title: Effects of suberoylanilide hydroxamic acid on rat cytochrome P450 enzyme activities.
abstract: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is the first approved histone deacetylase (HDAC) inhibitor for the treatment of cutaneous T-cell lymphoma after progressive disease following two systemic therapies. The rats were randomly divided into SAHA groups (low, medium and high dosage) and control group. The SAHA group rats were given 12.3, 24.5, and 49 mg/kg SAHA, respectively, by continuous intragastric administration for 7 days. The influence of SAHA on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C19, CYP2D6 and CYP2C9 were evaluated by cocktail method, they were responsed by the changes of pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metroprolol and omeprazole. The five probe drugs were given to rats through intragastric administration, and the plasma concentration were determined by UPLC-MS/MS. The result of SAHA group compared to control group, there were statistical pharmacokinetics difference for bupropion, phenacetin, tolbutamide and metroprolol. Continuous intragastric administration for 7 days may induce the activities of CYP2C19 of rats, inhibit CYP1A2 and slightly inhibit CYP2B6 and CYP2D6 of rats. This may give advising for reasonable drug use after co-used with SAHA. The results indicated that drug co-administrated with SAHA may need dose adjustment. Furthermore, continuous intragastric administration of SAHA for 7 days, liver cell damaged, causing liver cell edema, in liver metabolism process.
authors.affiliation: Medical Experimental Teaching Center, Wenzhou Medical University Wenzhou 325035, China.
authors.forename: Kezhi
authors.initials: K
authors.lastname: Lin
authors.affiliation: Shanghai Institute of Pharmaceutical Industry Shanghai 200437, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Pharmaceutical Industry Shanghai 200437, China.
authors.forename: Zezheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Pharmaceutical Industry Shanghai 200437, China.
authors.forename: Suping
authors.initials: S
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Pharmaceutical Industry Shanghai 200437, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Laboratory Animal Centre, Wenzhou Medical University Wenzhou 325035, China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Wen
authors.affiliation: The First Affiliated Hospital of Wenzhou Medical University Wenzhou 325035, China.
authors.forename: Yuancai
authors.initials: Y
authors.lastname: Zheng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016642:Bupropion / Q000097:blood / Q000493:pharmacokinetics; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology; D002853:Chromatography, Liquid; D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000008:administration & dosage* / Q000633:toxicity; D065702:Cytochrome P-450 CYP2B6 / Q000378:metabolism; D065686:Cytochrome P-450 CYP2B6 Inhibitors / Q000008:administration & dosage; D065731:Cytochrome P-450 CYP2C19 / Q000096:biosynthesis*; D065697:Cytochrome P-450 CYP2C19 Inducers / Q000008:administration & dosage* / Q000633:toxicity; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000008:administration & dosage; D003580:Cytochromes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004347:Drug Interactions; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D004790:Enzyme Induction; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000633:toxicity; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D010615:Phenacetin / Q000097:blood / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D014044:Tolbutamide / Q000097:blood / Q000493:pharmacokinetics; D000077337:Vorinostat
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065686:Cytochrome P-450 CYP2B6 Inhibitors; D065697:Cytochrome P-450 CYP2C19 Inducers; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003580:Cytochromes; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016642:Bupropion; D000077337:Vorinostat; D014044:Tolbutamide; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D010615:Phenacetin; D008790:Metoprolol; D009853:Omeprazole
keywords: CYP450; HDACi; SAHA; UPLC-MS/MS; cocktail; rat