The Pharmacokinetic Study Of Arbidol Hydrochloride

Arbidol hydrochloride was a new antiviral active chemical entity admitted by SFDA in 2006.In this paper,methods for concentration assay of this drug in biological matrix were developed,and the pharmacokinetic processes of arbidol in vivo were systematically studied.An HPLC-MS method,which was rapid,accurate and sensitive enough with an LLOQ of 1ng/mL,was developed and fully validated for the pharmacokinetic study of arbidol in rats.The environmental clean cloud-point extraction（CPE） technique was successfully applied to the preparation of biological sample during another quantification method development.Coupled with HPLC-UV detector,the method was proved to be simple,rapid,and reliable for arbidol assay in rat plasma samples.The pharmacokinetic processes of arbidol in rats after intravenous injection（9mg/kg） and oral administration with different doses（9,18 and 54mg/kg） were investigated.After intravenous injection of 9mg/kg,the drug reached its maximum concentration of 7038±1593ng/mL;AUC_0-t and AUC_0-∞,were 6117±1507 and 6703±1770ng·h/mL, respectively;T_1/2 was 3.0±1.3h.With the oral doses of 9,18 and 5mg/kg,T_max were 0.35±0.17,0.28±0.11 and 0.18±0.06h;C_maxwere 644.1±543.9,1002±298 and 4711±2361ng/mL;AUC_0-t were 1127±970,1956±895 and 6790±2749 ng·h/mL;AUC_0-∞ werel250±1070,2224±1058 and 7558±2877 ng-h/mL;T_1/2were 3.2±1.2,3.6±1.2 and 3.3±0.7h,respectively.The parameters obtained were then compared and analyzed. Dose-dependent linear relationships of AUC_0-1 and C_max for arbidol was found in the range of 9 to 54mg/kg after oral administration to rats.T_1/2 from each group showed no significant difference by rank sum test.Bioavailability of this drug was determined as 18 %.The tissue distribution of arbidol in rats after an oral administration of 54mg/kg was investigated.The results presented a quick and dispersive affinity to rat tissues of this drug. Only 5 min after administration,concentrations of arbidol in most of the tissues already reached a high level.Besides enteron,higher drug concentrations were also found in lung, liver and spleen,which was quite helpful for arbidol to show its biological efficacy.The maximum drug concentrations for most tissues were detected 15 min following administration except brain,whose drug concentration already reached the highest level 5 min after dosing,indicating a sound penetration through the BBB（blood-brain barrier） of arbidol.The excretion of arbidol from rats after an oral administration of 54mg/kg was investigated.The cumulative amount for arbidol was 2018±578μg in feces within 72h after administration,which amounted to 18.7%of the given dosage.In urine,the cumulative amount was only 2858±1744 ng,indicating a minor urinary excretion of the parent compound.The drug administrated was mainly excreted from the rat body within 0-24h period,and the amounts excreted over 24h were small and slow.The excretion of arbidol from bile was slight and constant,with the cumulative amount of 3044±1336 ng 0-24h after dosing.The data above suggested that most of the drug administrated has been metabolized,and enteropatic recycling of arbidol is not important in rats.The MS fragmentation pathways of arbidol by ESI source were studied and summarized with tandem mass spectrometry（UPLC-MS-MS） method.The result was quite essential and helpful for the later drug metabolism investigation.The UPLC-MS-MS system was used for the identification of arbidol metabolites from rat feces,urine and plasma samples.There were altogether 9 metabilites detected and identified,including 2 phaseâ… biotransformation product and 7 phaseâ…¡ones.It is concluded that arbidol metabolism was mainly accomplished in liver,after metabolic reactions such as N-demethylation,S-oxidation and O-conjugation with Glu or H₂SO₄,the metabolites were excreted with bile into the enteron,and finally got out of the rat body in feces.The major two metabolites identified were sulfate conjugate of N-demethylarbidol and glucuronide arbidol.The pharmacokinetic process of drug in human being was also characterized.Twenty healthy male Chinese volunteers,each had an oral dose of 200mg in dispersible tablet formation.T_max of arbidol was 0.7±0.3 h,C_max was 418.5±85.2 ng/mL,T_1/2 was 7.5±5.1 h,AUC（0-t） and AUC_0-∞were 2011.8±538.1 and 2285.9±645.4ng·h/mL,respectively. Protein binding rate of arbidol in human plasma was determined as（90.4±1.2）%.