In Vitro Metabolism and Transport Characteristics of Zastaprazan

Area of Science:

• Pharmacology
• Drug Metabolism
• Gastroenterology

Background:

• Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker developed for treating erosive esophagitis.
• Understanding the metabolic pathways and transporter interactions of JP-1366 is crucial for predicting its clinical pharmacokinetics.

Purpose of the Study:

• To investigate the metabolic stability and identify the major drug-metabolizing enzymes and transporters involved in the disposition of zastaprazan (JP-1366).

Main Methods:

• Incubation of JP-1366 with hepatocytes from various species (human, mouse, rat, dog, monkey) to assess metabolic stability and identify metabolites.
• Cytochrome P450 (CYP) screening and immune-inhibition assays using CYP antibodies to determine the specific CYPs involved in metabolism.
• Assessment of JP-1366 and its active metabolite M1 as substrates for major drug transporters (e.g., OCT, OAT, OATP, MATE, P-gp, BCRP).

Main Results:

• JP-1366 exhibited high metabolism in human, mouse, and dog hepatocytes, with 18 phase I and 5 phase II metabolites identified.
• CYP3A4 and CYP3A5 were identified as the major enzymes responsible for JP-1366 metabolism, with other CYPs playing minor roles.
• JP-1366 and its active metabolite M1 were not substrates for most tested drug transporters, except for M1 showing substrate specificity for P-gp.

Conclusions:

• Drug-metabolizing enzymes, particularly CYP3A4/3A5, play a significant role in determining the pharmacokinetics of zastaprazan.
• Drug transporters are likely to have a minimal impact on the absorption, distribution, and excretion of zastaprazan.