Carrefour Celecoxib Pre-clinical Pharmacokinetic Studies

Objective This thesis is designed to finish the preclinical pharmacokinetics study oflefucoxib, and provide research base for its clinical study.Methodâ‘ HPLC-UV and HPLC-FLD were employed to determinate lefucoxib inbiological matrix, and then pharmacokinetic parameters were calculated.â‘¡WithLC-MSⁿ and ¹H NMR, metabolites of lefucoxib in rats were deduced, whichprovided great help in the study of biotransformation of lefucoxib.â‘¢CYP450reaction phenotyping study of lefucoxib in vitro with liver microsome incubation.â‘£Study lefucoxib's impact on the protein content of CYP450 by comparing withcontrol groups.ResultsAbsorption: Peak plasma levels of lefucoxib in beagle dogs occur 0.9～2.1 h after anoral dose(8.5, 25.5, 75.5 mg·kg^-1). Area under the curve (AUC_0-t) was roughly doseproportional across the current dose range, which supports the result thatpharmacokinetics of lefucoxib in beagle dogs were linear. As for Wistar rats, peakplasma levels occur 8～10h after oral administration (25, 75, 225 mg·kg^-1), and therewas a less than proportional increase in both C_max and AUC_0-t. Maybe the absorption oflefucoxib in rats depended on the dose of administration.Distribution: After an oral dose (75 mg·kg^-1) in rats, the concentration of lefucoxib ingastrointestinal tract was much higher than that in other tissues, which indicated thatlefucoxib distributed mainly in gastrointestinal tract and the absolute bioavailabilitywill be low. In addition, the concentration of lefucoxib in fats was persistently high,and even could be detected 48 hrs after oral administration. Therefore, it can beconcluded that the elimination of lefucoxib in fat was relatively slow.Metabolism: The primary metabolic pathway of lefucoxib in rats was hydroxylation,and three kinds of hydroxylefucoxib were identified as the metabolites of lefucoxib.Lefucoxib metabolism was primarily mediated via cytochrome P450 2C19, 3A2, 2A6and 1A2.Excretion: 48 hrs after a single oral dose of lefucoxib in rats (75 mg·kg^-1), mostunchanged drug was excreted in the feces, accounting for 75.8ï¼…of the dose. Nolefucoxib was detected in urine. As for the bile, less than 1ï¼…of the dose is found 46hrs after oral administration. Drug inreractions: Percentage of plasma protein binding of lefucoxib was more than85ï¼…, indicating that it had better be avoided using together with other drugs that werehighly binded with plasma protein. Lefucoxib was metabolized via 4 P450 isoforms,making the toxicology effects due to inhibition of P450 occur rarely.Conclusion This thesis conducted systematic and in-depth preclinical pharmacokineticstudy of lefucoxib both in vivo and in vitro, and it provides crucial information for itsclinical research.