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. Objective: 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.

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

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.