title: Early recognition of patients with decreased methotrexate clearance following high-dose methotrexate infusion therapy.
abstract: The purpose of this study was to identify the patients with decreased methotrexate (MTX) clearance as early as possible after the start of high-dose methotrexate (HD-MTX) infusion. Fifty-six patients (age: 18 approximately 83 years) received a HD-MTX infusion (dosage: 1.9 approximately 3.8 g/m2) for 6 h. These patients were retrospectively divided into a low-clearance group and a high-clearance group based on the serum MTX concentration at 48 h (1 microM). Six out of the 56 patients showed decreased MTX clearance. The MTX concentrations in the low-clearance group were significantly higher than those in the high-clearance group even in earlier sampling times than at 48 h. The average MTX concentrations were 330 microM at 6 h, 72 microM at 12 h, and 16 microM at 24 h in the low-clearance group, and those in the high-clearance group were 210 microM, 18 microM, and 1.0 microM, respectively. The estimated elimination half-lives (t1/2) at 6 approximately 12 h and 12 approximately 24 h after the start of the infusion were also significantly longer in the low-clearance group (2.8 vs. 1.7 h and 5.0 vs. 2.8 h, respectively). Therefore, we proposed convenient criteria based on the mean + 1 S.D. of the high-clearance group: the concentration > 270 microM at 6 h and > 32 microM at 12 h; the t1/2 value > 2.1 h at 6-12 h. All 6 patients were recognized as belonging to the low-clearance group at an early stage after HD-MTX infusion by using our proposed criteria. These results indicate that patients with decreased MTX clearance could be identified within the first 12 h after the start of HD-MTX infusion. The factors influencing the prolonged elimination of MTX were also investigated. A significant decrease in renal function on day 2 was observed in the low-clearance group. The MTX level at 12 h and the estimated t1/2 values were significantly correlated with BUN, Scr and Clcr on the 2nd day after HD-MTX therapy, suggesting that an alteration in renal function occurs within 12 h of the HD-MTX infusion. The prolonged elimination of MTX could be attributable to this decrease in renal function.
authors.affiliation: Department of Pharmaceutical Services, Hiroshima University Hospital, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Kihira
authors.forename: N
authors.initials: N
authors.lastname: Kuwata
authors.forename: S
authors.initials: S
authors.lastname: Arai
authors.forename: Y
authors.initials: Y
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Miyake
authors.forename: T
authors.initials: T
authors.lastname: Kitaura
authors.forename: K
authors.initials: K
authors.lastname: Fujimura
authors.forename: A
authors.initials: A
authors.lastname: Kuramoto
authors.forename: H
authors.initials: H
authors.lastname: Fukuchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000503:physiopathology; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate