Do we know why the renal clearance of some drugs (e.g. memantine) is sensitive to the change in urine pH?
Memantine is a medication taken to slow the progression of moderate-to-severe Alzheimer’s disease. It is a basic (alkaline) and lipophilic (fat-liking) drug (pKa 10 and logP 3).
Once memantine is renally filtered in the kidney (at glomerulus), it can be reabsorbed back to the blood circulation along with obligatory water reabsorption in the kidney. This is because it is a small and lipophilic drug molecule.
However, it is important to remember that only the uncharged unionized memantine can be reabsorbed!
The percentages unionized memantine at both urine pH 5 and 8 are low (less than 1%). However, the percentage unionized at pH 8 is 1000-fold higher than at pH 5 (based on its pKa)!
Consequently, more unionized memantine is reabsorbed at pH 8, less is excreted, renal clearance is lower and hence the systemic exposure (AUC) is higher.
Conversely, less unionized memantine is reabsorbed at pH 5, more is excreted, renal clearance is higher and hence systemic exposure (AUC) is lower.
Isn’t this pharmacokinetic phenomenon amazing!
In summary, next time when we examine whether renal clearance of a given drug is potentially sensitive to urine pH, we need to pay attention to the FOLD-CHANGE in its UNIONIZED SPECIES.
Read also:
- Effects of pKa on the Biological Properties of Ionizable Drugs
- Hydrophilic and Hydrophobic Properties of Drug Substance
Resource Person: Eric Chan, PhD