Pharmacokinetic interactions between tacrolimus and Wuzhi capsule in liver transplant recipients: Genetic polymorphisms affect the drug interaction.

Wuzhi capsule (WZC), a commonly used Chinese patent medicine to treat various types of liver dysfunction in China, increases the exposure of tacrolimus (TAC) in liver transplant recipients. However, this interaction has inter-individual variability, and the underlying mechanism remains unclear. Current research indicates that CYP3A4/5 and drug transporters influence the disposal of both drugs. This study aims to evaluate the association between TAC dose-adjusted trough concentration (C/D) and specific genetic polymorphisms of CYP3A4/5, drug transporters and pregnane x receptor (PXR), and plasma levels of major WZC components, deoxyschisandrin and γ-schisandrin, in liver transplant patients receiving both TAC and WZC. Liquid chromatography-tandem-mass spectrometry was used to detect the plasma levels of deoxyschisandrin and γ-schisandrin, and nine polymorphisms related to metabolic enzymes, transporters and PXR were genotyped by sequencing. A linear mixed model was utilized to assess the impact of the interaction between genetic variations and WZC components on TAC lnC/D. Our results indicate a significant association of TAC lnC/D with the plasma levels of deoxyschisandrin and γ-schisandrin. Univariate analysis demonstrated three polymorphisms in the genes ABCB1 (rs2032582), ABCC2 (rs2273697), ABCC2 (rs3740066), and PXR (rs3842689) interact with both deoxyschisandrin and γ-schisandrin, influencing the TAC lnC/D. In multiple regression model analysis, the interactions between deoxyschisandrin and both ABCB1 (rs2032582) and ABCC2 (rs3740066), post-operative day (ß < 0.001, p < 0.001), proton pump inhibitor use (ß = -0.152, p = 0.008), body mass index (ß = 0.057, p < 0.001), and ABCC2 (rs717620, ß = -0.563, p = 0.041), were identified as significant factors of TAC lnC/D, accounting for 47.89% of the inter-individual variation. In summary, this study elucidates the influence of the interaction between ABCB1 and ABCC2 polymorphisms with WZC on TAC lnC/D. These findings offer a scientific basis for their clinical interaction, potentially aiding in the individualized management of TAC therapy in liver transplant patients.

Effects of CYP3A5 gene polymorphism and Wuzhi capsule on early postoperative tacrolimus exposure and adverse reactions in renal transplant patients / 中国药房

OBJECTIVE To investigate the effects of CYP3A5 gene polymorphism and Wuzhi capsule （WZ） on early postoperative tacrolimus exposure and adverse reactions in renal transplant patients. METHODS A total of 132 patients who underwent renal transplantation and received tacrolimus + mycophenolic acids + prednisone after operation in our hospital from September 2021 to September 2023 were selected and divided into four groups according to genotypes （CYP3A5*1 or CYP3A5*3/*3） and with or without WZ （“ +WZ” meant drug combination， “ +NO WZ” meant without combination）. The blood trough concentration/daily dose （c0/D） values of the four groups were analyzed on the 14th day， 1 month and 3 months after renal transplantation. The incidence of acute rejection and the incidence of tacrolimus-related adverse reactions within 3 months after transplantation were compared among 4 groups. RESULTS On the 14th day， 1 month and 3 months after surgery （except for the CYP3A5*1+WZ group）， c0/D values of CYP3A5*1 genotype patients were significantly lower than those of CYP3A5*3/*3 genotype patients regardless of whether they were treated with WZ additionally （P＜0.05）. Within 3 months after surgery， although there was no significant difference in the incidence of acute rejection and tacrolimus-related adverse reactions among the four groups （P＞ 0.05）， the incidence of hyperglycemia in patients with CYP3A5*3/*3 was higher （41.67%）. CONCLUSIONS CYP3A5 gene polymorphism is significantly related to tacrolimus c0/D in kidney transplant patients. Under the premise of c0 monitoring of tacrolimus， patients with CYP3A5*1 genotype should be given WZ as soon as possible after surgery to accelerate tacrolimus to reach the therapeutic concentration range， while CYP3A5*3/*3 genotype is not recommended to be given WZ because of the higher risk of hyperglycemia.

