title: Predictability of idiosyncratic drug toxicity risk for carboxylic acid-containing drugs based on the chemical stability of acyl glucuronide.
abstract: Acyl glucuronides (AGs) formed from carboxylic acid-containing drugs have been considered to be a cause of idiosyncratic drug toxicity (IDT). Chemical stability of AGs is supposed to relate to their reactivity. In this study, the half-lives of 21 AGs of carboxylic drugs in potassium phosphate buffer (KPB), human serum albumin (HSA) solution, and human fresh plasma were analyzed in relation to the IDT risk derived from these drugs. The carboxylic drugs were classified into three safety categories of "safe," "warning," and "withdrawn" in terms of their IDT risk. As for the results, the half-lives of AGs in KPB correlated with the IDT risk better than those in HSA solution or in human fresh plasma with regard to the separation of the safe drugs from the warning drugs or the withdrawn drugs. In KPB, whereas the half-lives in the safe category were 7.2 h or longer, those in the withdrawn category were 1.7 h or shorter. The classification value of the half-life in KPB, which separated the safe drugs from the withdrawn drugs was calculated to be 3.6 h by regression analysis. In conclusion, this is the first report that clearly shows the relationship between the IDT risk and chemical stability of AGs in several in vitro systems. The KPB system was considered to be the best for evaluating the stability of AGs, and the classification value of the half-life in KPB serves as a useful key predictor for the IDT risk.
authors.affiliation: Hiromachi, Shinagawa-ku, Tokyo, Japan. sawamura.ryoko.yi@daiichisankyo.co.jp
authors.forename: Ryoko
authors.initials: R
authors.lastname: Sawamura
authors.forename: Noriko
authors.initials: N
authors.lastname: Okudaira
authors.forename: Kengo
authors.initials: K
authors.lastname: Watanabe
authors.forename: Takahiro
authors.initials: T
authors.lastname: Murai
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Masaya
authors.initials: M
authors.lastname: Tachibana
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohnuki
authors.forename: Kayoko
authors.initials: K
authors.lastname: Masuda
authors.forename: Hidehito
authors.initials: H
authors.lastname: Honma
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kurihara
authors.forename: Osamu
authors.initials: O
authors.lastname: Okazaki
mesh_terms: D000215:Acylation; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000145:classification / Q000493:pharmacokinetics* / Q000633:toxicity; D002021:Buffers; D002264:Carboxylic Acids / Q000737:chemistry*; D064420:Drug-Related Side Effects and Adverse Reactions; D020719:Glucuronides / Q000097:blood / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D016015:Logistic Models; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000097:blood / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D011237:Predictive Value of Tests; D012709:Serum Albumin / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D002264:Carboxylic Acids; D020719:Glucuronides; D004364:Pharmaceutical Preparations; D012709:Serum Albumin