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.
- 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 goal of the study was to evaluate a minipig (i.e. porcine) model as the human like model for preclinical evaluation of mechanisms involved in the renal excretion of high-dose methotrexate (HDMTX). Methotrexate is in man renaly excreted in combination of glomerular filtration and active tubular drug transport (in a proximal tubule). After intravenous MTX administration, more than 95% of the amount of delivered dose was detected in urine in the form of intact MTX. To compare glomerular filtration and other ways of renal MTX excretion, the ratio between MTX clearance and clearance of inuline (which evaluate the rate of glomerular filtration only) was calculated and analyzed. Renal clearance of MTX was higher than that of inuline (Cl/Cl = 1.50 (0.095 ml/min.kg). The results showed a significant correlation between Cl and pH of urine (r = 0.525, r = 0.7243, p < 0.001, figure 1). Similar correlations were found when comparing the results of Cl and glomerular filtration (r = 0.8589, r = 0.8939, p < 0.00001) (figure 2). Significant relationship was also evident between Cl and urine pH and GF together (simultaneously) (r = 0.8677). The renal clearance of MTX varied from 1.36 ml/min.kg (measured at pH 6.0) to 3.2 ml/min.kg (measured at pH 7.0). Finally, the results indicate a significant relationship between the renal and extrarenal clearance MTX (r = 0.7227, p < 0.0001).
- MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- inulin diagnostické užití MeSH
- koncentrace vodíkových iontů MeSH
- ledviny metabolismus MeSH
- methotrexát farmakokinetika moč MeSH
- miniaturní prasata MeSH
- moč MeSH
- prasata MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
OBJECTIVE: The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months) after the start of antipsoriatic therapy. METHODS: Ten male and female psoriatic patients who failed to respond to previous conventional therapy were treated with 15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the same occasions, MTX accumulation in erythrocytes obtained before MTX administration was investigated. Pharmacodynamics of MTX were evaluated using the psoriasis area and severity index (PASI) score. RESULTS: There were marked intersubject differences (range of coefficients of variation 34.9-76.3%) in the area under the curve (AUC), peak concentration (Cmax) and clearance (CL) of MTX. Total CL was proportional to renal clearance (CLR) (r2 = 0.735, P < 0.0001) which accounted for 73 (19)% of the former. There was a strong linear relationship (r2 = 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of drug administration, the urinary excretion of MTX was 46-99% of the dose, while that of 7-OH MTX was 1.5-8.6%. In 8 of 10 patients, more than 70% of the MTX dose was recovered. No intraindividual variations of MTX kinetic parameters during treatment were observed. MTX concentrations in erythrocytes reached the steady-state concentration in the range 40.7-170 nmol.l(-1) after 2 months of therapy. Pharmacodynamic measurement versus pharmacokinetics revealed a significant inverse relationship between PASI score and MTX AUC (rs = -0.912, P < 0.002) and between PASI score and erythrocytic MTX (rs = -0.988, P < 0.002). CONCLUSION: The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration.
- MeSH
- časové faktory MeSH
- dermatologické látky aplikace a dávkování farmakokinetika krev moč MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- methotrexát aplikace a dávkování farmakokinetika krev moč MeSH
- psoriáza * farmakoterapie krev moč MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky MeSH
- práce podpořená grantem MeSH