The pharmacokinetic study of tacrolimus and Wuzhi capsule in Chinese liver transplant patients.

Objectives: Wuzhi Capsule (WZC) is often administrated with tacrolimus in liver transplant patients to reduce the toxicity of tacrolimus and relieve the financial burden of patients. We aimed to investigate the interaction between Wuzhi Capsule (WZC) and tacrolimus in liver transplant patients. Methods: We applied the LC-MS/MS analytical method previously established to study the pharmacokinetic characteristics of the analytes in 15 liver transplant patients. CYP3A5 genotypes were determined in 15 donors and recipients, and they were categorized into CYP3A5 expressers and non-expressers respectively. Results: The influences of CYP3A5 in donors and recipients on the pharmacokinetics of tacrolimus with or without WZC were also studied. We found that 1) WZC could influence the metabolism of tacrolimus, which shortened the Tmax of tacrolimus and decreased V/F and CL/F. 2) Moreover, our results showed that, in donors, the CL/F of tacrolimus were significantly lower in CYP3A5 (CYP3A5*1) expressers (decreased from 24.421 to 12.864) and non-expressers (decreased from 23.532 to 11.822) when co-administration with WZC. For recipients, the decreased trend of CL/F of tacrolimus was seen when co-administrated with WZC by 15.376 and 12.243 in CYP3A5 expressers and non-expressers, respectively. Conclusion: In this study, the pharmacokinetics effects of WZC on tacrolimus were identified. The co-administration of WZC can increase the tacrolimus blood concentration in Chinese liver transplant patients in clinical practice.

Population pharmacokinetics and dosage optimisation of tacrolimus coadministration with Wuzhi capsule in adult liver transplant patients.

This study aimed to establish a population pharmacokinetic model of tacrolimus coadministration with Wuzhi capsule and optimise the dosage regimen in adult liver transplant patients.Totally 1327 tacrolimus trough concentrations from 116 adult liver transplant patients were obtained for model development. A one-compartment model with first-order absorption and elimination was used to analyse the data, and the final model was internally verified using a goodness-of-fit diagnostic plot, bootstrap methods, and visual prediction test. A total of 29 patients with 250 tacrolimus trough concentrations were used for external validation via prediction-based diagnostics. Additionally, the simulation was used to optimise the recommended dose of tacrolimus and Wuzhi capsules.The estimated apparent clearance and volume of the distribution of tacrolimus were 15.4 L/h and 1210 L, respectively. The tacrolimus daily dose, Wuzhi capsule daily dose, postoperative time, alanine transaminase, haemoglobin, total bilirubin, direct bilirubin, estimated glomerular filtration rate, and urea, concomitant with voriconazole and fluconazole, were identified as significant covariates affecting the pharmacokinetic parameters. Internal and external validation showed that the final model was stable and reliable for predicting performance.The final model could provide guidance for dosage optimisation of tacrolimus coadministered with Wuzhi capsules in adult liver transplantation patients.

Examination of the Impact of CYP3A4/5 on Drug-Drug Interaction between Schizandrol A/Schizandrol B and Tacrolimus (FK-506): A Physiologically Based Pharmacokinetic Modeling Approach.

Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug-drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes' inhibitory profiles, including a 50% inhibitory concentration (IC50) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.

Effects of Ethanolic Extract of Schisandra sphenanthera on the Pharmacokinetics of Rosuvastatin in Rats.

