ABSTRACT
To determine the relationship between the effect of wuzhi capsules on the blood concentration of tacrolimus as compared to diltiazem and with regard to cytochrome P450 (CYP)3A5 gene polymorphisms, 170 patients who underwent renal transplantation from November 2014 to March 2018 and used tacrolimus combined with diltiazem 30 mg bid were selected in this study retrospectively. Patients were divided into an observation group (105 patients) and a control group (65 patients) according to whether they used wuzhi capsules after the operation. The polymorphisms of CYP3A5*3 were determined and the effect of wuzhi capsules on the blood concentration of tacrolimus, as compared with that of diltiazem was determined in patients with different CYP3A5*3 genotypes. This study complies with relevant ethical norms. The results show that compared with diltiazem, an increase of tacrolimus C0/D was significantly correlated with the patient's CYP3A5*3 genotype in both the self-control and the control group. CYP3A5 expressers in the observation group were able to increase the tacrolimus C0/D by about 76.8% by replacing the wuzhi capsules with diltiazem, but this effect was not observed in CYP3A5 non-expressers. In CYP3A5 expressers wuzhi capsules had a greater ability relative to diltiazem to increase the blood concentration of tacrolimus.
ABSTRACT
Objective To compare the effect of Compound Wurenchun Capsule (CWC) and Wuzhi Capsule (WZC), CWC single and long-term administration on the pharmacokinetics of tacrolimus (FK506). Methods Twenty-four rats were randomly divided into FK506, CWC + FK506, WZC + FK506 and CWC7d + FK506 groups, with six rats in each group. Rats in FK506, CWC + FK506, and WZC + FK506 groups were given a single gavage with FK506, CWC + FK506, and WZC + FK506 respectively. Rats in CWC7d + FK506 group was given a multiple gavage regimen of daily CWC gavage for 6 d, CWC and FK506 on day 7. Blood sample from orbit before and after gavage at different time points (CWC7d + FK506 group before and after the last administration) were tested for FK506 blood concentration and the pharmacokinetic parameters were calculated. Results Compared with FK506 group, peak blood concentration (Cmax) and area under the curve (AUC0-t) of FK506 increased significantly (P < 0.05, 0.01), body retention time (MRT0-t) of FK506 prolonged significantly (P < 0.05, 0.01), the apparent volume of distribution (V/F) and the drug elimination rate (CL/F) of FK506 decreased significantly (P < 0.01) in WZC + FK506 and CWC + FK506 groups. Compared with WZC + FK506 group, AUC0-t of FK506 increased significantly (P < 0.01), CL/F of FK506 decreased significantly (P < 0.01) in CWC + FK506 group. Compared with CWC + FK506 group, Cmax of FK506 increased significantly (P < 0.01), time to peak blood concentration (tmax) of FK506 shortened significantly (P < 0.05), AUC0-t of FK506 increased significantly (P < 0.05), CL/F of FK506 decreased significantly (P < 0.05) in CWC7d + FK506 group. Conclusion Both CWC and WZC can increase Cmax and AUC0-t, prolong MRT0-t, reduce V/F and CL/F of FK506. CWC is better than WZC in increasing AUC0-t and inhibiting CL/F of FK506. CWC long-term administration is better than single-dose in improving Cmax, AUC0-t and reducing tmax of FK506.
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.