Sepiapterin ADME: rapid BH4 conversion, but mass balance differs across species
- Sepiapterin, a prodrug-like precursor of the cofactor BH4 recently approved for phenylketonuria, is orally available and converted to BH4 quickly and extensively in every species tested.
- Radiolabel recovery was high in rats but low in monkeys and humans, plausibly due to volatile gut-derived metabolites and incorporation of the compound into endogenous biomolecules.
- Metabolism was extensive and metabolite profiles were broadly similar across rat, monkey and human, via reduction, oxidation, methylation and side-chain cleavage.
💡 Points Based on the abstract
Low radiolabel recovery in monkey and human is the red flag I'd chase before trusting the rat package. If label ends up in endogenous pools, total radioactivity can't be read as drug-related exposure, so the rat safety margin may not map cleanly. Next step: a parallel dose with a differently positioned label, plus BH4 and metabolite levels in plasma.