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In vitro and in vivo irreversible plasma protein binding of beclobric acid enantiomers
Author(s) -
Mayer Sascha,
Mutschler Ernst,
SpahnLangguth Hildegard,
Benet Leslie Z.
Publication year - 1993
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530050304
Subject(s) - chemistry , enantiomer , glucuronic acid , diastereomer , glucuronide , chromatography , hydrolysis , in vivo , in vitro , derivatization , carboxylic acid , racemic mixture , bovine serum albumin , metabolism , high performance liquid chromatography , stereochemistry , biochemistry , polysaccharide , microbiology and biotechnology , biology
Acyl glucuronides are known to be labile conjugates, which undergo hydrolysis and bind irreversibly to proteins. The lipid‐regulating agent (±)‐beclobrate is immediately converted to the free acid after oral administration. Further metabolism leads to formation of the corresponding diastereomeric acyl glucuronides. Beclobric acid glucuronides were quantified by indirect measurement with an HPLC method based on chiral fluorescent derivatization of the carboxylic acid and subsequent normal‐phase chromatography. The renal clearance of unchanged drug is low, with almost all drug excreted into urine as glucuronic acid conjugates. Beclobric acid glucuronide is also detectable in plasma. In vitro degradation studies with beclobric acid glucuronide (at a concentration of 5 μM in 150 m M phosphate buffer pH 7.4) exhibited a minor tendency for acyl migration and hydrolysis, i.e., a higher stability than has been observed for the acyl glucuronides of most other drugs. The in vitro degradation half‐lives of the two beclobric acid β‐1‐O‐acyl glucuronides were 22.7 and 25.7 h. After incubation with pooled plasma and human serum albumin in buffer pH 7.4 irreversible binding was measured in vitro. No significant difference between the two enantiomers was detected with respect to the magnitude of in vitro irreversible binding. In 3 healthy male volunteers the extent of irreversible binding of both beclobric acid enantiomers to plasma proteins was investigated after single and multiple oral doses of racemic beclobrate (100 mg once daily). Irreversible binding of both enantiomers was observed in all volunteers. The adduct densities for (−)‐ and (+)‐beclobric acid after single 100 mg beclobrate doses were 0.147 × 10 −4 and 0.177 × 10 −4 mol/mol protein. Multipie dosing increased irreversible binding 3‐ to 4‐fold. © 1993 Wiley‐Liss, Inc.