Pharmacokinetics Of Cytosine Arabinoside Research Articles

Pharmacokinetics of cytosine arabinoside in cerebrospinal fluid and of its metabolite in leukemic cells

Concentrations of ara-CTP in leukemic cells isolated from CSF and of ara-C in lumbar CSF were measured following intraventricular ara-C administration in two girls with refractory meningeal leukemia. CSF samples were collected with a permanent intrathecal-lumbar catheter. In contrast to the comparatively short retention of ara-C in the CSF (t1/2 1.8 to 2.9 hours), there was a high accumulation and an extremely long retention of ara-CTP in the leukemic cells (t1/2 8.1 to 36 hours). The patients included in this study had an ara-C-resistant disease. No obvious relationship was seen between concentrations of ara-C in the CSF and of ara-CTP in the leukemic cells. Similar studies were performed after simultaneous intraventricular administration of hydrocortison and ara-C. Hydrocortison did not increase ara-CTP retention in the leukemic cells, nor did it effect CSF pleocytosis.

Use of the circuit simulation program SPICE2 for analysis of the metabolism of anticancer drugs

Complex networks of biological processes are analogous to electrical circuits. For each step in a biological or electrical network, flow is dependent on the driving force and the conductivity of the step. The relationship between biological flows and their driving forces can therefore be expressed as relationships between analogous currents and voltages. The time dependence of approach to equilibrium or a steady state is determined by the rates of depletion of material in various compartments. Electrical capacitance is therefore analogous to compartment volume. Once these generalized concepts of flow, force and capacitance are recognized, it becomes clear that computer programs designed for analysis of electrical circuits may be used for simulation of biological networks. A set of simple mathematical descriptions of the individual steps and a diagram showing how the steps are arranged with respect to each other are all that is necessary to perform a simulation; there is no need for computer programming skills or differential equations. The use of SPICE2 for simulation of the cellular and plasma pharmacokinetics of cytosine arabinoside (araC) is described as an example. A network model is developed which considers cellular pharmacokinetics (membrane transport, intracellular phosphorylation and dephosphorylation), and plasma pharmacokinetics following infusions of araC.

Central nervous system pharmacokinetics of high-dose cytosine arabinoside.

The cerebrospinal fluid (CSF) pharmacokinetics of cytosine arabinoside (Ara-C) was determined in 8 patients with metastatic cancer in the central nervous system. High dose (3 gm/M2) one-hour intravenous infusions of Ara-C were given with serial CSF sampling obtained from indwelling Ommaya reservoirs. CSF was analyzed by high pressure liquid chromatography. Mean Ara-C elimination half life of 140 minutes in CSF was eight times longer than that in plasma. The peak mean CSF concentration of Ara-C (2.1 micrograms /ml) was about 7% of the plasma concentration (30 micrograms/ml). A total of 28 treatment courses were administered with minimal hematopoietic, gastrointestinal and neurological toxicities. A schedule of administration of 2 high-dose treatments 12 hours apart repeated every two weeks should maintain cytotoxic CSF concentrations which could prove useful in the management of CNS leukemia and lymphoma.

The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high-dose therapy.

