Effect Of Wuzhi Capsule And Duyiwei Capsule On Metabolic Behavior Of Bortezomib In Rats

BackgroundBortezomib（commercially known as Velcade）was jointly developed by Takeda,Japan and Johnson&Johnson,and was approved by the FDA in May 2003 for the treatment of relapsed and refractory multiple myeloma（MM）.Since the market,the combination of bortezomib monotherapy and other conventional chemotherapy drugs has achieved good results in patients with newly diagnosed,relapsed/refractory multiple myeloma,so it has rapidly become a first-line chemotherapy for multiple myeloma.However,in clinical applications,we found the following problems:（1）Adverse reactions mainly based on peripheral neuropathy.In the application of bortezomib,bortezomib-induced peripheral neuropathy（BIPN）is considered to be the most important adverse reaction and is considered to be the most important dose limiting factor,resulting in 12% of patients having to reduce doses,5%-8% of patients had to give up using bortezomib;（2）a serious financial burden.In an article published in the 2017 issue of Blood magazine,the high price of all these newly developed anti-tumor drugs has become an important factor restricting their widespread use.In many countries,especially in developing countries like China,it has brought enormous economic pressure on patients and society.In addition,the effectiveness and adverse reactions of bortezomib are quite different in patients.Therefore,the exploration of drug treatment programs and the intervention of adverse reactions have always been the direction of researchers’efforts to improve patient compliance and drugs,also the effectiveness and safety of treatment.The efficacy level of bortezomib is related to its plasma exposure level.Since the plasma exposure level of the drug is largely determined by its pharmacokinetics in vivo,the inactivation of bortezomib metabolism is mainly mediated by CYP3A4.Based on its metabolic characteristics,we propose a hypothetical protocol:by using a combination of CYP3A4 inhibitors.Intervention of the metabolic process of bortezomib in the body,reducing the dose used to reduce economic costs.In the early stage of our research group,high-performance liquid chromatography-tandem mass spectrometry（LC-MS/MS）was established for the determination of blood concentration in bortezomib.Based on the principle of drug interaction,the CYP3A4 medium inhibitor erythromycin was initially explored for boron.The impact of the pharmacokinetic behavior of teszomi in vivo confirms our hypothesis.However,because erythromycin is of little value in patients with multiple tumors,and even has the risk of causing secondary infections,both Chinese medicine Wuzhi Capsule and Duyiwei Capsule have been reported to have CYP3A inhibitory effect.Therefore,we systematically investigated The effect of the traditional Chinese medicine Wuzhi capsule with hepatoprotective activity and the analgesic effect of the traditional Chinese medicine preparation Duyiwei capsule on the pharmacokinetic behavior of bortezomib in rats,where the bortezomib administration method is divided into three types,including Single intravenous administration,multiple intravenous administration,and single subcutaneous or intravenous administration;Wuzhi capsules/Duyiwei capsules are also divided into three types,including single administration,multiple administration,and clinically administered chemotherapy simultaneously.Method and results1.The effects of a single administration of Wuzhi Capsule/Duyiwei Capsule on the pharmacokinetics of a single intravenous injection of bortezomib were investigated by in vivo experiments in rats.Taking the recognized CYP3A4 potent inhibitor ketoconazole as a positive control and physiological saline as a negative control,the pharmacokinetic interaction of Wuzhi Capsule/Duyiwei Capsule with Bortezomib was explored.The results showed that ketoconazole could significantly inhibit the in vivo metabolism of bortezomib,and the AUC_0→t（ng·h/mL）level of bortezomib was increased by 162.80%.The Wuzhi Capsule/Duyiwei capsule also played a role in inhibiting bortezomib.The AUC_0→t（ng·h/mL）level of bortezomib in the two groups increased by 38.45% and 137.9%,respectively.2.The effects of single doses of low-,medium-,and high-dose Wuzhi Capsule/Duyiwei capsules on the pharmacokinetics of a single intravenous bortezomib in vivo were investigated by in vivo experiments in rats.In the single tail vein administration of bortezomib,the rats were intragastrically pretreated with different doses of Wuzhi Capsule/Duyiwei capsules.The results showed that Wuzhi Capsule/Duyiwei Capsules were given in a single dose（Wuzhi Capsule 150 mg/kg,Duyiwei Capsule 100 mg/kg） in combination with the bortezomib AUC_0→t（ng·h/mL）levels increased by 38.45% and 137.9%,respectively,higher than other dose levels of the combination of traditional Chinese medicine,which played the best inhibition of bortezomib metabolism（optimal dose）,and the dose is much less than the dose of erythromycin（1.25 g/time）for the same CYP3A inhibitory efficacy.3.The effects of a single intravenous injection of bortezomib on the metabolic behavior of bortezomib after multiple administrations（3 or 7 consecutive days） at the optimal dose were investigated by in vivo rat experiments.Prior to the administration of bortezomib,the rats were administered continuously for 3 or 7 consecutive days using conventional doses of Wuzhi Capsule/Duyiwei capsules.The results showed that the pre-continuous treatment of Wuzhi Capsule/Duyiwei Capsule did not significantly inhibit the in vivo metabolic process of bortezomib,and the AUC_0→t（ng·h/mL）level of bortezomib was not significantly improved.4.We recommended the frequency of dosing according to bortezomib:2 injections per week for 