Abstract
SZJ-1207 is a natural product extracted from Stephanotis mucronata (Blanco) Merr which has significant antidepressant effects in various depression mouse models, without obvious acute toxicity or sedative-hypnotic side effects. The aim of this study was to preliminarily clarify the pharmacokinetic characteristics of SZJ-1207 in rats after a single intragastric and intravenous administration. In this study, sensitive and reliable UPLC-MS/MS quantification methods were established and then successfully applied to the pharmacokinetic study of SZJ-1207 in rats. The linear range of SZJ-1207 were 0.5–400 ng mL−1 in plasma, feaces, bile and 20–4,000 ng mL−1 in urine, respectively (r > 0.99). All methods met the requirements of ICH M10. The results of pharmaconetic study showed that Cmax, AUC(0-t) and AUC(0-∞) had linear relationships with the administered doses in the range of 0.5–4.5 mg kg−1. There was a significant gender difference in the AUC (0-t) of 0.5 and 1.5 mg kg−1 and Cmax of 1.5 mg kg−1 after ig (P < 0.05). The excretion rates of SZJ-1207 were 8.46 ± 4.82% in feces, 1.89 ± 1.08% in urine, and 0.179 ± 0.118% in bile. The oral absolute bioavailability of SZJ-1207 was calculated as 64.64%.
1 Introduction
Depression severely impairs psychosocial functioning and quality of life, which places a huge burden on patients and their families. Current medication treatments show important limitations, such as slow action onset and adverse side effects. They do not always lead to positive outcomes and in fact, about 30–40% of the patients have complete remission after a course of treatment. 30% of the patients still show residual symptoms with the increasing risk of recurrence, which affects social function after significant clinical response [1].
Complementary and alternative medicine is becoming more popular globally [2]. About 16–44% of patients with mental illnesses use complementary and alternative medicines [3], and a significant majority of them suffer from depression [4]. Chinese herbal medicine (CHM) is the most popular ajunct as antidepressant in China [5]. A large number of people believe that CHM has certain advantages and potential in the prevention and treatment of diseases due to its clinical application for years [6]. Some studies have shown that CHM monotherapy is superior to placebos [7]. Compared with antidepressants alone, the combination treatment of CHM and first-line antidepressants can significantly improve efficacy and reduce the side effects [8].
Previous studies have found that many natural products with antidepressant activity have steroid structures, such as Lilium brownii var. viridulum saponins [9], gypenosides [10], ginsenoside [11], and Panax notoginseng saponins [12], which suggest that natural products with steroidal structures may have similar effect. SZJ-1207 is a natural antidepressant product extracted from the dried stems of Stephanotis mucronata (Blanco) Merr. Sp. Blancoanae with a steroid structure exhibited in Fig. 1. Preliminary studies have shown that SZJ-1207 has effects in a variety of depression mouse models, while no obvious acute toxicity and sedative-hypnotic side effects have been observed [13]. The pharmacokinetic property of SZJ-1207 in mice have been studied in our former research, and the results revealed that this compound had rapid, fairish absorption and fast elimination [14]. However, SZJ-1207 may have different pharmacokinetic characteristics in species. Clarifying the pharmacokinetic and excretion characteristics of SZJ-1207 in rats can provide more data to support the further development of SZJ-1207.
2 Materials and methods
2.1 Chemicals and reagents
SZJ-1207 (purity = 99.53%) and Deacylmetaplexigenin (DMP, purity = 98.0%) were provided by the Natural Medicine Research Group of Hangzhou Medical College. Methyl tert-butyl ether (MTBE) and pure water were purchased from TEDIA (USA) and Watsons (China), respectively. 0.9% saline and sodium heparin were purchased from Biosharp (China). UPLC-grade methanol, and acetonitrile were purchased from Merck (Germany). Sutent 50 was from Virbac (France). Sodium carboxymethyl cellulose (CMC-Na) was purchased from Macklin (China). Ammonia solution was purchased from Aladdin (China).
2.2 Experimental animals
Sprague Dawley rats (body weight range, 220 ± 20 g), half male and half female, were purchased from Zhejiang Center of Laboratory Animals (animal license number, SYXK (Zhejiang, China) 2019–0002). Only drinking water (no food) was provided 12 h before the experiment. The animal experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals, and the study protocols were approved by Institutional Animal Care and Use Committee, ZJCLA (Approval number: ZJCLA-IACUC-20010165).
2.3 Drug administration
Based on the effective dose of 1.0 mg kg−1 of SZJ-1207 in the pharmacodynamic study in C57BL/6 mice, the doses for pharmacokinetic study in SD rats were obtained. In this study, 24 rats were randomly divided equally into 4 groups with respect to weight and gender. Three groups were intragastrically administered (ig) with 0.5, 1.5, 4.5 mg kg−1 of SZJ-1207 in 0.5% carbox-methylcellulose sodium, respectively. The fourth group was administered intravenously with 1.5 mg kg−1 of SZJ-1207 in saline (containing 0.1% methanol).
In the excretion study, 6 rats were ig with 1.5 mg kg−1 of SZJ-1207 to collect urine and feces samples. Another 6 rats were treated with the same dose to collect bile samples.
