Study On Clinic Pharmacokinetics And Pharmacodynamics Of Dexmedetomidine Hydrochloride In Chinese

OBJECTIVE:Dexmedetomidine hydrochloride,a new alpha2-adrenoceptor agonist,can reduce requirements for opioids and anesthetic agents,attenuate the hemodynamic responses to tracheal intubation and surgical stimuli,and decrease intraocular pressure,the agitation and nausea during anesthesia recovery phase.These properties prove it to be a useful anesthetic adjunctive drug.A growing number of research articles abroad have emerged reporting the use as adjunctive drug in ICU and clinical anesthesia.However,dex has not been gone on sale,and there are no clinic studies in China.My study was designed to observe the pharmacokinetics and the effects on sedation,circulation,respiration, plasma eortisol in healthy Chinese adults after being infused domestic dexmedetomidine hydrochloride.METHODS:30 health volunteers(15 males and 15 females)who provided informed consent were stratified by sex and devided into three groups randomly:group A,group B and group C.Each group included 10 health volunteers and received dexmedetomidine i.v.by a single 10-min infusion of 0.5μg/kg(group A),1.0μg/kg(group B),1.5μg/kg (group C)by ulnar vein.All of the subjects were monitored electrocardiography(ECG),heart rate(HR),Systolic Blood pressure(SBP),Diastolic Blood pressure(DBP),pulse oxygen saturation (SPO₂),OAA/S(observe's assessment of alertness/sedation scale).Those monitorings were performed and venous blood samples were collected in heparinized tubes just before the start of the infusion and at 0,5, 10,15,25,30,45,60,90,120,150,180,240,360 and 480 min after the finish of drug administration.Those blood samples were used to analysis plasma Dex and cortisol concentration.Plasma Dex was measured in HPLC-MS/MS.Plasma cortisol was measured in competive radiommunoassay.All PK parameters were implemented by DAS Ver 2.0.All reported data were expressed as mean±S.E.M.For statistical comparison between data sets,we used repeated measures analys variance(ReANOVA)for repeated measure variable or One-Way ANOVA for completely random design data.Significance was established at P＜0.05.RESULTS:The PK of dexmedetomidine was fitted to two-compartment linearity elimination model.The distribution half-life of dexmedetomidine was 3.2-5.5 min,and the terminal half-life was 92.4-106.9 min,and clearance was 0.038-0.046 L/min/kg,and the averaged residence time was 237.3-268.5 min.In the three doses infusion groups,dexmedetomidine had significant time effect(P＜0.05),no dose effect and no dose-time interaction(P＞0.05)for OAA/S,HR,SBP,DBP,SpO₂ and plasma cortisol.It indicated that the clinic effects changed significantly with time,and did not change with doses,and that the tendencies of those changes were similar among the three groups.The maximal decrease of OAA/S in group A,B,C was(30.0±17)%, (42.0±11)%,(42.0±14)%respectively,and that of HR was(24.0±7)%, (32.7±11)%,(30.2±5)%,and that of SBP was(23.5±3)%,(23.5±2)%, (24.1±2)%,and that of DBP was(21.4±8)%,(30.3±13)%,(28.7±11)%, and that of SpO₂ was(1.8±1.2)%,(2.0±1.8)%,(2.2±1.4)%.The maximal degree of decrease was not different among the three groups,but the recover time was longer with the increasing of dose.The recover time of OAA/S in group A,B,C was 60,90,120 min respectively,and that of HR was 120,180,180 min,and that of SBP was 360,360,480 min,and that of DBP was 90,240,480 min,and that of SpO₂ was 45,360,360 min.CONCLUSIONS:Within the doses of 0.5-1.5μg/kg,the PK of dexmedetomidine in healthy Chinese was fitted to two-compartment linearity elimination model,and it made significant sedation effect with significant decrease of HR,SBP,DBP,SpO₂ and the plasma concentration of cortisol in those conscious healthy Chinese volunteers, and with the increasing of Dex,the clinical effects intension were not different,but the recover time was longer.