Patchouli alcohol as an effective adjuvant for artemisinin-based combination therapies: Metabolic profiling, pharmacokinetics and mechanistic validation.

Malaria remains a globally fatal disease, and the emergence of drug resistance necessitates the discovery of novel adjuvant drugs for artemisinin-based combination therapies (ACTs). Patchouli alcohol (PA), the primary active component of Pogostemon cablin Benth, has demonstrated antimalarial potential. This study investigates the synergistic antimalarial effect of PA in combination with sodium artesunate (SA) and explores its pharmacokinetics and mechanism of action. Pharmacokinetic parameters were assessed using GC-MS/MS and analyzed with DAS software, while PA metabolites were identified via GC-MS and HPLC-Q-Exactive Plus Orbitrap MS. PA exhibited dose-dependent pharmacokinetics, with proportional increases in Cmax and AUC across doses and a consistent Tmax of 30 min. Additionally, significant gender-related differences in exposure were observed. Metabolic profiling identified 30 metabolites in plasma, urine and feces, primarily through dehydrogenation, sulfation and glucuronidation. Phase I metabolic reactions occurred more frequently in plasma, while phase II metabolic reactions more in urine and fecal samples. The rich metabolic reactions provided more possibilities for the exertion of its pharmacological effects. Network pharmacology and molecular docking predicted and validated PA's antimalarial mechanism, with strong binding interactions (M14-MMP9, SA-TNF, M14-PTGS2, SA-PTGS2, SA-CASP3, PA-MMP9). These results provide critical insights into the metabolic profile and mechanism of PA, supporting its development as a promising adjuvant for ACTs.