In Vitro Metabolism and Transport Characteristics of Zastaprazan

• Published in: Pharmaceutics Vol. 16; no. 6; p. 799
• Main Authors: Lee, Min Seo, Lee, Jihoon, Pang, Minyoung, Kim, John, Cha, Hyunju, Cheon, Banyoon, Choi, Min-Koo, Song, Im-Sook, Lee, Hye Suk
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-06-2024; MDPI
• Subjects: Acids; Analysis; Chemical bonds; Dosage and administration; Drug delivery systems; Drug dosages; Drug metabolism; drug transporters; drug-metabolizing enzymes; Drugs; Enzymes; Gastroesophageal reflux; Metabolism; metabolite identification; Metabolites; Pharmacokinetics; Potassium; potassium-competitive acid blocker (P-CAB); Proton pump inhibitors; Protons; Testing; Ulcers; Vehicles; zastaprazan (JP-1366); South Korea; United States > US; Netherlands; drug transporters; zastaprazan (JP-1366); potassium-competitive acid blocker (P-CAB); drug-metabolizing enzymes; metabolite identification
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics16060799

Zastaprazan (JP-1366), a novel potassium-competitive acid blocker, is a new drug for the treatment of erosive esophagitis. JP-1366 is highly metabolized in human, mouse, and dog hepatocytes but moderately metabolized in rat and monkey hepatocytes when estimated from the metabolic stability of this compound in hepatocyte suspension and when 18 phase I metabolites and 5 phase II metabolites [i.e.,
-dearylation (M6), hydroxylation (M1, M19, M21), dihydroxylation (M7, M8, M14, M22), trihydroxylation (M13, M18), hydroxylation and reduction (M20), dihydroxylation and reduction (M9, M16), hydrolysis (M23), hydroxylation and glucuronidation (M11, M15), hydroxylation and sulfation (M17), dihydroxylation and sulfation (M10, M12),
-dearylation and hydroxylation (M3, M4),
-dearylation and dihydroxylation (M5), and
-dearylation and trihydroxylation (M2)] were identified from JP-1366 incubation with the hepatocytes from humans, mice, rats, dogs, and monkeys. Based on the cytochrome P450 (CYP) screening test and immune-inhibition analysis with CYP antibodies, CYP3A4 and CYP3A5 played major roles in the metabolism of JP-1366 to M1, M3, M4, M6, M8, M9, M13, M14, M16, M18, M19, M21, and M22. CYP1A2, 2C8, 2C9, 2C19, and 2D6 played minor roles in the metabolism of JP-1366. UDP-glucuronosyltransferase (UGT) 2B7 and UGT2B17 were responsible for the glucuronidation of M1 to M15. However, JP-1366 and active metabolite M1 were not substrates for drug transporters such as organic cation transporter (OCT) 1/2, organic anion transporter (OAT) 1/3, organic anion transporting polypeptide (OATP)1B1/1B3, multidrug and toxic compound extrusion (MATE)1/2K, P-glycoprotein (P-gp), and breast cancer-resistant protein (BCRP). Only M1 showed substrate specificity for P-gp. The findings indicated that drug-metabolizing enzymes, particularly CYP3A4/3A5, may have a significant role in determining the pharmacokinetics of zastaprazan while drug transporters may only have a small impact on the absorption, distribution, and excretion of this compound.