2 weeks（ie on days 1,4,8 and 11） after 10 days of discontinuation（ie from day 12to day 21）.In vivo experiments in rats were conducted to investigate the difference in pharmacokinetic behavior of the last bortezomib in the optimal combination of Wuzhi Capsule/Duyiwei Capsule in different combinations:（1）Group 1:Only given on Day 1 Wuzhi Capsule/Duyiwei Capsule,on the 4th day,Wuzhi Capsule/Duyiwei Capsule and Bortezomib were administered at the same time.After the metabolism of the Wuzhi Capsule/Duyiwei capsule on the 4th day,the combination of Bortezomib on the 4th day was combined.Whether the metabolic behavior of Wuzhi Capsule still has influence;（2）Group 2:On the 1st and 4th day,Wuzhi Capsule/Duyiwei Capsule and Bortezomib were administered simultaneously,and the metabolism of Bortezomib on the 4th day after re-administration was investigated.Whether the behavior is affected.The results showed that the metabolism of bortezomib in the first group of rats after taking the Wuzhi Capsule/Duyiwei capsules after 3 days of metabolism was not significantly different from that of the blank control group on the 4th day;the second group,The combination of Wuzhi Capsule/Duyiwei Capsule and bortezomib can significantly inhibit the metabolism of bortezomib in rats on the 4th day.Among them,Wuzhi Capsule and Duyiwei Capsule can increase the AUC_0→t（ng·h/mL） of bortezomib respectively reached 183.7%and 251.1%.5.According to the frequency of clinical application of bortezomib,the effects of pretreatment of Wuzhi Capsule/Duyiwei Capsule（ie,combined administration on Day 1,Day4,Day 8,and Day 11）on the metabolic behavior of Bortezomib in vivo were investigated.The results showed that the conventional dose of Wuzhi Capsule/Duyiwei Capsule was pre-administered to the rats half an hour before the administration of bortezomib,which inhibited the metabolism of bortezomib in vivo,and the inhibition characteristics were similar.In the intervention group of Wuzhi Capsule,except for the combination of the first day,the AUC_0→t（ng·h/mL）of bortezomib was increased to 33.34%,and the in vivo increase of bortezomib AUC_0→t（ng·h/mL）of other treatment group was was more than 70%;in the same group of capsules,except for the combination of the first day,the AUC_0→t（ng·h/mL）of bortezomib was increased by 137.9%,and the other treatment groups were bortezomib.The increase in body AUC_0→t（ng·h/mL）exceeded 200%.6.To investigate the effect of Wuzhi Capsule/Duyiwei Capsule on the pharmacokinetics of bortezomib in a single,intravenous/subcutaneous injection of bortezomib.The results showed that the levels of AUC_0→t（ng·h/mL）after intravenous and subcutaneous injection of bortezomib in the combination group were increased by 38.45% and 162.4%,respectively.In the combination of the Duyiwei capsule group,bortezomib was administered intravenously and subcutaneously.The subsequent AUC_0→t（ng·h/mL）levels increased by 137.9% and 230.1%,respectively.ConclusionThis study firstly confirmed and verified the inhibitory effect of Wuzhi Capsule/Duyiwei Capsule on the metabolism of bortezomib in rats,but the characteristics of inhibiting the metabolism of bortezomib in vivo were not the same.Among them,the single-dose and different-dose Wuzhi capsule pretreatment administration showed a dose-dependent increase in the in vivo exposure level of bortezomib.The results of the medium-dose and high-dose groups were not significant,considering the clinical dose.In the case of feasibility,the conventional dose of 150 mg/kg is selected as the optimal dose;the optimal dose of Wuzhi capsules for multiple times（continuous 3 or 7 days）does not increase the exposure level of bortezomib;The optimal dose Wuzhi capsules is in accordance with the frequency of bortezomib administration,and is only used half an hour before the administration of bortezomib,which has a significant inhibitory effect on the metabolism of bortezomib in vivo.When the optimal dose of Wuzhi capsule is administered in a single combination,The in vivo metabolic inhibition of bortezomib after subcutaneous administration was stronger than that after the intravenous administration of bortezomib.Compared with other dose levels,the single dose of the conventional capsule（100 mg/kg） can make the in vivo exposure level of bortezomib the highest,so the dose is selected as the optimal dose;After administration of multiple doses（continuous 3 or 7 days）,it did not increase the exposure level of bortezomib;according to the frequency of clinical application of bortezomib,the optimal dose of the unique capsule was pretreated half an hour before the administration of bortezomib.It can exert a strong inhibitory effect on the metabolic behavior of bortezomib,and the inhibitory effect is stronger than that of the Wuzhi capsule using the same dosage regimen;the optimal dose of the Duyiwei capsule is administered in a single combination,and the bortezomib in vivo metabolic inhibition after subcutaneous administration is stronger than that after the intravenous administration of bortezomib,and the inhibition is stronger than that of the Wuzhi capsule of the same administration schedule.In summary,based on the combination of drugs,it can indeed inhibit the in vivo metabolism of bortezomib to achieve the expected goal of reduction and synergy;in the same dosage regimen,the in vivo exposure of bortezomib in the combination of the Duyiwei capsules can be higher than Wuzhi capsule combined with the drug group,and the group has confirmed in the early stage that the Duyiwei capsule has a certain protective effect on the BIPN of rats.Therefore,the Duyiwei capsule may be the best drug for the intervention of bortezomib with the dose reduction.The mechanism of inhibition of bortezomib metabolism is worth exploring further.