Two-dimensional chromatography for enantiomeric analysis of mitotane and its metabolite o,p′-DDA in patients with adrenocortical carcinoma indicates enantioselective metabolism

A 2D-LC method was developed to quantify the enantiomers of mitotane and its metabolite, o,p′-DDA modified to n-Propyl ester, revealing that mitotane undergoes enantioselective metabolism. [Display omitted] •A new chromatography was developed for chiral mitotane and its metabolite monitoring.•Mitota...

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Published in:	Bioorganic chemistry Vol. 141; p. 106835
Main Authors:	Stadler, Gabriela, de Almeida Veiga, Alan, Rita Corso, Claudia, Bach de Assis, Camila, de Toledo Nogueira, Beatriz, Regina Rocha Martins, Lucia, Cruz Bonk, Beatriz, Lada Degaut Pontes, Flávia, Cavalcante de Figueiredo, Bonald, Mera de Souza, Lauro
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 01-12-2023
Subjects:	Chiral chromatography Drug metabolism o,p’-DDD o,p’-dichlorodiphenyl acetic acid o,p’-dichlorodiphenyldichloroethane Two-dimensional chromatography o,p’-dichlorodiphenyldichloroethane Drug metabolism o,p’-DDD Chiral chromatography Two-dimensional chromatography o,p’-dichlorodiphenyl acetic acid
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Summary:	A 2D-LC method was developed to quantify the enantiomers of mitotane and its metabolite, o,p′-DDA modified to n-Propyl ester, revealing that mitotane undergoes enantioselective metabolism. [Display omitted] •A new chromatography was developed for chiral mitotane and its metabolite monitoring.•Mitotane undergoes a chiral-oriented metabolism, observed in the ratio of enantiomers.•The ratio of mitotane to metabolites varies greatly between different patients. Mitotane is a chiral drug used to treat adrenocortical carcinoma, being metabolized to the o,p’-dichlorodiphenyl acetic acid (o,p’-DDA), also a chiral compound. Despite of its therapeutic significance, the overall ratios and enantiomers have not been known. In this study, we analyzed the enantiomers of mitotane and o,p’-DDA in the plasma of patients by a newly developed chiral-phase method employed in two-dimensional chromatography. Important differences were observed in the ratio of (S)/(R)-mitotane, which varied substantially from 1:1.2 to 1:10 whereas the (S)/(R)-o,p’-DDA ratio was relatively conserved, at approximately 2:1. These findings provide evidence for the enantioselective metabolism and provide a method for further analyses of mitotane and metabolites, which can explain the variation in the therapeutic response.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0045-2068 1090-2120
DOI:	10.1016/j.bioorg.2023.106835