleus assay). Cytarabine caused the transformation of hamster embryo cells and rat H43 cells in vitro. Cytarabine was clastogenic to meiotic cells; a dose-dependent increase in sperm-head abnormalities and chromosomal aberrations occurred in mice given IP cytarabine. /Cytarabine liposome injection/ [Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 1144]**PEER REVIEWED**
  
• ALTERNATIVE and IN VITRO TESTS: A single dose of ara-c injected to mice triggers differentiation and initiation of DNA synthesis in quiescent splenic CFU-S (pluripotent hemopoietic stem cells). The accelerated differentiation which precedes proliferation is preferentially oriented toward erythropoiesis at the expense of granulopoiesis. Thus, CFU-S of the spleen behave in an identical manner to bone marrow CFU-S. Therefore, splenic CFU-S do not in any way counterbalance bone marrow CFU-S perturbations and thus contribute to the efforts of hemopoietic restoration after drug treatment in mice. [SAINTENY F ET AL; LEUK RES 5 (4-5): 373 (1981) ]**PEER REVIEWED**
  
• IMMUNOTOXICITY: Administration of repeated high doses of cytarabine to normal C57BL/6 mice causes a depression of in vitro cytotoxic T-cell development against allogeneic tumor cells. This low cytotoxic T-cell response occurs in the absence of a decrease in the number of cytotoxic T-cell precursor cells. Apparently, cytarabine removes a helper cell required for interleukin II formation. [MERLUZZI VJ ET AL; CANCER TREAT REP 66 (3): 535 (1982) ]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Mouse ip 3779 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 289]**PEER REVIEWED**
  
• LD50 Mouse oral 3150 mg/kg [Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 289]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• Less than 20% of a dose of conventional cytarabine is absorbed from the GI tract, and the drug is not effective when administered orally. Following subcutaneously or im injection of conventional cytarabine H 3, peak plasma concentrations of radioactivity occur within 20-60 min and are considerably lower than those attained after iv administration. Continuous iv infusions of conventional cytarabine produce relatively constant plasma concn of the drug in 8-24 hr. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 993]**PEER REVIEWED**
  
• Cytarabine is rapidly and widely distributed into tissues and fluids, including liver, plasma, and peripheral granulocytes. Following rapid IV injection of cytarabine in one study, approximately 13% of the drug was bound to plasma proteins. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 993]**PEER REVIEWED**
  
• Cytarabine crosses the blood-brain barrier to a limited extent. During a continuous IV or subcutaneous infusion, cytarabine concentrations in the CSF are higher than those attained after rapid IV injection and are about 40-60% of plasma concentrations. Most of an intrathecal dose of cytarabine diffuses into the systemic circulation but is rapidly metabolized and usually only low plasma concentrations of unchanged drug occur. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 993]**PEER REVIEWED**
  
• The drug apparently crosses the placenta. It is not known if cytarabine or ara-U is distributed into milk. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 993]**PEER REVIEWED**
  
• Cytarabine and ara-U are excreted in urine. After rapid IV, IM, subcutaneous, or intrathecal injection or continuous IV infusion of cytarabine, about 70-80% of the dose is excreted in urine within 24 hours. Approximately 90% of the urinary drug excretion occurs as ara-U and about 10% as unchanged cytarabine. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 994]**PEER REVIEWED**
  
• The pharmacokinetics of DepoCyt administered intrathecally to patients at a 50 mg dose every 2 weeks is currently under investigation. However, preliminary analysis of the pharmacokinetic data show that following DepoCyt intrathecal administration in patients, in either the lumbar sac or by intraventricular reservoir, peak levels of free cytarabine were observed within 5 hours in both the ventricle and lumbar sac. /Cytarabine liposome injection/ [Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 1143]**PEER REVIEWED**
  
• While on therapy for acute myeloid leukemia, a 15-yr old girl developed extensive punctate keratitis of both eyes following high dose cytarabine therapy (HD-Ara-C). Pharmacokinetic monitoring showed an increase of the Ara-C plasma levels up to twice the steady-state level within 10 minutes after discontinuation of the Ara-C infusion. Calculations of Ara-C plasma half-life, plasma clearance and volume of distribution were within the expected range. Owing to the short half-life of Ara-C in blood due to rapid deamination, varying infusion velocities will result in markedly varying plasma levels. Higher peak plasma levels lead to proportionally higher diffusion into compartments like tears, aqueous humor and cerebrospinal fluid. In compartments which lack noteworthy deaminase activity, dose intensity will be much more enhanced than in plasma. Peak plasma levels, therefore, may be assoc with multifold local toxicity without concurrent increase of hematological toxicity. Esp when the drug is given in small volumes of infusion, these considerations should be taken into account. Precise control of infusion parameters and application of artificial tears for dilution of the Ara-C conc on the corneal surface should be part of keratitis prophylaxis. [Boos J et al; Int J Clin Pharmacol Ther Toxicol 31 (12): 593-6 (1993)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• Cytarabine is rapidly and extensively metabolized mainly in the liver but also in kidneys, GI mucosa, granulocytes, and to a lesser extent in other tissues by the enzyme cytidine deaminase, producing the inactive metabolite 1-ß-d-arabinofuranosyluracil (ara-U, uracil arabinoside). After the initial distribution phase, more than 80% of the drug in plasma is present as ara-U. In the CSF, only minimal amounts of cytarabine are converted to ara-U because of low CSF concentrations of cytidine deaminase. Intracellularly, cytarabine is metabolized by deoxycytidine kinase and other nucleotide kinases to cytarabine triphosphate, the active metabolite of the drug. Cytarabine triphosphate is inactivated by a pyrimidine nucleoside deaminase, which produces the uracil derivative. [McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 994]**PEER REVIEWED**
  
• The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U (1-(beta)-D-arabinofuranosyluracil or uracilarabinoside), followed by urinary excretion of ara-U. In contrast to systemically administered cytarabine, which is rapidly metabolized to ara-U, conversion to ara-U in the CSF is negligible after intrathecal administration because of the significantly lower cytidine deaminase activity in the CNS tissues and CSF. The CSF clearance rate of cytarabine is similar to the CSF bulk flow rate of 0.24 mL/min. /Cytarabine liposome injection/ [Physicians Desk Reference 61st ed, Thomson PDR, Montvale, NJ 2007., p. 1143]**PEER REVIEWED**
  
• Cytarabine must be converted to the 5'-monophosphate nucleotide by deoxycytidine kinase to be active. Ara-cytidine diphosphate &/or ara-cytidine triphosphate are presumably the form that inhibit DNA polymerase & block ribonucleoside diphosphate reductase. [Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982., p. 792]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.