CYP3A-Mediated Metabolism of Zastaprazan in Humans and Associated Drug-Drug Interactions

  • Pharmaceutics. 2026 Jun 10;18(6):718. doi: 10.3390/pharmaceutics18060718.
Kai-Juan Cao  1  2 ,  Long Fu  3 ,  Yu-Chen Sun  1 ,  Jian Meng  1 ,  Qin Huang  3 ,  De-Cheng Deng  3 ,  Hai-Tang Hu  3 ,  Zhi-Hui Han  3 ,  Gang Guo  1 ,  Xue Zhou  3  4 ,  Xiao-Yan Chen  1  2
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. Livzon Pharmaceutical Group Inc., Zhuhai 519000, China.
  • 4. School of Pharmacy, Fudan University, Shanghai 200433, China.
PMID: 42357334 DOI: 10.3390/pharmaceutics18060718
Abstract

Background/Objectives: Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker (P-CAB) used for the treatment of gastroesophageal reflux disease (GERD). To date, its metabolic pathways and metabolism-related drug-drug interactions (DDIs) in humans remain incompletely elucidated. This study aimed to determine the relative contributions (fm) of Cytochrome P450 isoforms to JP-1366 elimination and assess its DDI potential. Methods/Results: In vitro metabolic studies using human liver microsomes (HLMs) revealed that JP-1366 was first metabolized to M1, which subsequently underwent further oxidation, glucuronidation, and N-dealkylation. Mono-oxidation was estimated to contribute more than 46% to the overall metabolic clearance of JP-1366. Reaction phenotyping identified CYP3A as the major enzyme (fm = 96.1%), followed by CYP1A2 (1.49%) and CYP2C9 (2.41%). By integrating in vitro data, clinical pharmacokinetic data and clarithromycin coadministration DDI data, a physiologically based pharmacokinetic (PBPK) model was developed and validated. Simulations predicted significant DDIs with strong CYP3A inhibitor (ketoconazole), with AUC ratios of 3.80. Moderate inhibitors (fluconazole and fluvoxamine) caused mild increases (AUC ratios: 1.14-1.74). Conversely, strong and moderate CYP3A inducers, rifampicin and efavirenz, produced pronounced DDIs, with AUC ratios of 0.22 and 0.50, respectively. Furthermore, simulations predicted that although JP-1366 functions as a CYP enzyme inhibitor, it would not cause clinically meaningful changes in the plasma exposure of corresponding CYP substrate drugs; however, potential interactions with CYP3A substrates still warranted consideration. Conclusions: JP-1366 is predominantly cleared via a CYP3A-dominated metabolic pathway. The PBPK simulations suggest that JP-1366 may be a moderately sensitive CYP3A substrate and a moderate inhibitor of sensitive CYP3A substrates, while its perpetrator DDI risk toward Other major CYP pathways appears limited. These findings support caution or monitoring when JP-1366 is co-administered with strong CYP3A modulators or sensitive CYP3A substrates.

Keywords
CYP3A-mediated metabolism; [14C]JP-1366; drug–drug interaction; gastroesophageal reflux disease; physiologically based pharmacokinetics.
Products