Article Figures & Data
Figures
- Fig. 1.
The primary metabolic pathway of VEN in humans.
- Fig. 2.
The remaining VEN and generated demethylation metabolites, ODV, NDV, and NODV, after 60-minute incubation of VEN in HLM (A) or RLM (B). Data for each component were normalized to spiked VEN concentration in reaction mixtures and represented as means ± S.D. in triplicates.
- Fig. 3.
Michaelis-Menten plots for formation of ODV by RLM (A), HLM (B), CYP2D6*1/*1 (C), and CYP2D6*10/*10 (D). Data were presented as means ± S.D. in triplicates.
- Fig. 4.
Inhibitory effects of ZJP (150 μg/ml), coptisine (CPS, 30 μM), berberine (BBR, 30 μM), quinine (QNN, 2 μM), quinidine (QND, 2 μM), and ketoconazole (KTZ, 2 μM) on the metabolism of VEN and formation of ODV, NDV, and NODV in HLM (A–D) and RLM (E–H). Each column represented the remaining VEN (% control) or product formation (% spiked VEN). Data were presented as means ± S.D. in triplicates. *P < 0.05 compared with the control. Cntl, control.
- Fig. 5.
Inhibitory effects (IC50) of ZJP (A–D), coptisine (E–H), and berberine (I–L) on ODV formation in HLM, RLM, CYP2D6*1/*1, and CYP2D6*10/*10, respectively. Data were presented as means ± S.D. in triplicates. The curve represented the fitting of the observed ODV formation rate (% control) (y) vs. the inhibitor concentration (x). Conc., concentration.
- Fig. 6.
Mean plasma concentration-time profiles of VEN (A), ODV (B), and NDV (C) after intragastric administration of VEN alone or coadministration with ZJP (VEN+ZJP) in rats (n = 6). Data were presented as means ± S.D. Conc., concentration.
- Fig. 7.
Hepatic exposures of VEN (A), ODV (B), NDV (C), NODV (D), and ODV/VEN ratio (E) at 2 hours after intragastric administration of VEN alone or coadministration with ZJP (VEN+ZJP) in rats (n = 6). Data were presented as means ± S.D. *P < 0.05 compared with the VEN group. Conc., concentration.
Tables
- TABLE 1
Mass spectrometry parameters for measuring VEN and its metabolites, ODV, NDV, and NODV
Analytes Transition (m/z) Spray Voltage (V) Temp. (°C) DP (V) CE (V) CXP (V) EP (V) VEN 278.2 > 58.1 5500 400 46 46 12 10 ODV 264.2 > 58.1 5500 400 46 46 12 10 NDV 264.2 > 246.1 5500 400 35 14 12 10 NODV 250.2 > 232.1 5500 400 30 14 12 10 Diphenhydramine 256.0 > 167.1 5500 400 46 25 12 10 Temp., temperature. DP, declustering potential. CE, collision energy. CXP, CXP, cell exit potential. EP, entrance potential.
Subject Km (μM) Vmax (nmol/min per Milligram Protein or nmol/min per Picomoles P450) CLint (μl/min per Milligram Protein or μl/min per Picomoles P450) RLM 41.2 ± 23.4 0.480 ± 0.013 11.7 ± 5.5 HLM 39.9 ± 1.1 0.182 ± 0.004 5.7 ± 0.2 rhCYP2D6*1/*1 11.3 ± 3.2 0.014 ± 0.003 1.2 ± 0.3 rhCYP2D6*10/*10 148.2 ± 26.5 0.013 ± 0.002 0.088 ± 0.016 - TABLE 3
IC50 of ZJP, berberine, and coptisine toward VEN metabolism in microsomes and rhCYP2D6
Inhibitors IC50 value ODV NDV NODV RLM ZJP (μg/ml) 129.9 ± 2.6 >575 42.8 ± 8.0 Berberine (μM) 64.5 ± 11.5 >1000 59.5 ± 18.6 Coptisine (μM) 27.0 ± 6.2 >200 16.9 ± 0.1 HLM ZJP (μg/ml) 30.5 ± 5.5 >288 11.5 ± 10.2 Berberine (μM) 30.5 ± 9.6 >500 >500 Coptisine (μM) 2.3 ± 1.3 >100 >100 rhCYP2D6*1/*1 ZJP (μg/ml) 15.4 ± 4.5 N/A N/A Berberine (μM) 2.5 ± 0.9 Coptisine (μM) 0.7 ± 0.2 rhCYP2D6*10/*10 ZJP (μg/ml) 2.3 ± 1.0 N/A N/A Berberine (μM) 1.5 ± 0.2 Coptisine (μM) 2.2 ± 0.2 N/A, not applicable.
- TABLE 4
Pharmacokinetic parameters of VEN, ODV, and NDV in rats after oral administration of VEN alone or VEN combined with ZJP
Analyte Groups Cmax (ng/ml) Tmax (h) t1/2 (h) CLz/F (l/h per kilogram) AUC0–24 (µg/l × h) VEN VEN 3.47 ± 0.80 1.0 ± 0.6 2.4 ± 2.2 231.7 ± 18.6 11.1 ± 0.9 VEN+ZJP 2.01 ± 0.85* 3.1 ± 1.8* 4.0 ± 2.2 198.7 ± 151.3 15.5 ± 7.6 ODV VEN 4.82 ± 4.18 1.1 ± 0.9 6.2 ± 3.3 172.7 ± 123.5 19.3 ± 11.3 VEN+ZJP 3.41 ± 2.00 2.1 ± 1.4 10.9 ± 6.5 116.8 ± 66.8 23.7 ± 12.8 NDV VEN 1.24 ± 0.90 2.0 ± 1.8 5.1 ± 2.9 468.0 ± 208.7 6.45 ± 4.34 VEN+ZJP 1.91 ± 1.02 3.6 ± 2.2 6.1 ± 4.5 215.4 ± 132.1* 13.5 ± 5.7* ↵* P < 0.05 compared with VEN group. CLz/F, apparent oral clearance.
Data Supplement
- Supplemental Data -
Supplementary Table 1 - The contents of four alkaloids in Zuojin Pill.
Supplementary Table 2 - Mass spectrometry parameters for measuring four major alkaloids of
ZJP (berberine, coptisine, evodiamine, and rutaecarpine).Supplementary Table 3 - Intra- and inter-batch precision and accuracy of coptisine, berberine,
evodiamine, and rutaecarpine in rat livers (Mean ±S.D., n = 5).Supplementary Table 4 - Stability of coptisine, berberine, evodiamine, and rutaecarpine in rat
livers (Mean ±S.D., n = 3).Supplementary Table 5 - Intra-batch precision and accuracy of VEN, ODV, NDV, and NODV
in rat livers (Mean ±S.D., n = 5).Supplementary Figure 1 - Inhibitory effects (IC50) of quinidine (A) and quinine (B) on ODV
formation in HLM and RLM, respectively. Data were presented as mean ± S.D. in triplicates.
- Supplemental Data -
In this issue
Influence of Zuojin Pill on Venlafaxine
