Renal excretion and pharmacokinetics of methotrexate and 7-hydroxy-methotrexate following a 24-h high dose infusion of methotrexate in children

Abstract

In children with lymphoid malignancies 18 courses of methotrexate (18-200 mg/kg) administered as a 24-h infusion were monitored. Plasma concentrations and renal excretion rates of methotrexate (MTX) and 7-hydroxymethotrexate (7-OHMTX) were determined. A low correlation was found between the administered dose of MTX and the body exposure to MTX or 7-OHMTX. Although 84% of the MTX eventually recovered from the urine was excreted during the 24 h of the infusion, the renal clearance of MTX was markedly lower during the time of the infusion than after it. There were courses with a low and others with a high renal clearance of MTX during the infusion, despite the same urine flow. A low MTX renal clearance was correlated with a high body exposure to MTX. As the same variations were also seen in the same patient during successive courses, pharmacokinetical characterization of patients appears questionable. The renal clearance of 7-OHMTX was significantly lower than the renal clearance of MTX, and the body exposure to 7-OHMTX ranged from 2-40% of the MTX body exposure. Treatment courses with a low or a high body exposure to 7-OHMTX were not associated with different urinary recoveries of the metabolite. Differences in MTX hydroxylation could not be substantiated. Because the concentration of 7-OHMTX is high soon after the end of an infusion, a specific method of MTX determination should be chosen for controlling treatment.

Aldehyde Oxidase-catalysed Oxidation of Methotrexate in the Liver of Guinea-pig, Rabbit and Man

“…In conclusion, even though we have shown that, in-vitro, liver aldehyde oxidase from man catalyses the oxidation of methotrexate to 7-hydroxymethotrexate, turnover is low. During high-dose therapy 33% of the parent drug is (Ertmann et al 1985;Winograd et al 1986). Despite this, aldehyde oxidase is responsible for some of this conversion; perhaps the closely related xanthine oxidase is also responsible for the formation of 7-hydroxymethotrexate.…”

“…After high-dose therapy with the folate antagonist, methotrexate (10-methyl-4-pteroyl-L-glutamic acid), serum levels of its major metabolite, 7-hydroxymethotrexate, can be up to 100 times those of the parent drug, and up to 33% of the dose is excreted as 7-hydroxymethotrexate (Ertmann et al 1985;Winograd et al 1986). However, the metabolic origins of 7-hydroxymethotrexate, at least in man, are unclear.…”

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

“…Inthe caseof7-OHMTX, itwasassumed that10%ofthe MTX dosewastransformedintothe metabolite. Asimilarapproachwasu sed in apopulation studyw ithadult cancerpatients [22].Itiss upported bymeasurements of the cumulativeexcretiono fMTX and 7-OHMTXin adults withsolid cancers [23], in children withl ymphoid malignancies [12]a s well asbyour measurementof the cumulativerecovery of the dosei nurine collected upto1 20 hi ntwop atients (65% and 55 %asMTX, and 8% and 9% as7 -OH MTX, respectively). Totalclearanceatt he steady-statewascalculated asfollows: CL =R/c ss whereRisthe rateofthe infusion and c ss isthe steady-statep lasmac oncentration.…”

“…Population pharmacokinetica nalysishas notbeen performed yetin children withALL and older studiesdo notr eport the kineticsof 7-OHMTX in sufficientdetail. Furthermore,onlyfewstudiesexamined the renalexcretion of MTX and 7-OH MTX in children treated withHDMTX [12].…”

Methotrexate renal clearance by low-dose dopamine in severe nephrotoxicity

“…2,3 One patient receiving low-dose dopamine 2-3 mg/kg bw/min infusion. Dopamine at ''renal'' dosage is a known glomerular vasodilator, that reduce resistances and improves renal blood flow.…”