Enantioselectivity in blood-cerebrospinal fluid barrier permeability of substituted p-phenylenediamine quinones in patients with leptomeningeal metastasis

Substituted p-phenylenediamine quinones (PPD-Qs), widespread environmental contaminants arising from rubber antioxidants, exhibit documented toxicity and have been detected in human biological matrices. Penetration behaviors of various PPD-Qs across the blood-cerebrospinal fluid barrier remain unclear, particularly at the enantiomer-specific level. This study investigated this penetration behaviors using enantiomer-specific analysis of six PPD-Qs in 138 matched serum-cerebrospinal fluid sample pairs from Chinese adult patients with leptomeningeal. All targeted PPD-Q homologues were frequently detected, with 2-((4-methylpentan-2-yl)amino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione (6PPD-Q), 2,5-bis((5-methylhexan-2-yl)amino)cyclohexa-2,5-diene-1,4-dione, and 2-(isopropylamino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione (IPPD-Q) being predominant in both serum and cerebrospinal fluid samples. The mean enantiomeric fraction value of 6PPD-Q in cerebrospinal fluid (0.35 ± 0.070) was lower than that in human serum (0.43 ± 0.071). IPPD-Q (0.26) had the highest mean cerebrospinal fluid-to-serum concentration ratio (R_CSF/serum), followed by 6PPD-Q (0.24) and 2,5-bis(phenylamino)cyclohexa-2,5-diene-1,4-dione (0.23). Furthermore, sinister-6PPD-Q (0.26) exhibited a significantly higher mean R_CSF/serum compared with rectus-6PPD-Q (0.21). These findings provide the first evidence of enantioselective transfer across the human blood-cerebrospinal fluid barrier for PPD-Qs within a patient cohort with leptomeningeal metastasis.