title: Ring-oxidative biotransformation and drug interactions of propofol in the livers of rats.
abstract: Propofol, an intravenous anesthetic agent, is widely used for inducing and maintaining anesthesia during surgical procedures and for sedating intensive care unit patients. In the clinic, rapid elimination is one of the major advantages of propofol. Meanwhile, the biotransformation and drug interactions of propofol in rat livers are still little known. In this study, we evaluated the ring-oxidative metabolism of propofol in phenobarbital-treated rat livers and possible drug interactions. Administration of phenobarbital to male Wistar rats significantly increased levels of hepatic cytochrome P450 (CYP) 2B1/2 and microsomal pentoxyresorufin O-dealkylase (PROD) activity. Analyses by high-performance liquid chromatography and liquid chromatography mass spectroscopy revealed that propofol was metabolized by phenobarbital-treated rat liver microsomes into 4-hydroxypropofol. In comparison, PROD activity and 4-hydroxy-propofol production from propofol metabolism were suppressed by orphenodrine, an inhibitor of CYP2B1/2, and a polyclonal antibody against rat CYP2B1/2 protein. Furthermore, exposure of rats to propofol did not affect the basal or phenobarbital-enhanced levels of hepatic CYP2B1/2 protein. Meanwhile, propofol decreased the dealkylation of pentoxyresorufin by phenobarbital-treated rat liver microsomes in a concentration-dependent manner. Taken together, this study shows that rat hepatic CYP2B1/2 plays a critical role in the ring-oxidative metabolism of propofol into 4-hydroxypropofol, and this anesthetic agent can inhibit CYP2B1/2 activity without affecting protein synthesis.
authors.affiliation: Brain Disease Research Center, Department of Anesthesiology, Wan-Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Graduate Institute of Medical Sciences and Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences and Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan ; Department of Laboratory Medicine, China Medical University Hospital, Taichung 404, Taiwan.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology, Shuang-Ho Hospital, Taipei Medical University, Taipei 235, Taiwan.
authors.forename: Yih-Giun
authors.initials: YG
authors.lastname: Cherng
authors.affiliation: National Research Institute of Chinese Medicine, Taipei 112, Taiwan.
authors.forename: Ming-Jaw
authors.initials: MJ
authors.lastname: Don
authors.affiliation: Brain Disease Research Center, Department of Anesthesiology, Wan-Fang Hospital, Taipei Medical University, Taipei 116, Taiwan ; Graduate Institute of Medical Sciences and Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, 250 Wu-Xing Street, Taipei 110, Taiwan ; Anesthetics Toxicology Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan.
authors.forename: Ruei-Ming
authors.initials: RM
authors.lastname: Chen
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001711:Biotransformation; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D010634:Phenobarbital / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015742:Propofol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase; D015742:Propofol; D010634:Phenobarbital