Purpose: Wuzhi capsule (WZ) is a proprietary Chinese medicine prepared from the ethanolic extract of Schisandra sphenanthera that is commonly used to treat liver injury. Statins are widely used in patients with hyperlipidemia, coronary heart disease, metabolic syndrome, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Co-administration of statins with WZ is possible in clinical practice. WZ has obvious inhibitory effects on the bioavailability of atorvastatin and simvastatin; however, the drug-herb interactions between WZ and rosuvastatin have not been addressed. We explored the effects of WZ on the pharmacokinetics of rosuvastatin in Sprague-Dawley rats to promote a rational use of statins. Methods: Eighteen male rats were randomly and evenly divided into three groups: control group (gavage feeding of rosuvastatin 10 mg·kg-1), single dose group (gavage feeding of a single dose of WZ 150 mg·kg-1 followed by rosuvastatin 10 mg·kg-1) and multiple doses group (gavage feeding of WZ 150 mg·kg-1 for 7 days followed by rosuvastatin 10 mg·kg-1 on the seventh day). Plasma samples were collected at different times before and after rosuvastatin administration. The other 18 female rats were tested the same way as the male rats. All samples were analyzed by a validated LC-MS/MS method, and the pharmacokinetic parameters were calculated using a non-compartmental model. Results: In both male and female rats, there were no statistically significant differences in rosuvastatin pharmacokinetic parameters between the control group, the single dose group, and the multi-dose group. Conclusion: Acute or long-term intake of WZ had no obvious effect on the pharmacokinetics of rosuvastatin, and therefore rosuvastatin could be used as an alternative to atorvastatin and simvastatin when WZ is clinically required in conjunction with statins. An appropriate pharmacodynamic study is needed to encourage the safe use of this combination.

Effect of drug combination on tacrolimus target dose in renal transplant patients with different CYP3A5 genotypes.

Various factors, including genetic polymorphisms, drug-drug interactions, and patient characteristics influence the blood concentrations of tacrolimus in renal transplant patients. In the present study, we established a population pharmacokinetic model to explore the effect of combined use of Wuzhi capsules/echinocandins and the patients' biochemical parameters such as haematocrit on blood concentrations and target doses of tacrolimus in renal transplant patients with different CYP3A5 genotypes. The aim of the study was to propose an individualised tacrolimus administration regimen for early renal transplant recipients.In this retrospective cohort study, we included 240 renal transplant recipients within 21 days of surgery (174 males and 66 females, mean age 39.4 years), who received tacrolimus alone (n = 54), in combination with Wuzhi capsules (99) or caspofungin (57) or micafungin (30). We collected demographic characteristics, clinical indicators, CYP3A5 genotypes, and 1950 steady-state concentrations of tacrolimus and included them in population pharmacokinetic model. An additional 110 renal transplant recipients and 625 steady-state concentrations of tacrolimus were included for external validation of the model. The population pharmacokinetic model was established and Monte Carlo was used to simulate probabilities for achieving the target concentration for individual tacrolimus administration.A two-compartment model of first-order absorption and elimination was developed to describe the population pharmacokinetics of tacrolimus. CYP3A5 genotypes and co-administration of Wuzhi capsules, as well as time after renal transplantation and haematocrit, were important factors affecting the clearance of tacrolimus. We found no obvious change in trend in the scatter plot of tacrolimus clearance rate vs. haematocrit. The Monte Carlo simulation indicated the following recommended doses of tacrolimus alone: 0.14 mg⋅kg-1⋅d-1 for genotype CYP3A5*1*1, 0.12 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.10 mg⋅kg-1⋅d-1 for CYP3A5*3*3. For patients receiving the combination with Wuzhi capsules, the recommended doses of tacrolimus were 0.10 mg⋅kg-1⋅d-1 for CYP3A5*1*1, 0.08 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.06 mg⋅kg-1⋅d-1 for CYP3A5*3*3 genotypes. Caspofungin or micafungin had no effect on the clearance of tacrolimus in renal transplant recipients.The population pharmacokinetics of tacrolimus in renal transplant patients was evaluated and the individual administration regimen of tacrolimus was simulated. For early kidney transplant recipients receiving tacrolimus treatment, not only body weight, but also CYP3A5 genotypes and drugs used in combination should be considered when determining the target dose of tacrolimus.

