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

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 (AUC_0-∞) 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 (AUC^{300 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.