Predictability of idiosyncratic drug toxicity risk for carboxylic acid-containing drugs based on the chemical stability of acyl glucuronide.
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 The carboxylic drugs were classified into three safety categories of "safe," "warning," and "withdrawn" in terms of their IDT risk.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in HSA solution or in human fresh plasma with regard to the separation of the safe drugs from the warning drugs or the withdrawn drugs. In KPB, whereas the half-lives in the safe category were 7.2 h or longer, those in the withdrawn category were 1.7 h or shorter. The classification value of the half-life in KPB, which separated the safe drugs from the withdrawn drugs was calculated to be 3.6 h by regression analysis.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.
Sawamura
Ryoko
R
Hiromachi, Shinagawa-ku, Tokyo, Japan. sawamura.ryoko.yi@daiichisankyo.co.jp
Okudaira
Noriko
N
Watanabe
Kengo
K
Murai
Takahiro
T
Kobayashi
Yoshimasa
Y
Tachibana
Masaya
M
Ohnuki
Takashi
T
Masuda
Kayoko
K
Honma
Hidehito
H
Kurihara
Atsushi
A
Okazaki
Osamu
O
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002021:Buffers; D002264:Carboxylic Acids; D020719:Glucuronides; D004364:Pharmaceutical Preparations; D012709:Serum Albumin