Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-β-D-arabinofuranosylcytosine in nonhuman primates

J. A. Lopez, G. P. Beardsley, J. G. Krikorian, R. W. Mortara, R. P. Agarwal

Research output: Contribution to journalArticle

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Abstract

The pharmacokinetics of 1-β-D-arabinofuranosylcytosine (ara-C) in plasma, cerebrospinal fluid (CSF), and urine was studied in nonhuman primates. Conventional and high-dose schedules of ara-C were administered i.v. and intraventricularly through indwelling Ommaya reservoirs. ara-C and its metabolite 1-β-D-arabinofuranosyluracil (ara-U) were measured by high-pressure liquid chromatography. Due to rapid peripheral deamination (230 nm ara-C/hr/ml plasma), the half-life of ara-C in plasma after a 140-mg/kg i.v. 1-hr infusion was short (3.7 min). Peak plasma concentrations of ara-C, ranging between <0.1 and 49 μg/ml, were dose dependent (ara-C, 15 to 140 mg/kg). Under these conditions, ara-C was undetectable in CSF. About 53% of the administered dose (140 mg/kg) was excreted in urine during the first 5 hr mostly as ara-U. Intraventricular administration of 50 and 250 mg of ara-C resulted in peak lumbar CSF levels of 435 and 2235 μg/ml, respectively, at about 155 and 80 min postinjection. Concomitant ara-U levels were one-tenth of those of ara-C and increased progressively, suggesting deamination of the drug in the central nervous system. The half-life of ara-C in CSF ranged between 50 and 60 min. Administration of 50 mg of ara-U intraventricularly resulted in peak lumbar ara-U levels of 595 μg/ml at about 180 min with a prolonged clearance. Concomitant plasma levels throughout the study were less than 0.1 μg/ml, suggesting slower equilibrium. No hematological or nervous system toxicity was observed during these studies. The clinical implications of these findings are discussed.

Original languageEnglish
Pages (from-to)5190-5193
Number of pages4
JournalCancer Research
Volume43
Issue number11
StatePublished - Dec 1 1983
Externally publishedYes

Fingerprint

Cytarabine
Primates
Cerebrospinal Fluid
Pharmacokinetics
Arabinofuranosyluracil
Deamination
Half-Life
Urine
Central Nervous System Agents
Nervous System
Appointments and Schedules
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lopez, J. A., Beardsley, G. P., Krikorian, J. G., Mortara, R. W., & Agarwal, R. P. (1983). Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-β-D-arabinofuranosylcytosine in nonhuman primates. Cancer Research, 43(11), 5190-5193.

Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-β-D-arabinofuranosylcytosine in nonhuman primates. / Lopez, J. A.; Beardsley, G. P.; Krikorian, J. G.; Mortara, R. W.; Agarwal, R. P.

In: Cancer Research, Vol. 43, No. 11, 01.12.1983, p. 5190-5193.

Research output: Contribution to journalArticle

Lopez, JA, Beardsley, GP, Krikorian, JG, Mortara, RW & Agarwal, RP 1983, 'Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-β-D-arabinofuranosylcytosine in nonhuman primates', Cancer Research, vol. 43, no. 11, pp. 5190-5193.
Lopez JA, Beardsley GP, Krikorian JG, Mortara RW, Agarwal RP. Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-β-D-arabinofuranosylcytosine in nonhuman primates. Cancer Research. 1983 Dec 1;43(11):5190-5193.
Lopez, J. A. ; Beardsley, G. P. ; Krikorian, J. G. ; Mortara, R. W. ; Agarwal, R. P. / Cerebrospinal fluid and plasma pharmacokinetics of high doses of 1-β-D-arabinofuranosylcytosine in nonhuman primates. In: Cancer Research. 1983 ; Vol. 43, No. 11. pp. 5190-5193.
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abstract = "The pharmacokinetics of 1-β-D-arabinofuranosylcytosine (ara-C) in plasma, cerebrospinal fluid (CSF), and urine was studied in nonhuman primates. Conventional and high-dose schedules of ara-C were administered i.v. and intraventricularly through indwelling Ommaya reservoirs. ara-C and its metabolite 1-β-D-arabinofuranosyluracil (ara-U) were measured by high-pressure liquid chromatography. Due to rapid peripheral deamination (230 nm ara-C/hr/ml plasma), the half-life of ara-C in plasma after a 140-mg/kg i.v. 1-hr infusion was short (3.7 min). Peak plasma concentrations of ara-C, ranging between <0.1 and 49 μg/ml, were dose dependent (ara-C, 15 to 140 mg/kg). Under these conditions, ara-C was undetectable in CSF. About 53{\%} of the administered dose (140 mg/kg) was excreted in urine during the first 5 hr mostly as ara-U. Intraventricular administration of 50 and 250 mg of ara-C resulted in peak lumbar CSF levels of 435 and 2235 μg/ml, respectively, at about 155 and 80 min postinjection. Concomitant ara-U levels were one-tenth of those of ara-C and increased progressively, suggesting deamination of the drug in the central nervous system. The half-life of ara-C in CSF ranged between 50 and 60 min. Administration of 50 mg of ara-U intraventricularly resulted in peak lumbar ara-U levels of 595 μg/ml at about 180 min with a prolonged clearance. Concomitant plasma levels throughout the study were less than 0.1 μg/ml, suggesting slower equilibrium. No hematological or nervous system toxicity was observed during these studies. The clinical implications of these findings are discussed.",
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