title: Assessment of effects of IR and IPC on activities of cytochrome P450 isozymes in rats by a five-drug cocktail approach.
abstract: OBJECTIVE
  To evaluate the effects of ischemia and reperfusion (IR) and ischemic preconditioning (IPC) on the metabolic activities of cytochrome P450 (CYP) isozymes in rats by a five-drug cocktail approach.
  
  
  METHODS
  Cocktail approach was used to evaluate the influence of IR and IPC on the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam, respectively. Rats were randomly divided into IR, IPC and sham groups, and then injected the mixture of five probe drugs. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by a HPLC method with UV detection. The pharmacokinetic parameters were calculated by the software of DAS 2.0.
  
  
  RESULTS
  The parameters including t(1/2β), CLs, AUC, MRT and K10 exhibited a similar tendency for both IR and IPC groups. Compared with sham group, CLs and K10 of five probe drugs were significantly lower (p < 0.05), AUC and t(1/2β) of five or some probe drugs were significantly increased in IR and IPC groups (p < 0.05). Compared with IPC group, CLs of five probe drugs were decreased and AUC were significantly increased in the IR group (p < 0.05).
  
  
  CONCLUSIONS
  IR can variably decrease the activities of CYP isozymes in rats and this decrease can be attenuated by IPC.
authors: Department of Pharmacology, College of Basic Medicine, Tianjin Medical University , No. 22 Qixiangtai Road, Tianjin , P.R. China.
authors: Qin
authors: Q
authors: Li
authors: Ying
authors: Y
authors: Liu
authors: Jianjie
authors: J
authors: Jiao
authors: Caili
authors: C
authors: Zhang
authors: Jianshi
authors: J
authors: Lou
mesh_terms: D000818:Animals; D002110:Caffeine / Q000008:administration & dosage / Q000378:metabolism; D002753:Chlorzoxazone / Q000008:administration & dosage / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004338:Drug Combinations; D004347:Drug Interactions / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D019194:Ischemic Preconditioning / Q000379:methods*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000378:metabolism; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology*; D014044:Tolbutamide / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D007527:Isoenzymes; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D008790:Metoprolol; D002753:Chlorzoxazone; D008874:Midazolam