Effect of Wuzhi capsules on cyclosporine A concentration in children with aplastic anemia immunotherapy: a single-center observational study.

OBJECTIVE: This research aimed to assess the effect of Wuzhi capsules (WZC) on the blood concentration of cyclosporine A (CsA) in renal aplastic anemia recipients. METHODS: This observational study was carried out at the Hematology Oncology Center, Beijing Children's Hospital between November 2019 and February 2020. A total of 102 Chinese AA recipients receiving CsA (6 mg/kg/d) with or without WZC were included in this study. Baseline data, such as age, therapeutic drug monitoring data, and follow-up information were collected. The promotion concentration of CsA was calculated, and the pharmaceutical economics evaluation with combination of two drugs was also carried out. RESULTS: Dose- and body weight-adjusted trough concentrations (C0/D/W) of CsA in the WZC group were found to be significantly higher than that in the non-WZC group (P < 0.01). The average C0 of CsA increased by (63.27 ± 45.81) ng/mL. The incidence of adverse events was also not statistically significant between the two groups (P > 0.05). CONCLUSION: WZC can increase CsA concentration without increasing adverse drug reactions. Efficient and convenient immunosuppressive effects on AA recipients can be achieved via immunosuppressant therapy in combination with WZC.

Effect of hepar-protecting Wuzhi capsule on pharmacokinetics and dose-effect character of tacrolimus in healthy volunteers.

Wuzhi capsule (WZC), a preparation of Fructus Schisandra sphenanthera extract, has been used widely for the treatment of viral and drug-induced hepatitis in China. This study aimed to determine the pharmacokinetic parameters of tacrolimus (TAC) when co-administered with WZC and the dose-effect of WZC on tacrolimus in healthy volunteers. The effect of an increased dosage of WZC (1, 2, 6, and 8 capsules once daily) on the relative oral exposure of tacrolimus was assessed to explore the dose-response relationship between WZC and tacrolimus using bioanalysis, pharmacokinetic, and genotypical analyses. The influence of CYP3A5 and MDR1 genetic polymorphisms on the WZC dose was elucidated by maintaining the Ctrough of tacrolimus in Chinese healthy volunteers. When co-administered with WZC, the Tmax of tacrolimus was increased significantly while the apparent oral clearance was decreased. The plasma tacrolimus level in volunteers with high CYP3A5 expression was much lower than that in those with mutant CYP3A5. However, polymorphisms of MDR1 exon26 C3435T, exon21 G2677T/A, and exon12 C1236T were not associated with plasma tacrolimus levels. Our findings provide important information on interactions between modern medications and herbal products, thus facilitating a better usage of tacrolimus in patients receiving WZC.

Study on alleviate effect of Wuzhi capsule (Schisandra sphenanthera Rehder & E.H. Wilson extract) against mycophenolate mofetil-induced intestinal injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra sphenanthera Rehder & E.H. Wilson (S. sphenanthera) is a botanical medicine included in the 2020 edition of the ChP that has a variety of medicinal activities, including hepatoprotective, anticancer, antioxidant and anti-inflammatory properties. Wuzhi capsule (WZ) is a proprietary Chinese medicine made from an ethanolic extract of S. sphenanthera that is commonly used to treat drug-induced liver injury. However, there are no research reports exploring the effects of WZ on the prevention of mycophenolate mofetil (MMF)-induced intestinal injury and its underlying mechanisms. AIM OF THE STUDY: This experiment aimed to evaluate the ameliorative effect of WZ on MMF-induced intestinal injury in mice and its underlying mechanisms. MATERIALS AND METHODS: A mouse model of MMF-induced intestinal injury was established and treated with WZ during the 21-day experimental period. The pathological characteristics of the mouse ileum were observed. Tight junction (TJ) protein changes were observed after immunofluorescence staining and transmission electron microscopy, and ROS levels were measured by using DHE fluorescent dye and the TUNEL assay for apoptosis. The expression of p65, p-p65, IκBα, p-IκBα, the TJ proteins occludin and ZO-1 and the apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3 and caspase-3 were analysed by Western blot. Levels of DAO, ET, TNF-α, IL-1ß, IL-6, IFN-γ, MDA and SOD were analysed by using kits. RESULTS: MMF activated the NF-κB signaling pathway to cause intestinal inflammation, increased intestinal permeability, changed the expression of TJ protein in the intestinal epithelium, and increased oxidative stress and apoptosis levels. WZ significantly downregulated the expression of p-p65 and p-IκBα to relieve the inflammatory response, reduced intestinal permeability, maintained intestinal TJ protein expression, and reduced intestinal oxidative stress and apoptosis. CONCLUSION: Our research suggested that MMF can cause intestinal injury; by contrast, WZ may exert anti-inflammatory, antioxidant and apoptosis-reducing effects to alleviate MMF-induced intestinal injury.

