Chronopharmacokinetics of oral methotrexate and 6-mercaptopurine: Is there diurnal variation in the disposition of antileukemic therapy?

The chronopharmacokinetics of the orally administered antileukemic drugs, 6-mercaptopurine and methotrexate, were examined in 13 children with acute lymphoblastic leukemia (ALL) to establish if there is a pharmacokinetic basis for the lower relapse rate associated with adminis-tration of these agents in the evening. Children with ALL in complete remission had plasma drug concentrations monitored for 8 h following an oral dose of either meth-otrexate or 6-mercaptopurine administered in the morn-ing (8 a.m.) and the evening (8 p.m.). Total drug exposure to oral methotrexate, as measured by the mean area under the plasma concentration-time curve (AUC), was 2.75 p.M o h following the morning dose and 2.77 p.M o h in the evening. For 6-mercaptopurine, the mean morning AUC (198 ng o h/ml) was higher than that following the evening dose (167 ng o h/ml) (p > 0.05); but compared to the wide interpatient variability observed with this drug, this 20% difference is not likely to be clinically significant. These results indicate that the suggested benefit of evening drug administration is not likely to be a result of diurnal variation in drug disposition.