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20101
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Subject: Veterinary Pharmacology and Toxicology × Author: SESHAIAH V, PAMULAPATI × End date: 2011 × Start date: 2010 × Type: Thesis ×
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    ThesisItemOpen Access
    STUDIES ON THE EFFECT OF MORIN, A CYP 2C9 AND CYP3A4 INHIBITING FLAVONOID ON THE PHARMACOKINETICS OF MELOXICAM IN RABBITS
    (SRI VENKATESWARA VETERINARY UNIVERSITY TIRUPATI – 517 502. (A.P) INDIA, 2010-12) SESHAIAH V, PAMULAPATI; SRINIVASA RAO, G (Major); BHARAVI, K; ANAND KUMAR, P
    ABSTARCT: Meloxicam is a novel non-steroidal anti-inflammatory drug with selectivity towards cyclo-oxygenase 2 (COX-2) compared to COX-1. It is extensively metabolized in the liver, primarily by polymorphic cytochrome P450 2C9 (CYP2C9) enzyme, and to a minor extent by CYP3A4 enzyme, to four pharmacologically inactive metabolites and only negligible amounts of the parent drug are found in urine and feces. The effect of morin, a flavonoid known to be dual inhibitor of CYP2C9 and CYP3A4 on the plasma concentrations and pharmacokinetics of meloxicam was studied in male rabbits in the present study in three phases. In phase I, meloxicam alone was administered orally at a dose rate of 1.5 mg.kg-1 whereas in phase II and III the rabbits were given morin by oral route at 10 and 20 mg.kg-1, respectively 30 min before oral administration of meloxicam (1.5 mg.kg-1). Blood was collected at predetermined time intervals by marginal ear vein into heparinized tubes and plasma was separated immediately after blood collection by centrifugation. Meloxicam concentrations in plasma were determined by a validated HPLC method. Pharmacokinetic parameters were calculated by non compartmental technique. In the control group (phase I) where no pretreatment was carried out before the single oral bolus administration of meloxicam (1.5 mg.kg-1), meloxicam was detectable up to 24 h, with the Cmax (Mean±SE, 1.006±0.19 μg.ml-1) at 5.6±0.97 h. The important pharmacokinetic parameters of meloxicam after single oral bolus administration were : β, 0.086±0.11 h-1; t½β, 8.960±1.63 h; AUC0-∞, 12.256±0.91 μg.h.mL-1 ; AUMC0-∞, 167.923±10 μg.h 2.mL-1; Vdss, 1.85±0.4 L.kg-1; ClB, 0.13±0.01 L.kg-1.h -1; and MRT, 14.14±1.66 h. Morin (10mg.kg-1, PO) was given 30 min before administration of meloxicam (1.5mg.kg-1,PO) as pretreatment to rabbits in phase II. The mean value of Cmax obtained was 0.86±0.06 μg.mL-1, which was not significantly low from the control group (phase I). The important pharmacokinetic parameters of meloxicam obtained were : β, 0.082±0.01 h-1; t½β, 8.87±0.99 h; AUC0-∞, 13.16±0.3 μg.h.mL-1; AUMC0-∞, 188.33±17.51 μg.h 2.mL-1; Vdss, 1.62±0.13 L.kg-1; ClB, 0.11±0.0 L.kg-1.h -1; and MRT, 14.27±1.2 h. Upon morin pretreatment prior to meloxicam administration pharmacokinetic parameters such as AUC0-∞, ClB , t½β, Vdss and MRT did not increase significantly from the control group (phase I). In the phase III Morin was given at the dose rate of (20.mg.kg-1, PO) 30 min before administration meloxicam (1.5mg.kg-1,PO). The mean value of Cmax obtained in this phase was 1.39±0.07 μg.mL-1, which was significantly higher from the control group (phase I). There was a significant increase in plasma concentrations of meloxicam at all time points in phase III rabbits when compared to control group of rabbits in phase I after administration of meloxicam. The important pharmacokinetic parameters of meloxicam were : β, 0.09±0.01 h-1; t½β 8.78±1.17 h; AUC0-∞, 21.88±0.30 μg.h.mL-1; AUMC0-∞, 306.25±32.9 μg.h 2.mL-1; Vdss, 0.95±0.08 L.kg-1; ClB, 0.07±0.0 L.kg-1.h -1and MRT 13.95±1.34 h. Upon morin pretreatment at 20 mg.kg-1 prior to meloxicam administration pharmacokinetic parameters such as AUC0-∞, and ClB, were altered significantly from the control group (phaseI).