Beneficial effects of Wuzhi Capsule on tacrolimus blood concentrations in liver transplant patients with different donor-recipient CYP3A5 genotypes.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (Tac) is an immunosuppressant that is widely used to prevent allograft rejection in patients after liver transplantation. Its metabolism mainly depends on the cytochrome P450 3A5 (CYP3A5), which has genetic polymorphisms. Recently, a Chinese herbal medicine known as Wuzhi Capsule (WZC) was shown to increase Tac blood concentrations by inhibiting the activity of CYP3A in animal studies in rats. To date, it remains unexplored whether WZC can be efficiently used to enhance the blood concentration of Tac in liver transplant patients with different donor-recipient CYP3A5 genotypes. METHODS: A total of 185 liver transplant patients were enrolled and two-way ANOVA was carried out, then they were divided into four groups according to the combinations of donor-recipient CYP3A5 phenotypes. WZC was given to patients when the dose of Tac was ≥4 mg, and the dose-adjusted C0 (C0 /D) of Tac measured twice in succession was ≤1 ng/ml/mg. The blood trough concentration of Tac (C0 ), C0 /D, and dose- and body weight-adjusted C0 (C0 /D/W) was analysed on days 7 and 14 after liver transplantation. RESULTS: The genotypes of donor and recipient or WZC had significant effects on C0, C0/D and C0/D/W. There were significant differences in the Tac blood concentrations between the groups. The recipient expression (*1)/donor expression (*1) (R+/D+) group had the lowest C0 , C0 /D and C0 /D/W among the four groups. Furthermore, a larger proportion of patients in the CYP3A5 expression groups required Tac dose adjustment to achieve a therapeutic effect and were given Tac with WZC. Notably, the use of WZC significantly increased the blood concentrations of Tac in the CYP3A5 expression groups and greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC in the CYP3A5 expression groups. What is more, WZC reduced the hospitalization cost of patients to a certain extent. WHAT IS NEW AND CONCLUSION: WZC significantly increased the C0 , C0 /D and C0 /D/W in the CYP3A5 expression groups and reduced the hospitalization expenses of patients to a certain extent. What is more, greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC.

The Influence of Wuzhi Capsule on the Pharmacokinetics of Cyclophosphamide.

