Development of Integrated Parent-Metabolite Pharmacokinetic Model With Apparent Presystemic Metabolism to...

Alverine is an antispasmodic agent characterized by extensive metabolism, and systemic exposure is largely driven by its metabolites. However, conventional parent-metabolite pharmacokinetic models typically assume metabolite formation solely from the systemic parent compound, which may not adequately capture route-dependent differences in metabolite exposure. This study aimed to develop an integrated parent-metabolite pharmacokinetic model to simultaneously describe alverine and its three major metabolites (M1, M2, and M3) in mice following intravenous (IV) and per-oral (PO) administration. Plasma concentration-time data were analyzed using a stepwise nonlinear mixed-effects model. Alternative structural models were evaluated to account for route-dependent metabolite appearance. Distinct route-dependent differences were observed in alverine metabolite exposure, with substantially higher levels following PO administration, particularly for M2, despite limited parent exposure. A model without presystemic metabolism, which assumed parent-derived formation alone, failed to adequately describe these data, leading to an overprediction of early parent concentrations. The final model incorporated presystemic metabolism for M1 and M3, significantly improving model fit (ΔOFV = -138.10) and providing an adequate description of both parent and metabolite profiles across routes. These findings suggest that systemic metabolite exposure following oral dosing is strongly influenced by presystemic processes that cannot be captured by parent-driven formation alone. The proposed model provides a parsimonious structural framework to account for these effects without requiring detailed mechanistic information. This approach may be broadly applicable to compounds exhibiting metabolite-dominant exposure and highlights the importance of flexible structural models in pharmacometric analyses of route-dependent pharmacokinetics.