Theory 10/Pharmacology & Drug Action /Pharmacokinetics/3 min
Toxicity Is a pH Problem
A drug can be perfectly selective and still accumulate where it does damage. The sorting signal is pH.
Off-target toxicity of weakly basic drugs is set by the pH of the tissues that sequester them rather than by receptor affinity, so toxicity should be predicted from tissue pH and lysosomal trapping rather than from selectivity assays.
01The evidence
- Drug-drug interactions involving lysosomes have been reviewed as a mechanism with clinical consequences, with weakly basic compounds accumulating in acidic compartments by ion trapping.PubMed review
- Lysosomal trapping has been characterised in model cells as producing cytoplasmic vacuolation and cytotoxicity, a pattern that follows accumulation rather than receptor binding.Toxicology in Vitro
02The tension
Selectivity is optimised against receptor panels, and toxicity is discovered in the clinic. The two are treated as separate problems, with toxicity attributed to off-target binding that the panel missed. But many toxic drugs are highly selective, and their toxicity tracks tissue distribution instead.
03The theory
A weak base is uncharged in the cytosol and charged in an acidic compartment. The charged form cannot cross back, so it accumulates. Any tissue with a large acidic compartment volume, such as lung, kidney or macrophages, will concentrate the drug far above plasma levels.
Toxicity then follows the tissue's pH and compartment volume rather than the drug's receptor profile. Two drugs with identical selectivity but different pKa will have different toxicity, and the difference is calculable from the Henderson-Hasselbalch relation.
The prediction is that toxicity should correlate with predicted lysosomal accumulation, and that the correlation should be better than with any receptor-panel metric. It also predicts that alkalinising a compartment, for instance with a weak base competitor, should reduce accumulation and toxicity.
The practical consequence is that pKa and tissue pH belong in the lead-selection criteria alongside selectivity, and that a cheap calculation could replace a costly surprise.
04What this is not
The panel approach assumes toxicity comes from binding the wrong receptor. This assumes it comes from being in the wrong compartment, which is a physicochemical property that panels do not measure.
05Predictions
- P1Toxicity should correlate with predicted lysosomal accumulation better than with receptor-panel selectivity.
- P2Two drugs matched on selectivity but differing in pKa should differ in toxicity in the predicted direction.
- P3Competing weak bases should reduce accumulation and toxicity without changing receptor occupancy.
06What would refute it
Toxicity tracking selectivity after accumulation is controlled would leave the compartment account as a secondary factor.
07What it would change
It would add physicochemical distribution to lead selection, and catch a class of toxicity before the clinic.
08Evidence base
- Drug-drug interactions involving lysosomes — PubMed reviewhttps://pubmed.ncbi.nlm.nih.gov/22616667/
- Lysosomal trapping, vacuolation and cytotoxicity in model cells — Toxicology in Vitrohttps://www.sciencedirect.com/science/article/abs/pii/S1347436723000228