BACKGROUND: Cyclophosphamide is approved for the treatment of a variety of tumors, yet the use of cyclophosphamide is limited by kidney and liver toxicity. In the clinic, the Wuzhi capsule is approved to attenuate cyclophosphamide toxicity in the kidney and liver. OBJECTIVES: We aimed to investigate the effects of the principal ingredients of Wuzhi capsule, schisandrin A (SIA) and schisantherin A (STA), on the pharmacokinetics of cyclophosphamide. METHODS: The essential pharmacokinetic data and physicochemical parameters of SIA, STA, and cyclophosphamide were collected. Physiologically based pharmacokinetic (PBPK) models of SIA, STA, and cyclophosphamide were built in Simcyp Simulator and verified using published clinical pharmacokinetic data. The verified PBPK models were used to predict potential herb-drug interactions (HDIs) between cyclophosphamide and SIA and STA in cancer patients. RESULTS: The area under the plasma concentration-time curve (AUC) of cyclophosphamide was increased by 18% and 1% when co-administered with STA and SIA at a single dose, respectively, and increased by 301% and 29% when co-administered with STA and SIA at multiple doses, respectively. The maximum concentration (Cmax) of cyclophosphamide was increased by 75% and 7% when co-administered with STA and SIA at multiple doses, respectively. CONCLUSION: The AUC and Cmax of cyclophosphamide were increased when cyclophosphamide was combined with the Wuzhi capsule, compared to cyclophosphamide alone. Our study shows that the adverse drug reactions and toxicity of cyclophosphamide should be closely monitored and an effective dosage adjustment of cyclophosphamide may need to be considered when co-administered with the Wuzhi capsule.

UPLC-MS/MS method for the determination of Lenvatinib in rat plasma and its application to drug-drug interaction studies.

Lenvatinib (LEN) is a multitargeted tyrosine kinase inhibitor registered for the first-line treatment of unresectable advanced hepatocellular carcinoma. Wuzhi capsule (WZC) is a traditional Chinese medicine preparation; it is used to decrease the aminotransferase level of the liver and protect liver function. Thus, patients with hepatocellular carcinoma (HCC) are potentially treated with a combination of LEN and WZC, but there is no information about the interaction between the two drugs. We developed a simple, rapid, and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantitative determination of lenvatinib in rat plasma. Liquid-liquid extraction of plasma samples was carried out with ethyl acetate. Chromatographic separation of analyte was performed using gradient elution with acetonitrile and 0.1% formic acid water. The positive ion multi-response monitoring mode was used, and the target of the parent and daughter ions of LEN and IS were m/z 427.1→370 and m/z 432.1→370, respectively. All the validation projects were in accordance with the guidelines. Good linearity of 0.2-1000 ng/mL (r > 0.999) was achieved. The lower limit of quantification was 0.2 ng/mL. The precision and accuracy are acceptable. The method was successfully applied to pharmacokinetics and drug interaction analysis. The results show that WZC can significantly increase the Cmax (maximum plasma concentration) and AUC (area under the concentration-time curve) of LEN. An UPLC -MS/MS method that can be used for studying drug-drug interaction as a valuable tool was developed in this study. Drug-drug interactions were observed between the WZC and LEN.

Clinical Evaluation of the Efficacy and Safety of Co-Administration of Wuzhi Capsule and Tacrolimus in Adult Chinese Patients with Myasthenia Gravis.

BACKGROUND: Tacrolimus has been recommended as an effective immunosuppressant for patients with myasthenia gravis (MG), while the high price, variable bioavailability, and narrow therapeutic window restrict its clinical application. Wuzhi capsule (WZC) could improve tacrolimus blood concentration by inhibiting the metabolism of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). There are few studies focused on the coadministration of WZC and tacrolimus in autoimmune diseases. This study was aimed at quantifying the efficacy and safety of coadministration of WZC and tacrolimus in adult Chinese patients with MG. METHODS: In this retrospective study, 122 patients with MG on tacrolimus were enrolled. The initial tacrolimus dose was 2 mg/d. Patients with standard initial tacrolimus concentration were classified into group A (standard-dose group). Those failed to reach target concentration were divided into group B (high-dose group) and group C (co-administering WZC group), according to treatment adjustment of increasing tacrolimus dose and co-administration of WZC, respectively. A logistic analysis was used to identify factors associated with clinical outcome. Adverse drug reactions (ADRs) were recorded for safety analysis. RESULTS: The tacrolimus concentration after coadministration of WZC was remarkably increased. It was higher compared with simply increasing the tacrolimus dose (p<0.001). The multivariate logistic analysis indicated that the baseline quantitative MG score was a predictive factor for clinical outcomes (OR=0.189; 95% CI 0.082-0.436; p<0.001). Fourteen patients (11.5%) reported ADRs after tacrolimus therapy. ADRs incidence was not related to WZC coadministration. CONCLUSION: The coadministration of WZC and tacrolimus can substantially elevate the tacrolimus concentration. It is a safe and economic treatment for adult Chinese patients with MG. Patients with a worse disease condition tend to present a better clinical outcome after tacrolimus therapy.

