title: Diurnal variation of methotrexate disposition in children with acute leukaemia.
abstract: There is recent evidence that survival is improved when maintenance therapy for acute lymphocytic leukaemia in children is given at night. We have examined the possibility that diurnal variation in methotrexate pharmacokinetics may contribute to this improvement. In 6 children with leukaemia there was a significant fall in methotrexate plasma clearance at night (from 5.6 to 4.7 ml.kg-1.min-1). Renal clearance of methotrexate tended to fall at night and unbound renal clearance fell significantly (from 17.5 to 8.5 ml.min-1.kg-1 P less than 0.05). Creatinine clearance did not exhibit diurnal variation, whereas there was a significant fall in the non-glomerular clearance of methotrexate (from 14.8 to 6 ml.min-1.kg-1). Since methotrexate is a weak organic acid, its tubular secretion depends on urinary pH. At night urinary pH is more acidic, and this may result in more reabsorption and hence reduced renal clearance.
authors.affiliation: Division of Clinical Pharmacology, Hospital of Sick Children, Toronto, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Ferrazzini
authors.forename: H
authors.initials: H
authors.lastname: Sohl
authors.forename: I
authors.initials: I
authors.lastname: Robieux
authors.forename: D
authors.initials: D
authors.lastname: Johnson
authors.forename: E
authors.initials: E
authors.lastname: Giesbrecht
authors.forename: G
authors.initials: G
authors.lastname: Koren
mesh_terms: D000208:Acute Disease; D002648:Child; D002675:Child, Preschool; D002940:Circadian Rhythm; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007938:Leukemia / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D008727:Methotrexate