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).

Ustav farmakologie Univerzita Karlova Praha Lékarská fakulta v Hradci Králové

Renal excretion of methotrexate in an in vivo model in minipigs

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$a Renální exkrece MTX v modelu in vivo u miniprasete / $c J. Cermanová, J. Chládek, L. Sispera, J. Martínková,

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$a Renal excretion of methotrexate in an in vivo model in minipigs

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$a 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).

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