PHARMACOKINETICS AND DISTRIBUTION OF 6-MERCAPTOPURINE ADMINISTERED INTRAVENOUSLY IN CHILDREN WITH LYMPHOBLASTIC-LEUKEMIA

Objective: The pharmacokinetics of 6-mercaptopurine, including cerebro spinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nuc leotide concentrations were determined in children randomised to recei ve intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n degrees 58881. Results: After 1 month of oral treatment at a dose of 50 mg . m(-2) . day(-1), the pha rmacokinetic parameters were determined after the first i.v. administr ation of 1 g . m(-2) (bolus dose of 0.2 g . m(-2) followed by an 8-h i nfusion of 0.8 g . m(-2)) in 11 patients: systemic clearance was 23.02 l . h(-1), volume of distribution was 0.75 l . kg(-1), and eliminatio n half-life was 1.64 h. The erythrocyte thioguanine concentrations wer e 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 concen tration was 3.78 mu mol . l(-1), 1-6 h after the beginning of infusion (n = 28) and the CSF to plasma ratio was 0.15 (n = 16), In patients r eceiving the oral dose of 50-165 mg . m(-2) . day(-1) of 6-mercaptopur ine, CSF concentrations were below 0.18 mu mol . l(-1) 1-24 h after dr ug intake (n = 67), and the CSF to plasma ratio was not calculated. Co nclusion: Following the i.v. administration of 6-mercaptopurine, we ob served high CSF concentrations of 6-mercaptopurine and an acute increa se of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n degrees 5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. admin istration reduces the incidence of CNS relapses.