Effects of Wuzhi Capsules on Blood Concentration of Tacrolimus in Renal Transplant Recipients

Lin, Yan; Yang, Zhiqiang; Shi, Yunying; Ren, Jing; Yang, Cuili; Wan, Zhengli; Bai, Yang; Luo, Limei; Wang, Lanlan; Li, Yi

doi:10.12659/aot.918980

Cited by 19 publications

(22 citation statements)

References 34 publications

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“…In recent years, studies in human and animals have confirmed the positive impact of WZC on increasing tacrolimus blood concentration, which by inhibiting CYP3A‐mediated metabolism and P‐gp‐mediated efflux of tacrolimus 5,17 . The effects of clinical and genetic variables on tacrolimus pharmacokinetics were quantified by examining changes in tacrolimus concentration/dose ratios ( C 0 / D ), a measure used in numerous previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…There are two main active components in WZC: schisantherin A (STA) and schisandrin A (SIA). Previous studies have indicated that tacrolimus blood concentrations were increased in the presence of Schisandra sphenanthera extract in transplant recipients 4,5 . Several studies have indicated that WZC can significantly increase tacrolimus whole blood concentration 6,7 …”

Section: What Is Known and Objectivementioning

confidence: 99%

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Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Cheng

Wang

et al. 2021

J Clin Pharm Ther

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What is known and objective Tacrolimus (FK506), an effective and potent calcineurin inhibitor, is the cornerstone of immunosuppression after kidney transplantation. Wuzhi capsule (WZC), a prescribed ethanol extract of Nan‐Wuweizi (Schisandra sphenanthera), is widely prescribed for kidney transplant recipients for the maintenance of tacrolimus concentration in clinical settings. Previous studies have demonstrated that WZC can increase the blood concentration of tacrolimus. However, it remains controversial whether to use WZC can be used to increase tacrolimus concentration in clinical practice. Our study aimed to evaluate the efficacy and safety of WZC combined with tacrolimus in the treatment of kidney transplant recipients. Methods One hundred and ninety four Chinese kidney transplant recipients were included in this retrospective study. The recipients were divided into two groups (non‐WZC group and WZC group). We investigated the effects of WZC on tacrolimus in terms of tacrolimus metabolism, laboratory tests, pharmacogenomics, renal function and adverse reactions. Results and Discussion The concentration/dose (C0/D) of tacrolimus was significantly higher in the WZC group than the non‐WZC group. The laboratory findings of blood routine tests, liver and kidney function were not significantly different between the two groups. The CYP3A5 genotype showed clearly associated with tacrolimus C0/D, whereas no significant difference was observed in patients with CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. The improvement of C0/D by administration of WZC was significant in CYP3A5 expressers compared to non‐expressers. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached the target tacrolimus concentration than the non‐WZC group. No significant differences in renal function and adverse reactions were observed between the groups. What is new and conclusion Wuzhi capsule can increase tacrolimus concentration without negative effects on renal function and adverse reactions, especially in CYP3A5 expressers. Efficient and economical synergistic effects can be achieved by the combined administration of WZC in kidney transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Section: What Is Known and Objectivementioning

confidence: 99%

Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Cheng

Wang

et al. 2021

J Clin Pharm Ther

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“…WZC co‐administration should be considered when the concentration of TAC is lower than 4 ng/ml, which may be due to the higher metabolic activity resulted from genotype mutation of CYP3A5 39 . A study of Yan L et al 12 showed that WZC could increase TAC trough concentration without adverse effects on allograft function, especially in CYP3A5 expressers. Routine therapeutic drug monitoring (TDM) testing can provide guidance for adjusting the TAC dose.…”

Section: Discussionmentioning

confidence: 99%

“…Drug‐drug interactions (DDIs) played a vital role in TAC pharmacokinetics 12 . Wuzhi capsule (WZC) is one of the Traditional Chinese Medicines (TCM) which is previously approved for liver function protection 13 .…”

Section: What Is Known and Objectivementioning

confidence: 99%

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

et al. 2021

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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.

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“…After LT, patients commonly require oral immunosuppressive agents as anti-rejection therapy to prevent allograft rejection. Tacrolimus (Tac) is widely used in most immunosuppressive regimes for LT patients mainly due to its high immunosuppressive effects and low drug-related side effects (6)(7)(8). However, both rejection of the transplanted liver and Tac-related adverse effects occur after LT in a proportion of patients.…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of traditional Chinese medicine Wuzhi Capsule on tacrolimus dose requirements in liver transplant patients with different donor-recipient CYP3A5 genotypes

Sun

et al. 2021

Preprint

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Background/Aims: Tacrolimus (Tac) is an immunosuppressant that is widely used to prevent allograft rejection in patients after liver transplantation. Recently, a Chinese herbal medicine known as Wuzhi Capsule (WZC) was shown to increase Tac blood concentrations by inhibiting the activity of CYP3A5 in animal studies in rats. To date, it remains unexplored whether WZC can be used to reduce the dose requirement for Tac in liver transplant patients with different donor-recipient CYP3A5 genotypes. Materials and Methods: A total of 185 liver transplant patients were enrolled and were divided into four groups according to the combinations of donor-recipient CYP3A5 phenotypes. WZC was given to patients who had C0/D of Tac ≤ 1 ng/ml per mg and required a dose of Tac ≥ 4 mg. Results: The 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. Conclusion: WZC significantly increased the C0, C0/D, and C0/D/W in the CYP3A5 expression groups.

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Effects of Wuzhi Capsules on Blood Concentration of Tacrolimus in Renal Transplant Recipients

Cited by 19 publications

References 34 publications

Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients

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

Beneficial effects of traditional Chinese medicine Wuzhi Capsule on tacrolimus dose requirements in liver transplant patients with different donor-recipient CYP3A5 genotypes

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