SRINIVASA RAO, G (Major)RAVI KUMAR, PSRINIVASA PRASAD, CHANAND KUMAR, PGANGADHARA. N. V. PRASAD, V2017-05-182017-05-182012-10http://krishikosh.egranth.ac.in/handle/1/5810011458THESESABSTRACT: Role of inflammation and curcumin on the activity of CYP1A2 (a cytochrome P 450 isozyme) were investigated in the present study by determining alterations in the pharmacokinetics of phenacetin and formation of metabolite paracetamol in wistar albino rats, weighing about 200-250g that were randomly divided into four groups consisting six in each group. Rats in group I (control) received phenacetin alone (150 mg.kg-1, PO). Group II received phenacetin 12 h after induction of inflammation using turpentine oil (0.4 mL, i.m). Group III received curcumin (400 mg.kg-1, PO) 60 min prior to administration of phenacetin and Group IV received phenacetin after induction of inflammation followed by curcumin pretreatment. Blood samples were collected from retro orbital sinus at predetermined time intervals prior to and at 0.166, 0.33, 0.67, 1.5, 2, 4, 8 and 12 h after administration of phenacetin. Plasma was separated and stored at -200C until analyzed for phenacetin and its metabolite paracetamol by HPLC assay. Based on plasma concentrations, the pharmacokinetic parameters were determined by compartmental methods. Mean Cmax of phenacetin in group I was 38.13 }2.20 μg.mL-1. There was significant decrease in mean Cmax of phenacetin in rats with inflammation (Group II: 19.50 }2.74 μg.mL-1), curcumin pretreated rats (Group III: 22.23 }2.70 μg.mL-1) and rats with inflammation receiving curcumin pretreatment (Group IV: 17.29 }2.62 μg.mL-1). Means of important pharmacokinetic parameters obtained for phenacetin after its oral administration in group I (control) were: elimination rate constant (β) 0.76 }0.2 h-1; elimination half-life (t.β) 1.22 }0.24 h; area under plasma concentration time curve (AUC0-∞) 90.82 }15.79 μg.h.mL-1; area under first moment curve (AUMC0- ∞) 204.98 }66.96 μg.h2.mL-1; volume of distribution at steady state (Vdss) 2.87 }0.37 L.kg-1; total body clearance (ClB) 1.88 }0.27 L.kg-1.h -1; and mean residence time (MRT) 2.00 }0.32 h and, For the metabolite paracetamol, Cmax, AUC0-∞, and t.β were 8.55 }1.64 μg.mL-1, 41.46 }6.36 μg.h.mL-1 and 2.75 }0.76 h respectively. In group II the mean pharmacokinetic parameters for phenacetin in rats with experimentally induced inflammation were : β, 0.38 }0.07 h-1; t.β, 2.23 }0.48 h; AUC0-∞, 59.53 }7.17 μg.h.mL-1; AUMC0-∞, 13207.76 }58.11 μg.h2.mL-1; Vdss, 8.03 }1.26 L.kg-1; ClB, 2.71 }0.33 L.kg-1.h-1; MRT, 3.26 }0.69 h. It was found that there was a significant (p<0.001) increase in the volume of distribution in rats with inflammation. For the metabolite paracetamol, mean Cmax, AUC0-∞, and t.β were 5.74 }0.87 μg.mL-1, 35.72 }9.61 μg.h.mL-1 and 4.58 }2.32 h respectively. In group III mean pharmacokinetic parameters for phenacetin in curcumin pretreated rats were: β, 0.79 }0.21 h-1; t.β, 1.45 }0.52 h; AUC0-∞, 52.01 }8.54 μg.h.mL-1; AUMC0-∞, 144.61 }63.84 μg.h2.mL-1; Vdss, 5.37 }1.09 L.kg-1; ClB, 3.35 }0.58 L.kg-1.h -1 ; MRT, 2.30 }0.70 h. and, For the metabolite paracetamol, mean Cmax, AUC0-∞, and t.β were 4.82 }1.00 μg.mL-1, 27.19 }3.05 μg.h.mL-1 and 3.57 }0.62 h respectively. In group IV pharmacokinetic parameters for phenacetin in rats with inflammation followed by curcumin pretreatment were: β, 0.55 }0.08 h-1; t.β, 1.42 }0.21 h; AUC0-∞, 47.57 }10.26 μg.h.mL-1; AUMC0-∞, 119.64 }36.16 μg.h2.mL-1; Vdss, 7.01 }0.73 L.kg-1; ClB, 3.88 }0.74 L.kg-1.h -1; MRT, 2.28 }0.29 h and, For the metabolite paracetamol, Cmax, AUC0-∞, and t.β were 5.39 }0.91 μg.mL-1, 29.84 }8.52 μg.h.mL-1 and 2.56 }1.04 h respectively. A significant (P<0.01) decrease in AUC0-∞, while increase in Vdss and clearance for phenacetin was found in rats with inflammation which received curcumin pretreatment. There were no significant alterations in either plasma concentrations or pharmacokinetic parameters of paracetamol (metabolite of phenacetin) in all the four groups. Thus results of the present study indicated that inflammation increased the rate of absorption with shorter half-life for phenacetin. Either inflammation or curcumin pretreatment or both have no role on the activity of CYP1A2 in rats which was indicated by unaltered paracetamol (metabolite) concentrations and pharmacokinetic parameters among all the four groups.ennullThesis