October 1990

Diurnal Variation in the Pharmacokinetics and Myelotoxicity of Mercaptopurine in Children With Acute Lymphocytic Leukemia

Author Affiliations

From the Divisions of Clinical Pharmacology (Dr Koren) and Hematology-Oncology (Drs Langevin, Olivieri, Zipursky, and Greenberg), Department of Pediatrics, the Department of Biochemistry (Ms Giesbrecht), and The Research Institute, The Hospital for Sick Children, Toronto, Departments of Pediatrics (Drs Koren, Olivieri, Zipursky, and Greenberg) and Pharmacology (Dr Koren), The University of Toronto, Canada.

Am J Dis Child. 1990;144(10):1135-1137. doi:10.1001/archpedi.1990.02150340081028

• During their maintenance therapy, children with acute lymphoblastic leukemia are treated with a daily dose of mercaptopurine for several years. A recent retrospective analysis has suggested that administration of the drug in the evening results in a better prognosis. We compared the disposition pharmacokinetics of mercaptopurine administered in the morning vs in the evening in 13 children with acute lymphoblastic leukemia. Elimination half-life of mercaptopurine was significantly longer in the evening than during the day (423 ±142 minutes vs 176 ± 22 minutes, mean ± SEM). The area under the concentration-time curve (AUC0-∞) was significantly larger in the evening (24713±3536 ng/mL per minute vs 17120±1474 ng/mL per minute). These differences were even more pronounced when comparing the area under the curve of the postdistributive phase (AUC300 mln.−∝ 7724 ± 2955 ng/mL per minute in the evening vs 2597 ± 712 ng/mL per minute during the day). In a second study, 12 children with acute lymphoblastic leukemia receiving mercaptopurine in the morning had their medication administration switched to the evening. Within 2 weeks there was a sharp fall in peripheral white blood cell counts in all patients (from 4.1 109/L to 2.2 - 109/L) mainly due to a drop in polymorphonuclear lymphocytes (from 2.78×109/L to 1.05×109/L). We conclude that the diurnal variations of mercaptopurine disposition result in clinically important myelotoxicity of the drug.

(AJDC. 1990;144:1135-1137)