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Chem Res Toxicol. 2015 Dec 21;28(12):2292-303. doi: 10.1021/acs.chemrestox.5b00315. Epub 2015 Nov 11.

Toxicity of Carboxylic Acid-Containing Drugs: The Role of Acyl Migration and CoA Conjugation Investigated.

Author information

1
Department of Chemistry, University of Oulu , P.O. Box 3000, 90014 Oulu, Finland.
2
Research Unit of Biomedicine, Department of Pharmacology and Toxicology, and Medical Research Center Oulu, University of Oulu , P.O. Box 5000, 90014 Oulu, Finland.
3
Admescope Ltd. , Typpitie 1, 90620 Oulu, Finland.
4
Administration Center, Oulu University Hospital , P.O. Box 10, 90029 OYS, Oulu, Finland.

Abstract

Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive. Here, 13 drugs with a carboxylic acid moiety were incubated with human liver microsomes to produce acyl glucuronide conjugates for the determination of acyl glucuronide half-lives by acyl migration and with HepaRG cells to monitor the formation of acyl CoA conjugates, their further conjugate metabolites, and trans-acylation products with glutathione. Additionally, in vitro cytotoxicity and mitochondrial toxicity experiments were performed with HepaRG cells to compare the predictability of toxicity. Clearly, longer acyl glucuronide half-lives were observed for safe drugs compared to drugs that can cause IDT. Correlation between half-lives and toxicity classification increased when "relative half-lives," taking into account the formation of isomeric AG-forms due to acyl migration and eliminating the effect of hydrolysis, were used instead of plain disappearance of the initial 1-O-β-AG-form. Correlation was improved further when a daily dose of the drug was taken into account. CoA and related conjugates were detected primarily for the drugs that have the capability to cause IDT, although some exceptions to this were observed. Cytotoxicity and mitochondrial toxicity did not correlate to drug safety. On the basis of the results, the short relative half-life of the acyl glucuronide (high acyl migration rate), high daily dose and detection of acyl CoA conjugates, or further metabolites derived from acyl CoA together seem to indicate that carboxylic acid-containing drugs have a higher probability to cause drug-induced liver injury (DILI).

PMID:
26558897
DOI:
10.1021/acs.chemrestox.5b00315
[Indexed for MEDLINE]

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