Related Experiment Video
Updated: Oct 7, 2026
Isolation and Cellular Phenotyping of Mesenchymal Stem Cells Derived from Synovial Fluid and Bone Marrow of Minipigs
Published on: July 2, 2016
[Renal excretion of methotrexate in an in vivo model in minipigs]
J Cermanová1, J Chládek, L Sispera
1Ustav farmakologie, Univerzita Karlova v Praze, Lékarská fakulta v Hradci Králové. cermanovaj@lfhk.cuni.cz
Abstract:
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).
Insights
The minipig model effectively mimics human renal excretion of high-dose methotrexate (HDMTX), showing clearance is influenced by urine pH and glomerular filtration. This supports its use in preclinical drug development.
Area of Science:
- Pharmacology
- Nephrology
- Preclinical Research
Context:
- High-dose methotrexate (HDMTX) is primarily renally excreted in humans.
- Understanding the mechanisms of renal excretion is crucial for optimizing HDMTX therapy and preventing toxicity.
- The minipig model offers a potential human-like preclinical platform for studying drug disposition.
Purpose:
- To evaluate the suitability of the minipig model for preclinical assessment of renal excretion of HDMTX.
- To investigate the relationship between methotrexate clearance, glomerular filtration, and urine pH in minipigs.
- To determine the correlation between renal and extrarenal clearance of methotrexate.
Summary:
- Methotrexate (MTX) is renally excreted via glomerular filtration and active tubular transport.
- In minipigs, renal clearance of MTX was significantly higher than inulin clearance (a marker for glomerular filtration).
- Significant correlations were observed between MTX clearance and urine pH, as well as glomerular filtration rate.
- MTX renal clearance ranged from 1.36 to 3.2 ml/min/kg across different urine pH levels.
- A strong relationship was found between renal and extrarenal MTX clearance.
Impact:
- The minipig model demonstrates high fidelity in replicating human-like renal excretion of HDMTX.
- Findings highlight the critical role of urine pH and glomerular filtration in modulating MTX renal clearance.
- This study validates the minipig as a valuable preclinical tool for investigating MTX pharmacokinetics and informing clinical strategies.
