Drug Interaction of Dasatinib with Thymoquinone: A Pharmacokinetic Study in Rats

Dasatinib (DAS), a multi-kinase inhibitor targeting Src and BCR-ABL families, is approved for Ph+ acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CML). Its metabolism by CYP3A4 and transported by efflux pump P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) render it susceptible to drug, food, and herbal interactions. This study investigated the potential impact of thymoquinone (TQ) co-administration on dasatinib pharmacokinetics (PK) and the subsequent risk of altered efficacy or toxicity. Wistar rats were pretreated with a daily oral dose of TQ (40 mg/kg) for one week before receiving a single oral dose of DAS (25 mg/kg). Blood samples were collected at different time points, and plasma concentrations of DAS were measured using UPLC-MS/MS. A non-compartmental analysis was applied to calculate the PK parameters of DAS. Additionally, the impact of TQ treatment on hepatic and intestinal protein expressions of CYP3A4, Pgp and BCRP were investigated using Western blot analysis. TQ pretreatment significantly altered the disposition of DAS in animals as compared to untreated animals. More specifically, a substantial increase in DAS Cmax (213.26%), AUC_0-t (166.53%), AUMC_0-∞ (0.34%), Kel (93.85%) and Tmax (83.33%) were observed (p<0.05). In addition, a significant reduction in DAS Vd (67.70%) and clearance CL (36.35%) of were evident in the TQ treatment group (p<0.05). Furthermore, TQ pretreatment inhibited CYP3A4 and Pgp and BCRP1 in the liver and lumen tissues. TQ pretreatment significantly alters the disposition of DAS in rats. This is likely due to an increase in DAS bioavailability via a modulation in the protein expressions of CYP3A4 and Pgp and BCRP1 in the liver and lumen tissues. Thus, the concurrent intake of TQ-containing products with DAS can lead to a serious interaction. Further clinical studies are warranted to evaluate the clinical impact of such observations.