Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic leukaemia.

OBJECTIVE: The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n.58881. RESULTS: After 1 month of oral treatment at a dose of 50 mg.m-2.day-1, the pharmacokinetic parameters were determined after the first i.v. administration of 1 g.m-2 (bolus dose of 0.2 g.m-2 followed by an 8-h infusion of 0.8 g.m-2) in 11 patients: systemic clearance was 23.02 1.h-1, volume of distribution was 0.75 l.kg-1, and elimination half-life was 1.64 h. The erythrocyte thioguanine concentrations were measured in the same 11 patients and increased significantly between the beginning and the end of infusion (10 pmol x 10(8) packed RBC) or within 24 h of infusion (223 pmol x 10(8) packed RBC). The CSF concentration was 3.78 mumol.1(-1), 1-6 h after the beginning of infusion (n = 28) and the CSF to plasma ratio was 0.15 (n = 16). In patients receiving the oral dose of 50-165 mg.m-2.day-1 of 6-mercaptopurine, CSF concentrations were below 0.18 mumol.1(-1), 1-24 h after drug intake (n = 67), and the CSF to plasma ratio was not calculated. CONCLUSION: Following the i.v. administration of 6-mercaptopurine, we observed high CSF concentrations of 6-mercaptopurine and an acute increase of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n[symbol: see text]5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. administration reduces the incidence of CNS relapses.

Cranial irradiation and cerebrospinal fluid levels of 6-mercaptopurine in children with acute leukemia.

We measured 6-mercaptopurine levels in the cerebrospinal fluid and plasma of 15 children undergoing treatment for acute leukemia. Plasma and cerebrospinal fluid samples obtained by lumbar puncture were collected before, during, and after cranial irradiation in order to evaluate a possible change in blood-brain barrier permeability to orally administered 6-mercaptopurine. Considerable interpatient variability has been observed in both plasma and cerebrospinal fluid 6-mercaptopurine levels. No statistical differences in the 6-mercaptopurine cerebrospinal fluid levels under the three different conditions could be detected. Our data suggest that cranial irradiation does not significantly influence the cerebrospinal fluid levels.

HPLC analysis of 6-mercaptopurine and metabolites in extracellular body fluids.

A convenient HPLC assay, which allows for the simultaneous measurement in extracellular fluids of 6-mercaptopurine and four of its metabolites, 6-thioguanine, 6-mercaptopurine riboside, 6-thioxanthine and 6-thiouric acid is described. Solid phase extraction allows for the clean isolation of analytes from plasma, urine or cerebrospinal fluid. The simultaneous determination of 6-mercaptopurine and some of its major metabolites in extracellular fluids may contribute to the monitoring of patient compliance, bioavailability, and individual variation in metabolism and absorption.

6-Mercaptopurine in cerebrospinal fluid during oral maintenance therapy of children with acute lymphoblastic leukemia.

In three children receiving oral remission maintenance therapy for acute lymphoblastic leukemia, the concentrations of 6-mercaptopurine (6-MP) in cerebrospinal fluid (CSF), plasma and red blood cells were compared. CSF samples were obtained from an Ommaya reservoir previously inserted for treatment of CNS relapse. At the time of the study, the children were all in remission and had been on oral 6-MP (42-63 mg m-2) once daily for at least 24 weeks. Immediately before dose intake on the day of study (about 24 h after last dose), the concentrations of 6-MP in CSF, plasma and red blood cells were rather similar and below 20 ng ml-1 in all patients. After dose intake, the concentrations in plasma and in red blood cells increased to 40-200 ng nl-1 within 0.5-4 h. In contrast, the concentration of 6-MP in the CSF remained fairly constant around 4-10 ng ml-1 throughout the time period studied (up to 4 h). It is concluded that 6-MP can be detected in CSF during oral maintenance therapy and that the drug has different pharmacokinetic profile in CSF to that in plasma and red blood cells. Further studies are necessary to evaluate the significance of the 6-MP concentrations obtained in CSF for the prevention of CNS relapse.

