The renal clearance of methotrexate (molecular weight 454 Da) was studied in 8 patients with normal renal function. Both urine flow rate and urine pH were found to change the renal clearances of methotrexate. Renal clearance increased with an increase in urine pH from 5.5 to 8.4. The renal clearance at normal urine pH was ~150 ml/min and the fraction unbound in plasma was 0.5.[Fill in the blank]
What do you expect to be the main mechanism/s of renal elimination of methotrexate?[Fill in the blank]
From this data, do you believe that methotrexate is a strong or weak acid or base? And why?[Fill in the blank]

Question

The renal clearance of methotrexate (molecular weight 454 Da) was studied in 8 patients with normal renal function. Both urine flow rate and urine pH were found to change the renal clearances of methotrexate. Renal clearance increased with an increase in urine pH from 5.5 to 8.4. The renal clearance at normal urine pH was ~150 ml/min and the fraction unbound in plasma was 0.5.[Fill in the blank]
What do you expect to be the main mechanism/s of renal elimination of ​methotrexate?[Fill in the blank]
From this data, do you believe that methotrexate is a strong or weak acid or base? And why?[Fill in the blank]

BlackTom AI · Accepted Answer

The question presents two fill-in-the-blank items based on the renal handling of methotrexate (MW 454 Da) in patients with normal renal function, noting that increasing urine pH from 5.5 to 8.4 increases renal clearance, the normal renal clearance is ~150 ml/min, and the fraction unbound in plasma is 0.5.

First blank — main mechanism(s) of renal elimination of methotrexate:
- The typical renal elimination of many small, polar drugs involves two key processes: glomerular filtration and tubular processes (secretion and/or reabsorption).
- Methotrexate has a molecular weight that allows glomerular filtration. However, the observation that increasing urine pH (alkalinization) increases renal clearance suggests an important role for active tubular secretion and differential reabsorption depending on ionization state.
- The most accurate combined mechanism is: glomerular filtration plus active tubular secretion with minimal tubular reabsorption. Glomerular filtration allows initial entry into the tubular fluid, and active tubular secretion (likely via organic anion transporters) removes methotrexate from the blood into the tubular lumen. Since tubular reabsorption would generally decrease with increased ionization (and MTX becomes more ionized in alkaline urine, reducing reabsorption), the net effect observed (higher clearance with higher pH) supports significant secretion with limited reabsorption.
- Why other possibilities are less consistent: if reabsorption were the dominant process, increasing urine pH would not necessarily increase clearance; if only filtration occurred, clearance would be close to the glomerular filtration rate (GFR) and less sensitive to pH; if only secretion occurred without filtration, the baseline clearance would differ and not align with the reported ~150 ml/min at normal pH.

Second blank — methotrexate as a strong or weak acid/base and why:
- The key observation is that renal clearance increases as urine pH rises (alkalinization). For acids, higher pH (more alkaline urine) increases ionization of the acid, reducing reabsorption and increasing excretion, which would increase clearance. For bases, higher pH would decrease ionization (or change ionization dynamics differently) and typically would not produce the same pattern as seen with MTX.
- Therefore, methotrexate behaves as a weak acid. The reasoning is that in alkaline urine, methotrexate becomes more ionized, making it less permeable across the renal tubule epithelium during reabsorption, thus increasing its tubular excretion and overall clearance.
- Alternative interpretations (e.g., if MTX were a weak base or a strong acid/base in a way inconsistent with the data) would not align with the observed increase in clearance with higher pH, which is characteristic of acid behavior in renal handling.
- In summary, the data support MTX acting as a weak acid, with enhanced clearance in alkaline urine due to reduced reabsorption from increased ionization and/or enhanced secretion under those conditions.

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