Abstract
Propofol O-glucuronidation has been used as probe reaction to phenotype UGT1A9 activity in human liver, thus a sensitive and specific method for determination of propofol O-glucuronide (PG) is urgently desirable. In the current study, a new LC–ESI-MS method for determination of PG in hepatic microsomes from human (HLM), monkey (CyLM), dog (DLM), minipig (PLM), rat (RLM) and mouse (MLM) was developed and validated using 4-methylumbelliferyl-β- d-glucuronide as an internal standard (IS). PG and IS was separated by a Shim-pack XR-ODS column (100 mm × 2.0 mm, 2.2 μm, Shimadzu) under gradient conditions with the mobile phase of acetonitrile and water containing 0.2% acetic acid (v/v). The mass spectrometric detection was performed under selected ion monitoring (SIM) for PG at m/ z 353 and IS at m/ z 351. The assay exhibited linearity over the range 0.05–30 μM for PG with the correlation coefficient of 0.9995. The intra- and inter-day precision was less than 7.2%, with accuracy in the range 93.8–107.5%. The developed method was successfully used for characterizing interspecies and human individual differences in the O-glucuronidation activity towards propofol, as well as investigating inhibitory effects of androsterone and phenylbutazone on propofol O-glucuronidation in HLM.
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