6-mercaptopurine: high-dose 24-h infusions in goats.

In vitro investigations have indicated the need for both prolonged exposure to 6-mercaptopurine (6MP) and the use of high concentrations to achieve maximal cell kill. After the customary oral administration the bioavailability of 6MP appeared to be low, and i.v. bolus injections resulted in short-lived high concentrations of 6MP, so prolonged infusions seemed rational. To test the feasibility of this approach 24-h infusions were given to goats. We used our improved HPLC method to quantitate 6MP and 6MP riboside (6MPR) in plasma, CSF, and urine. The concentrations of 6MPR were in excess of those of 6MP. Since 6MPR can easily be converted to 6MP, 6MPR acts as a depot for 6MP. Penetration of both 6MP and 6MPR into CSF was excellent. Of the total dose administered, 38% to 68% could be accounted for in the urine, with about equal amounts of 6MP and 6MPR. At doses of 20 and 10 mg kg-1 h-1 total concentrations of 6MP and 6MPR in excess of 100 microM were reached during 24-h infusions. However, all three experimental animals died due to toxicity. A dose of 2 mg kg-1 h-1 was tolerated; the total steady state concentration of 6MP and 6MPR in two experiments was about 10 microM. We conclude that the prolonged infusion of 6MP is feasible, and in view of the excellent penetration of 6MP and 6MPR into CSF, studies using prolonged infusions of thiopurines are warranted in man.

Kinetic model for disposition of 6-mercaptopurine in monkey plasma and cerebrospinal fluid.

The antipurine 6-mercaptopurine (6-MP) is effective in the induction and maintenance of remission in patients with acute lymphocytic leukemia. This report presents a compartmental model that describes the kinetics of 6-MP in the plasma and cerebrospinal fluid (CSF) of the monkey. Analysis is based on simultaneously measured plasma and CSF 6-MP concentrations after intravenous and intraventricular bolus administration. Results indicate that 6-MP administered intraventricularly remains largely in the CSF. Disappearance of 6-MP from CSF is principally due to convective losses at a rate equivalent to CSF turnover. Diffusion of 6-MP across the ependymal surface accounts for only 7% of the 6-MP appearing in the plasma. Conversely the dominant route for entry of 6-MP into the CSF from the plasma is entrainment in choroidally formed CSF. Only 12% of 6-MP in the CSF after intravenous administration can be accounted for by permeation of cerebral capillaries and diffusion through brain parenchyma and across the ependymal surface into CSF. These results indicate that the choroid plexus is not a significant barrier for the transfer of molecules like 6-MP from plasma to CSF.

Pharmacokinetics of 6-mercaptopurine (6MP) in the monkey. I. Disposition from plasma and cerebrospinal fluid following iv bolus.

The disposition profile of 6-mercaptopurine (6MP) was studied from plasma and cerebrospinal fluid (CSF) in the rhesus monkey following a single iv bolus dose (4 mg/kg). A new, sensitive, and specific high performance liquid chromatography procedure has been employed for drug quantitation in biological fluids. An equation consisting of three exponential terms was simultaneously fitted to the 6MP plasma and CSF concentration vs. time data using the SAAM 27 digital computer program. 6MP in plasma and CSF had a mean half-life (t1/2, lambda z) of 2.9 hr and an apparent volume of distribution (Vd, lambda z) of 3.00 liter/kg. Estimates of total body clearance average 0.731 +/- 0.412 liter/hr/kg and ranged between 0.446 and .1204 liter/hr/kg. In the postdistributive phase, the decline of 6MP concentration from the CSF paralleled plasma. The t1/2, lambda z obtained by fitting Ccsf vs. t data separately was not significantly different (p greater than 0.2) than the one obtained above in a simultaneous fitting of the data. Therefore, it appears that the unbound 6MP concentration in plasma may be the driving force in the diffusion of the drug into CSF. Comparison of experimental CSF/plasma ratio of 6MP with the theoretical values obtained using the pH-partition hypothesis is also discussed.