Pharmacokinetics Studies Of Rociverine Injection In Chinese Healthy Volunteers

Rociverine tablets was first listed in Italy in 1980,mainly for the genitourinary tract and bile duct antispasmodic,analgesic effect.Suitable for smooth muscle spasm caused by acute,subacute and chronic pain treatment.Pharmacological studies have shown that rociverine has a strong dual antispasmodic effect,but also has a papaverine-like effect,the role of selective in the visceral smooth muscle,inhibition of smooth muscle Ca²⁺flow,relaxation smooth muscle,does not affect vascular smooth muscle tension,but The cardiovascular system has no effect.In addition,rociverine also has atropine-like parasympathetic blockade,but lower than the adverse effects of atropine,the impact of muscle and nerve components of the reasonable ratio to ensure that the two components of the antispasmodic effect.In early years rociverine was often used as a preoperative medication for gastrointestinal endoscopy.In clinical studies,rociverine was shown to have an effect on midwifery,shortening uterine dilatation,time of delivery,and recovery time in dystocia.Some studies show that rociverine as an anticholinergic drug,the total effective rate of treatment of renal colic and anisodamine considerable?P>0.05?.There are also studies have shown that diclofenac sodium and lidocaine combined with rociverine maintenance medication on renal ciliary remission is significantly better than pethidine hydrochloride plus triamcinolone.Because rociverine less adverse reactions,can self-mitigation,and eliminate the possibility of addiction,and anisodamine adverse reactions were significantly higher than the rociverine,and the emergence of a variety of adverse reactions,So rociverine should be used in clinical practice?A study of the safety and tolerability of a single intravenous infusion of rociverine in healthy subjects was completed in the early stages and the results showed that a single intravenous infusion of 10 to 40 mg for healthy subjects Is safe and tolerant.Objective:To develop a LC-MS/MS method for the determination of rociverine in biological samples,study pharmacokinetic in human,which can provide valuable evidence and more information for preclinical studies.Methods:1.Validation of an analytical LC-MS/MS-method for the determination of rociverine in human plasma and urine.Chromatographic conditions are:Chromatographic column:Phenomenex Luna CN?150mm×2.0mm,3??;Mobile phase:Methanol:water?containing 0.1%Formic acid?=70:30,Flow rate:0.2 ml/min;Column temperature:40?;injection volume:10?l.MS conditions are:LC-ESI-MS/MS was performed in the selected ion monitoring?SRM?mode using target ions at m/z 340.0?114.0?12eV?for rociverine,at m/z 300.1?165.1?38eV?for rociverineInternal standardCodeine.Spray voltage:4.5kV;Capillary temperature:300?;Source CID:-1V;Sheath gas pressure:23Arb;Aux gas pressure:3Arb;Collision pressure:1.0;scaning time is 0.5s.2.Pharmacokinetic of rociverine in humanSingle administration:12 volunteers were equally divided randomly into 3groups?with half males and half females?,by LC-MS/MS method after intravenous administration of rociverine?10mg,20mg,40mg?.Blood samples?approximately 4ml?were collected from upper extremity veins at the following times:pre-dose,post-dose 5,10,15,30 min,and 0.5h,1h,2h,4h,6h,8h,10h,12h,16h,24h,36h,48h after the infusion was completed.Blood was collected into heparinized tubes and centrifuged at 3000r/min for 10min,the plasma was separated immediately and stored at-70?until analysis.Multiple administration:12 volunteers were given multiple administration after the end of the single administration.Respectively,early and late medication 1 times,each 20mg,continuous medication for 7 days.Blood samples were collected before the first administration on days 5,6 and 7,and the plasma samples were collected according to the method of single administration on the 7th morning.The plasma concentration of these samples was determined and the drug accumulation was evaluated.Blood was collected into heparinized tubes and centrifuged at 3000 r/min for 10 min,the plasma was separated immediately and stored at-70?until analysis.3.Metabolism of rociverine in the humanUrine samples of 12 volunteers were collected at the same time as a single administration test.Methods for collecting urine:Volunteers were evacuated before being dosed,and were collected and weighed before and after administration at 0-1h,1-2h,2-4h,4-8h,8-12h,12-16h,16-24h The total volume of each urine and the amount of 4ml placed in-20?storage in the refrigerator to be analyzed.Results:1.The LC-MS/MS method established in this experiment shows that the specificity and sensitivity are high,the standard curve,precision and accuracy,recovery rate and matrix effect and stability are all required for in vivo drug analysis.The method can be used for the study of pharmacokinetics of rociverine in human.2.Single administration:The pharmacokinetic parameters were calculated by the procedure of DAS 3.0.The results of rociverine parameters in low,medium and high dose groups were:C_max?ng/ml?:309.8±138.8?701.4±226.9?978.7±108.5;AUC_0-t?ng/ml*h?:578.2±280.6?1082.7±245.9?2058.5±628.3;T_1/2?h?:11.4±5.8?10.2±3.4?13.2±3.3;MRT_0-t?h?:4.4±1.9?4.8±1.6?6.1±1.6;V?L?:276.5±128.5?274.9±114.7?384.1±149.9;CL?L/h?:20.2±10.7?18.7±4.2?20.1±5.7.AUC_0-t and C_max of rociverine has good dose-effect relationship.The pharmacokinetic parameters were not statistically significant in gender in different dose groups using SPSS22.0 statistical software.Multiple administration:The pharmacokinetic parameters were calculated by the procedure of DAS 3.0.The pharmacokinetic parameters of rociverine of 20mg dose groups are:C_max?ng/ml?:578.8±90.5;AUC_0-t?ng/ml*h?:2235.3±543.0;T_1/2?h?:22.9±8.2;MRT_0-t?h?:13.4±2.0;V?L?:245.0±57.4;CL?L/h?:7.97±2.5.The pharmacokinetic parameters of the volunteers after intravenous administration of rociverine for 7 consecutive days were compared with the pharmacokinetic parameters of the same dose of 20 mg,and the two groups C_max and AUC_0-t were taken after the number of pairs of T test analysis,the difference between the two groups was not statistically significant?P>0.05?,AUC_0-t between the difference was statistically significant?P<0.05?.3.The result of drug metabolism shows:The average cumulative excretion rates of roxivirin in the urine of the 12 healthy volunteers after intravenous infusion of roxivirin injection 10,20,40 mg for 48 hours were?0.834±1.353?%??0.476±0.283?%and?0.389±0.371?%,respectively.Conclusion:1.The method was validated successfully to study rociverine in human plasma and urine.2.Between 10mg and 40mg,AUC and Cmax of rociverine has good dose-effect relationship.3.The cumulative urinary excretion rate of rociverine was less than 1%within 0-48 h after dosing.