The Influence of Wuzhi Capsule on the Pharmacokinetics of Cyclophosphamide

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.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.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.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.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.