Document Detail

Chronopharmacology of methotrexate pharmacokinetics in childhood leukemia.
MedLine Citation:
PMID:  1473196     Owner:  NLM     Status:  MEDLINE    
Survival has been shown to improve when maintenance therapy for acute lymphocytic leukemia in children is given at night rather during the day. We examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In a crossover study, we determined the pharmacokinetics of intravenous methotrexate at 10:00 and 21:00 h in six children with standard or high-risk leukemia. During the study, children refrained from concomitant drugs (6-mercaptopurine and trimethoprim sulfamethoxazole). There was a significant fall in methotrexate plasma clearance at night (from 5.6 +/- 3 ml/min/kg to 4.7 +/- 2.3 ml/min/kg p < 0.05). Renal clearance of methotrexate tended to decrease at night and unbound renal clearance decreased significantly (from 17.5 +/- 1.7 ml/min/kg to 8.5 +/- 3.6 ml/min/kg p < 0.05). Creatinine clearance did not exhibit diurnal variation, when comparing two 12-h collections, but there was a significant decrease in the nonglomerular clearance of methotrexate (from 14.8 +/- 5.2 to 6 +/- 4 ml/min/kg). Because it is a weak organic acid, the tubular secretion of methotrexate depends on urinary pH. At night urinary pH is more acidic. This may result in more reabsorption and hence reduced renal clearance.
G Koren; G Ferrazzini; H Sohl; I Robieux; D Johnson; E Giesbrecht
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chronobiology international     Volume:  9     ISSN:  0742-0528     ISO Abbreviation:  Chronobiol. Int.     Publication Date:  1992 Dec 
Date Detail:
Created Date:  1993-02-01     Completed Date:  1993-02-01     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8501362     Medline TA:  Chronobiol Int     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  434-8     Citation Subset:  IM    
Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, Ontario, Canada.
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MeSH Terms
Child, Preschool
Circadian Rhythm*
Drug Administration Schedule
Kidney / metabolism
Metabolic Clearance Rate
Methotrexate / administration & dosage,  pharmacokinetics*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy,  metabolism*
Reg. No./Substance:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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