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp.

BACKGROUND: Methotrexate (MTX) is an important anticancer agent and immunosuppressant with a narrow therapeutic window. Wuzhi capsule (WZC) is an extract of Schisandra which is widely used to treat liver diseases. Co-administration of MTX and WZC is common in the clinical setting, but research on the interaction between WZC and MTX is limited. This study aimed to investigate the effects of WZC on the pharmacokinetics of MTX in rats and to explore the role of membrane transport proteins OAT1/3 and P-gp in the interaction of these drugs. METHODS: Plasma MTX concentration was detected by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), and the messenger RNA (mRNA) and protein expression of OAT1/3 and P-gp was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses, respectively. RESULTS: The study results revealed that co-administration of WZC decreased the CLz/F and Vz/F of MTX, increased the Cmax and area under the curve [(AUC)0-24 h] of MTX, and inhibited OAT1/3 expression in the kidney and P-gp expression in the small intestine. CONCLUSIONS: The findings suggested that there is a drug interaction between WZC and MTX and that OAT1/3 in the kidney and P-gp in the small intestine may be the main targets mediating the drug interaction, and attention should be paid when they are used in combination.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

Investigation of the Impact of CYP3A5 Polymorphism on Drug-Drug Interaction between Tacrolimus and Schisantherin A/Schisandrin A Based on Physiologically-Based Pharmacokinetic Modeling.

Wuzhi capsule (WZC) is commonly prescribed with tacrolimus in China to ease drug-induced hepatotoxicity. Two abundant active ingredients, schisantherin A (STA) and schisandrin A (SIA) are known to inhibit CYP3A enzymes and increase tacrolimus's exposure. Our previous study has quantitatively demonstrated the contribution of STA and SIA to tacrolimus pharmacokinetics based on physiologically-based pharmacokinetic (PBPK) modeling. In the current work, we performed reversible inhibition (RI) and time-dependent inhibition (TDI) assays with CYP3A5 genotyped human liver microsomes (HLMs), and further integrated the acquired parameters into the PBPK model to predict the drug-drug interaction (DDI) in patients with different CYP3A5 alleles. The results indicated STA was a time-dependent and reversible inhibitor of CYP3A4 while only a reversible inhibitor of CYP3A5; SIA inhibited CYP3A4 and 3A5 in a time-dependent manner but also reversibly inhibited CYP3A5. The predicted fold-increases of tacrolimus exposure were 2.70 and 2.41, respectively, after the multidose simulations of STA. SIA also increased tacrolimus's exposure but to a smaller extent compared to STA. An optimized physiologically-based pharmacokinetic (PBPK) model integrated with CYP3A5 polymorphism was successfully established, providing more insights regarding the long-term DDI between tacrolimus and Wuzhi capsules in patients with different CYP3A5 genotypes.

Analysis of the clinical efficacy of three kinds of Chinese patent medicines assisting tacrolimus in the treatment of nephrotic syndrome / 中国临床药理学与治疗学