Subcutaneous bolus administration of cytosine arabinoside (Ara-C) has been used as an alternative to continuous intravenous infusion. However, the pharmacokinetics of subcutaneous bolus Ara-C have not been satisfactorily documented in man. The plasma concentrations of Ara-C were therefore compared following intravenous bolus injection, subcutaneous bolus injection, and intravenous infusion in five patients with acute myelogenous leukemia. A triphasic decline in plasma Ara-C levels was seen after intravenous bolus administration. Subcutaneous bolus Ara-C was rapidly absorbed (mean absorption half-life 3.4 ± minutes) and then declined biexponentially with initial and terminal half-lives similar to intravenous bolus injection. Ara-C concentrations were above the steadystate infusion levels for only 40 minutes following the intravenous bolus and for 100 minutes following subcutaneous bolus administration. The decline in plasma Ara-C concentrations continued rapidly following both these routes of administration and after five hours were approximately 10% of the steady-state infusion levels. This study demonstrates that it is not possible to achieve comparable steadystate levels of Ara-C with the same total dose given by twice or thrice daily subcutaneous bolus injection as by continuous intravenous infusion. High-dose Ara-C has been used to treat patients with relapsed acute leukemia resistant to Ara-C in conventional doses and may provide a means of overcoming such resistance. Significant concentrations of Ara-C are achieved in the cerebrospinal fluid (CSF) during conventional-dose intravenous infusions, and it seemed likely that much greater levels would be reached during these high-dose infusions. The pharmacokinetics of Ara-C in the plasma and CSF during high-dose intravenous infusions (1 g/m2) has therefore been investigated. Five patients were treated with a three-hour infusion preceded by a loading dose, and five patients received a one-hour infusion with no loading dose. The CSF Ara-C concentrations were similar during both infusions, and the concentrations in the CSF at the end of the infusions were higher than the plasma Ara-C levels obtained with intravenous infusion at conventional doses. In addition CSF Ara-C levels were measured in a patient with an Ommaya reservoir during intravenous infusion of 100 mg/m2 and 1 g/m2. It was demonstrated that Ara-C equilibrated rapidly betweenthe plasma and CSF and crossed the blood brain barrier as effectively at 1 g/m2 as at 100 mg/m2. Extrapolation of these data suggests that during therapy with high-dose Ara-C at a dose of 3 g/m2 12 hourly, Ara-C levels in the CSF in excess of 100 ng/ml (410 nmol/liter are likely to be maintained almost continuously, and should therefore be effective therapy for CNS leukemia.

Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia.

1 The pharmacokinetics of cytosine arabinoside were studied after a single i.v. bolus of 2 mg/kg ara-C in patients with newly diagnosed untreated AML, using a bioassay and GC-MS method to measure the plasma concentrations. 2 Most patients showed a bi- or tri-phasic decline in plasma concentrations with time. Plasma clearance was 3.9 to 18.1 l/min as measured by the GC-MS method, and terminal half-lives varied from 7--107 min. 3 There was poor correlation of the GC-MS assay with the bioassay, probably because the latter was interfered with by the release of endogenous nucleosides from blasts after after ara-C. 4 Plasma concentrations were measured by GC-MS during continuous infusions in 14 patients. Plasma clearances were much lower than after a bolus, 0.39 to 5.25 l/min. 5 There was no correlation of response (remission or fall in peripheral blast count) with exposure to ara-C calculated from infusion dose, clearance and duration of infusion. 6 This study shows that ara-C pharmacokinetics varies markedly from patient to patient and that there is a wide range in the plasma concentrations associated with therapeutic response.

Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia

In 14 patients with acute myeloid leukemia (AML) the plasma concentration of cytosine arabinoside (Ara-C) was determined at the start of the first course of treatment at various intervals after a bolus injection. In 10 patients plasma concentration/time data were fitted to a biexponential equation and pharmacokinetic parameters were estimated from the coefficient and exponents of such equations. The plasma half-life (t1/2) of Ara-C of the first phase varied from 1.2 to 1.9 min (mean 1.6). The t1/2 of the second phase varied from 8.8 to 18.9 min. All patients were treated with Ara-C alone in a dose of 100 mg/m2 for 10 or 14 days. There was poor treatment response in five patients with second-phase t1/2 of Ara-C ranging from 6.6 to 10.7 min whereas there was complete remission in nine patients with t1/2 exceeding 12.7 min. In three patients plasma Ara-C concentrations were measured during constant-rate infusion of different amounts of drug. It appeared that the plateau concentrations were directly proportional to the dose, which indicated that in the therapeutic range no enzyme capacity-limited elimination occurs.