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 administration 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 methotrexate or 6-mercaptopurine administered in the morning (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 microM.h following the morning dose and 2.77 microM.h in the evening. For 6-mercaptopurine, the mean morning AUC (198 ng.h/ml) was higher than that following the evening dose (167 ng.h/ml) (p greater than 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.
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
F M
FM
Balis
S L
SL
Jeffries
B
B
Lange
R F
RF
Murphy
K M
KM
Doherty
C A
CA
Arndt
N
N
Luery
D G
DG
Poplack
D000284:Administration, Oral; D002648:Child; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D006801:Humans; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism
D015122:Mercaptopurine; D008727:Methotrexate