Context: Peimine and paeoniflorin can be combined for the treatment of cough in paediatrics. The interaction during the co-administration could dramatically affect the bioavailability of drugs. Objective: The interaction between peimine and paeoniflorin was investigated in this study. Materials and methods: The pharmacokinetics of paeoniflorin (20 mg/kg) with or without the coadministration of peimine (5 mg/kg for 10 days before paeoniflorin) was orally investigated in Sprague-Dawley rats (n ¼ 6). The group without the peimine was set as the control group. The metabolic stability of paeoniflorin was studied in rat liver with microsomes. The effect of peimine on the absorption of paeoniflorin was investigated with Caco-2 cell monolayers. Results: The C max (244.98 ± 10.95 vs. 139.18 ± 15.14 lg/L) and AUC (0-t) (3295.92 ± 263.02 vs. 139.18 ± 15.14 hÁlg/L) of paeoniflorin was increased by peimine. The t 1/2 was prolonged from 5.33 ± 1.65 to 14.21 ± 4.97 h and the clearance was decreased from 15.43 ± 1.75 to 4.12 ± 0.57 L/h/kg. Consistently, peimine increased the metabolic stability of paeoniflorin with rat liver microsomes with the increased t 1/2 (56.78 ± 2.62 vs. 26.33 ± 3.15 min) and the decreased intrinsic clearance (24.42 ± 3.78 vs. 52.64 ± 4.47 lL/ min/mg protein). Moreover, the transportation of paeoniflorin was also inhibited by peimine as the efflux ratio decreased from 3.06 to 1.63. Discussion and conclusions: Peimine increased the systemic exposure of paeoniflorin through inhibiting the activity of CYP3A4 and P-gp. These results provide a reference for further in vivo studies in a broader population.

Context Anemarsaponin BII is one of the most active saponins isolated from Anemarrhena asphodeloides Bunge (Asparagaceae), a commonly used Chinese traditional paediatric medicine. Objective This study investigates the effects of anemarsaponin BII on the activity of CYP450s to provide more guidance for the clinical use of anemarsaponin BII. Materials and methods Using various diagnostic substrates, the effects of a fixed concentration of anemarsaponin BII (100 μM) on the activity of eight main isoforms of CYP450s (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6 and 2E1) was first studied with pooled human liver microsomes (HLMs). Then, dose-dependent (0, 2.5, 5, 10, 25, 50 and 100 μM anemarsaponin BII) and time-dependent (0, 5, 10, 15 and 30 min) experiments were performed to obtain corresponding kinetic parameters. Results Anemarsaponin BII showed significant inhibitory effects on the activity of CYP3A4, 2D6 and 2E1 with the IC 50 values of 13.67, 16.26 and 19.72 μM. Anemarsaponin BII acted as a non-competitive inhibitor of CYP3A4 with the K I value of 6.72 μM and competitive inhibitors of CYP2D6 and 2E1 with the K I values of 8.26 and 9.82 μM, respectively. Additionally, the inhibition of CYP3A4 was revealed to be time-dependent with the K I value of 4.88 μM and the K inact value of 0.053/min. Conclusions The inhibitory effect of anemarsaponin BII on the activity of CYP3A4, 2D6 and 2E1 indicated the potential drug–drug interaction between anemarsaponin BII and drugs metabolized by these CYP450s. Further in vivo experiments are needed to validate the potential drug–drug interactions.

Context: Peucedanol is a major extract of Peucedanum japonicum Thunb. (Apiaceae) roots, which is a commonly used herb in paediatrics. Its interaction with cytochrome P450 enzymes (CYP450s) would lead to adverse effects or even failure of therapy. Objective: The interaction between peucedanol and CYP450s was investigated. Materials and methods: Peucedanol (0, 2.5, 5, 10, 25, 50, and 100 lM) was incubated with eight human liver CYP isoforms (CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1), in pooled human liver microsomes (HLMs) for 30 min with specific inhibitors as positive controls and untreated HLMs as negative controls. The enzyme kinetics and time-dependent study (0, 5, 10, 15, and 30 min) were performed to obtain corresponding parameters in vitro. Results: Peucedanol significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC 50 values of 6.03, 13.57, and 7.58 lM, respectively. Peucedanol served as a non-competitive inhibitor of CYP3A4 with a K i value of 4.07 lM and a competitive inhibitor of CYP1A2 and 2D6 with a K i values of 3.39 and 6.77 lM, respectively. Moreover, the inhibition of CYP3A4 was time-dependent with the K i /K inact value of 5.44/0.046 min/lM. Discussion and conclusions: In vitro inhibitory effect of peucedanol on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. As these CYPs are involved in the metabolism of various drugs, these results implied potential drug-drug interactions between peucedanol and drugs metabolized by CYP1A2, 2D6, and 3A4, which needs further in vivo validation.