AIM: To explore the clinical efficacy of three different kinds of Chinese patent medicines combined with tacrolimus and hormone in the treatment of nephrotic syndrome (NS). METHODS: A total of 199 patients with NS treated in department of nephrology of our hospital from January 2018 to December 2020 were analyzed retrospectively. All patients were treated with tacrolimus combined with hormone regimen for 12 weeks. According to different treatment schemes, they were divided into 4 groups: 57 cases in the control group, 51 cases in the Bailing capsule group (Bailing group), 55 cases in the Huangkui capsule group (Huangkui group) and 36 cases in the Wuzhi capsule group (Wuzhi group). The general data of patients, the biochemical indexes before and after treatment, and the tacrolimus blood concentration were collected. RESULTS: After 12 weeks of treatment, 24 h UTP and ALB of each group were statistically different (P<0.01). Compared with the control group, Bailing group had statistically significant differences in the reduction of TG and TC (P<0.05), Huangkui group had statistically significant differences in the reduction of 24 h UTP and serum TC (P<0.05), Wuzhi group had statistically significant differences in the reduction of 24 h UTP and AST (P<0.05). The steady-state trough concentration (C

Initial dose optimization of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration with Wuzhi capsule.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus, an immunosuppressant, has been used to treat paediatric systemic lupus erythematosus, but the optimal initial regimen is not clear. The purpose of this study was to explore the optimal initial dose of tacrolimus for children with systemic lupus erythematosus using population pharmacokinetics and pharmacogenomics. METHODS: Clinical information, tacrolimus concentrations and related genetic polymorphisms were incorporated into a model using non-linear mixed-effects modelling (NONMEM) analysis. RESULTS AND DISCUSSION: The results showed that weight, the CYP3A5 genotype and combined treatment with Wuzhi capsule can affect tacrolimus clearance in children with systemic lupus erythematosus. Furthermore, at the same weight, the ratios of tacrolimus clearance were 1:2.49:0.57:1.4193 from people who were CYP3A5*3/*3 and did not take Wuzhi capsule, people who had the CYP3A5*1 allele and did not take Wuzhi capsule, people who were CYP3A5*3/*3 and took Wuzhi capsule, and people who had the CYP3A5*1 allele and took Wuzhi capsule, respectively. In addition, we found that 0.10 mg/kg split into two doses was suitable for people with weights from 10 to 60 kg who were CYP3A5*3/*3 and did not take Wuzhi capsule, who were CYP3A5*3/*3 and took Wuzhi capsule, and who had the CYP3A5*1 allele and took Wuzhi capsule. In people who had the CYP3A5*1 allele and did not take Wuzhi capsule, 0.15 mg/kg split into two doses was appropriate for those with weights from 10 to 40 kg and 0.10 mg/kg split into two doses was appropriate for those with weights from 40 to 60 kg. WHAT IS NEW AND CONCLUSION: This study is the first study to recommend an optimal initial regimen of tacrolimus for children with systemic lupus erythematosus based on the CYP3A5 polymorphism and coadministration of Wuzhi capsule.

Effect of wuzhi capsules on the blood concentration of tacrolimus relative to diltiazem and CYP3A5 gene polymorphisms / 药学学报

To determine the relationship between the effect of wuzhi capsules on the blood concentration of tacrolimus as compared to diltiazem and with regard to cytochrome P450 (CYP)3A5 gene polymorphisms, 170 patients who underwent renal transplantation from November 2014 to March 2018 and used tacrolimus combined with diltiazem 30 mg bid were selected in this study retrospectively. Patients were divided into an observation group (105 patients) and a control group (65 patients) according to whether they used wuzhi capsules after the operation. The polymorphisms of CYP3A5*3 were determined and the effect of wuzhi capsules on the blood concentration of tacrolimus, as compared with that of diltiazem was determined in patients with different CYP3A5*3 genotypes. This study complies with relevant ethical norms. The results show that compared with diltiazem, an increase of tacrolimus C0/D was significantly correlated with the patient's CYP3A5*3 genotype in both the self-control and the control group. CYP3A5 expressers in the observation group were able to increase the tacrolimus C0/D by about 76.8% by replacing the wuzhi capsules with diltiazem, but this effect was not observed in CYP3A5 non-expressers. In CYP3A5 expressers wuzhi capsules had a greater ability relative to diltiazem to increase the blood concentration of tacrolimus.