Effects of Wuzhi Capsule/Schisantherin A Combined with Cyclophosphamide on the Pharmacokinetics of Cyclophosphamide in Rats / 中国药房

ABSTRACT

OBJECTIVE: To study the effects of Wuzhi capsule/schisantherin A (SchA) combined with cyclophosphamide on the pharmacokinetics of cyclophosphamide (CTX) in rats. METHODS: A total of 36 rats were randomly divided into CTX group (via tail vein, iv, CTX solution 300 mg/kg), CTX+WZC group (ig, Wuzhi capsule 300 mg/kg+via tail vein, iv, CTX solution 300 mg/kg), CTX + SchA low-dose, medium-dose, high-dose and excessive high-dose groups (ig, SchA 30, 300, 3 000, 30 000 μg/kg+via tail vein, iv, CTX solution 300 mg/kg) with 6 rats in each group. Blood samples were collected from orbital venous plexus of rats before medication and 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 h after medication.UPLC-MS/MS method was applied for concentration determination of CTX and its metabolites [de-chloroethyl CTX (DC-CTX), 4-ketone CTX (4-keto CTX), carboxyl phosphamide (CPM)] in plasma of rats. The plasma concentration-time curve was obtained. The pharmacokinetic parameters were fitted by using DAS 2. 0 software. RESULTS: The maximum plasma concentration (cmax) of DC-CTX in CTX group, CTX+WZC group, CTX+SchA low-dose, medium-dose, high-dose and excessive high-dose groups were (22 167. 85 ±2 844. 93), (10 920. 53 ± 1 490. 89), (18 951. 29 ± 1 558. 81), (18 622. 08 ± 791. 19), (18 515. 20 ± 2 560. 61), (15 133. 21 ± 1 305. 07) μg/mL, respectively; the area under the curves (AUCo-48 h) were (173 864. 01 ± 65 342. 21), (100 996. 98 ± 33 530. 02), (137 028. 16 ± 45 975. 19), (131 650. 18 ± 53 196. 41), (113 699. 40 ± 34 131. 36), (110 773. 27 ± 30 307. 15) μg·mL/h, respectively. Compared with CTX group, cmax of DC-CTX in CTX group, CTX+SchA low-dose, medium-dose, high-dose and excessive high-dose groups were decreased by 50. 74％, 14. 51％, 16. 10％, 16. 48％, 31. 73％, respectively. AUC0-48 h were decreased by about 42. 23％, 21. 45％, 24. 63％, 33. 37％, 36. 55％, respectively; with statistical significance (P<0. 05). The pharmacokinetic indexes as t1/2, tmax had no significant change. CONCLUSIONS: To some degree, both WZC and SchA can reduce the generation of DC-CTX, which indicates both of them can inhibit CTX toxicity metabolism pathway so as to reduce the generation of toxic metabolite chloroacetaldehyde. The inhibitory effect of SchA on toxicity metabolism pathway is weaker than that of WZC, and does not have a dose-dependent inhibitory effect.