Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone in Patients with Cytochrome P450 2C93 Modeled after Virtual Oral Administrations and Likely Associated with Adverse Drug Events Reported in a Japanese Database

• Published in: Biological & pharmaceutical bulletin Vol. 46; no. 6; pp. 856 - 863
• Main Authors: Saito, Yoshiro, Murayama, Norie, Nakano, Hina, Sato, Tasuku, Shimizu, Makiko, Yamazaki, Hiroshi, Adachi, Koichiro, Tanaka, Yoichi, Ohyama, Katsuhiro
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.06.2023; Japan Science and Technology Agency
• Subjects: Administration, Oral; Adverse events; Celecoxib; Celecoxib - adverse effects; CYP2C9.1; CYP2C9.3; Cytochrome; Cytochrome P-450 CYP2C9 - genetics; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 Enzyme System; Cytochrome P450; Diclofenac; Diclofenac - adverse effects; Drug interaction; Drug interactions; Drug-Related Side Effects and Adverse Reactions; fraction metabolized; Homozygotes; Humans; Japan; Liver; Nonsteroidal anti-inflammatory drugs; pharmacokinetic modeling; Pharmacokinetics; Plasma; Prostaglandin endoperoxide synthase; Japan; CYP2C9.1; CYP2C9.3; fraction metabolized; pharmacokinetic modeling
• ISSN: 0918-6158; 1347-5215; 1347-5215
• DOI: 10.1248/bpb.b23-00189

The impacts of polymorphic cytochrome P450 (P450 or CYP) 2C9 on drug interactions and the pharmacokinetics of cyclooxygenase inhibitors have attracted considerable attention. In this survey, the prescribed dosage was reduced or discontinued in 150 and 56 patients, respectively, receiving celecoxib and diclofenac prescribed alone, as recorded in a Japanese database of adverse drug events. Among the factors underlying adverse events, intrinsic drug clearance rates may be a contributing factor. The pharmacokinetically modeled plasma concentrations of celecoxib after an oral 200-mg dose increased in CYP2C9*3 homozygotes: the area under the plasma concentration curve was 4.7-fold higher than that in CYP2C9*1 homozygotes. In patients with CYP2C9*3/*3, the virtual hepatic concentrations of diclofenac after three daily 25-mg doses for a week were 11-fold higher than the plasma concentrations in subjects with CYP2C9*1/*1. The in vivo and in vitro fractions of the victim drug metabolized by a specific polymorphic P450 form is an important determining factor for estimating drug–drug interactions. Virtual hepatic and plasma exposures estimated by pharmacokinetic modeling in patients harboring the impaired CYP2C9*3 allele could represent a causal factor for adverse events induced by celecoxib or diclofenac in a manner similar to that for drug interactions.