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High-dose methotrexate in children with acute lymphoblastic leukemia: 7-hydroxymethotrexate systemic exposure and urinary concentrations at the steady state correlate well with those of methotrexate
J. Chládková, J. Hak, J. Martínková, J. Chládek
Jazyk angličtina Země Německo
Typ dokumentu časopisecké články, práce podpořená grantem
Odkazy
PubMed
21265469
DOI
10.1055/s-0031-1296353
Knihovny.cz E-zdroje
- MeSH
- analýza rozptylu MeSH
- antimetabolity antitumorózní krev farmakokinetika moč MeSH
- dítě MeSH
- intravenózní infuze MeSH
- lidé MeSH
- lymfoblastická leukemie-lymfom z prekurzorových T-buněk metabolismus MeSH
- methotrexát analogy a deriváty krev farmakokinetika moč MeSH
- mladiství MeSH
- plocha pod křivkou MeSH
- poločas MeSH
- předškolní dítě MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The present study evaluated the pharmacokinetics of methotrexate (MTX, CAS 59-05-2) and 7-hydroxymethotrexate (7-OHMTX, CAS 5939-37-7) in children with acute lymphoblastic leukemia (ALL) with particular interest devoted to the renal excretion at the steady-state and to the relationships between total (CL) and renal clearances (CL(R)) of both compounds. Ten children (seven girls) aged 8.5 years (2.9-16) years with standard or medium-risk ALL received four 24-h i.v. infusions of high-dose MTX (HDMTX, 5 g/m2) with leucovorin (CAS 58-05-9) rescue according to the ALL-BFM-95 protocol. MTX and 7-OHMTX were assayed in plasma and urine by high-performance liquid chromatography. At the steady-state, the clearance (CL) of MTX (6.28 +/- 2.79 l h(-1)) was correlated with its CL(R) (r(s) = 0.79, p < 0.0001) which accounted for 61% (SD 26%) of the former. There were weak correlations between pretreatment values of creatinine clearance calculated using Schwartz's formula and the drug's CL (r(s) = 0.30, p < 0.05) or CLR (r(s) = 0.41, p < 0.02). In contrast, the CL(R) accounted for only 26% (SD 15%) of the metabolite's CL which was estimated assuming 10% conversion of MTX to 7-OHMTX. The CL values of both compounds were highly correlated (r(s) = 0.86, p < 0.0001). The CL(R) of the parent compound was on the average 9-fold higher (range: 3.5- to 17-fold) and was strongly correlated with the CL(R) of the metabolite (r(s) = 0.87, p < 0.0001). The ratio 7-OHMTX/MTX of urinary concentrations was between 2.4 and 9.8% with the mean value of 4.1%. This study suggests that during the 24-h i.v. infusions of HDMTX to children with ALL, the exposure of patients to 7-OHMTX can be reasonably well predicted from the knowledge of MTX concentrations. The steady-state renal CLs, total CLs as well as urinary concentrations of the parent compound and metabolite are highly correlated and the correlation of plasma concentrations is moderate. Therefore, it is unlikely that simultaneous evaluation of 7-OHMTX and MTX steady-state concentrations could improve the predictive performance of the latter towards the response or the risk of complications, although future larger studies should verify this conclusion.
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- $a Chládková, Jiřina, $d 1963- $7 xx0076213 $u Department of Paediatrics, Charles University in Prague, Faculty of Medicine and Hospital, Hradec Králové, Czech Republic
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- $a High-dose methotrexate in children with acute lymphoblastic leukemia: 7-hydroxymethotrexate systemic exposure and urinary concentrations at the steady state correlate well with those of methotrexate / $c J. Chládková, J. Hak, J. Martínková, J. Chládek
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- $a The present study evaluated the pharmacokinetics of methotrexate (MTX, CAS 59-05-2) and 7-hydroxymethotrexate (7-OHMTX, CAS 5939-37-7) in children with acute lymphoblastic leukemia (ALL) with particular interest devoted to the renal excretion at the steady-state and to the relationships between total (CL) and renal clearances (CL(R)) of both compounds. Ten children (seven girls) aged 8.5 years (2.9-16) years with standard or medium-risk ALL received four 24-h i.v. infusions of high-dose MTX (HDMTX, 5 g/m2) with leucovorin (CAS 58-05-9) rescue according to the ALL-BFM-95 protocol. MTX and 7-OHMTX were assayed in plasma and urine by high-performance liquid chromatography. At the steady-state, the clearance (CL) of MTX (6.28 +/- 2.79 l h(-1)) was correlated with its CL(R) (r(s) = 0.79, p < 0.0001) which accounted for 61% (SD 26%) of the former. There were weak correlations between pretreatment values of creatinine clearance calculated using Schwartz's formula and the drug's CL (r(s) = 0.30, p < 0.05) or CLR (r(s) = 0.41, p < 0.02). In contrast, the CL(R) accounted for only 26% (SD 15%) of the metabolite's CL which was estimated assuming 10% conversion of MTX to 7-OHMTX. The CL values of both compounds were highly correlated (r(s) = 0.86, p < 0.0001). The CL(R) of the parent compound was on the average 9-fold higher (range: 3.5- to 17-fold) and was strongly correlated with the CL(R) of the metabolite (r(s) = 0.87, p < 0.0001). The ratio 7-OHMTX/MTX of urinary concentrations was between 2.4 and 9.8% with the mean value of 4.1%. This study suggests that during the 24-h i.v. infusions of HDMTX to children with ALL, the exposure of patients to 7-OHMTX can be reasonably well predicted from the knowledge of MTX concentrations. The steady-state renal CLs, total CLs as well as urinary concentrations of the parent compound and metabolite are highly correlated and the correlation of plasma concentrations is moderate. Therefore, it is unlikely that simultaneous evaluation of 7-OHMTX and MTX steady-state concentrations could improve the predictive performance of the latter towards the response or the risk of complications, although future larger studies should verify this conclusion.
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