2.4 Sample collection and preparation
In pharmacokinetic study, blood samples were collected by jugular vein into heparinized tubes at 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 h after ig administration, and at 0, 0.08, 0.17, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 h after the tail vein administration. Then, each blood sample was immediately centrifuged at 8,000 rpm, 4 °C for 5 min. The aliquot of plasma was transferred into another tube and stored at −80 °C until analysis.
In excretion study, each rat was placed alone in metabolic cage after ig. Urine samples were collected at 0–0.5, 0.5–1, 1–3, 3–6, 6–12, 12–24 h with volume recorded. Feces samples were collected at 0–2, 2–4, 4–6, 6–12, and 12–24 h. The feces were dried and ground into powder with weight recorded. 10 mg of feces was mixed with 100 μL of saline, vortexed for 3 min and sonicated for 15 min to obtain fecal homogenate samples. The samples were stored at −80 °C.
After the rats were anesthetized with Sutent 50, bile duct cannulation was performed. Rats were ig with SZJ-1207 upon awakening. Bile was collected at 0–0.5, 0.5–1, 1–3, 3–6, 6–12, and 12–24 h and the volume was recorded. Samples were stored at −80 °C for analysis.
SZJ-1207 was extracted from matrices with a liquid-liquid extraction method. 10 μL DMP (25 ng mL−1 for plasma, 50 ng mL−1 for bile and feces, 200 ng mL−1 for urine) was added into 50 μL samples and vortexed for 1 min. 10 μL 2.5% ammonia (except plasma) and 400 μL MTBE were added, vortexed for 3 min, centrifuged for 5 min (4,000 rpm, 4 °C). The supernatant was separated and dried with N2, and the residue was re-dissolved with 100 μL of 30% acetonitrile. After centrifugation for 10 min (13,000 rpm, 4 °C), the supernatant was analyzed by UPLC-MS/MS.
2.5 Instruments and conditions
The AB SCIEX API 5500 Triple Quad UPLC-MS/MS System was used for SZJ-1207 analysis. The chromatographic separation was carried out at 40 °C using a Waters ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm).
The mobile phase consisted of water (A) and acetonitrile (B). The flow rate was 0.3 mL min−1. The isocratic elution procedure for plasma analysis was 0–3 min: 50% B. Gradient elution program for excretions analysis was set as follows: 0–0.8 min, 20% B; 0.8–1 min, 20–50% B; 1–1.6 min, 50% B; 1.6–1.7 min, 50–90% B; 1.7–3 min, 90% B; 3–3.1 min, 90–20% B; 3.1–4 min, 20% B. The injection volume was 10 μL.
Quantification was performed in negative mode. The dominating mass spectrometer parameters are shown in Table 1. The ion source parameters were as follows: source temperature, 550 °C; ion spray voltage, −4,500 V; curtain gas, 35 psi; collision gas, 8 psi. And the product ion mass spectra in negative mode are shown in Fig. 2.
Ion pairs, declustering potential, collision energy, and collision cell exit potential of SZJ-1207 and DMP
| Compound | Q1 → Q3 (m/z) | Declustering potential (V) | Collision energy (V) | Collision cell exit potential (V) |
| SZJ-1207 | 381.4 → 245.1 | −206 | −39 | −18 |
| DMP | 379.3 → 343.3 (for plasma samples) | −180 | −27 | −10 |
| DMP | 379.3 → 221.2 (for excretion samples) | −180 | −35 | −10 |
Product ion mass spectra of SZJ-1207 (A) and DMP (B)
Citation: Acta Chromatographica 37, 2; 10.1556/1326.2024.01221
2.6 Method validation
The validation of the method was complying with ICH M10 [15].
2.7 Data analysis and statistics
UPLC-MS/MS data were obtained from Analyst software (version 1.6.3) and analyzed by MultiQuant (version 3.0.2) and Excel 2019. Pharmacokinetic parameters were calculated by non-compartmental analysis applying Phoenix WinNonlin software (version 8.1.0). Dose proportionality assessment was performed with confidence interval based on the power model approach [16]. R 4.2 was used for the statistical analysis of t test and linear regression. The data were represented as mean ± SD. The p value was corrected by the Benjamini–Hochberg false discovery rate (BH-FDR) and p < 0.05 was considered statistically significant difference.
3 Results
3.1 Method validation
All contents of method validation met the requirements.
3.1.1 Selectivity and specificity
In the blank plasma, feces, urine and bile samples, no endogenous interference was observed at the retention time of SZJ-1207 and DMP, and the peak shapes of the two components to be measured in plasma, feces, urine, and bile were good. The chromatograms of blank samples, blank samples containing SZJ-1207 and DMP are shown in Figs 3 and 4.
Representative chromatograms of SZJ-1207 (A) and DMP (B) for blank matrix samples.
a: plasma, b: urine, c: feces, d: bile
Citation: Acta Chromatographica 37, 2; 10.1556/1326.2024.01221
Representative chromatograms of SZJ-1207 (A) and DMP (B) for LLOQ samples.
a: plasma, b: urine, c: feces, d: bile
Citation: Acta Chromatographica 37, 2; 10.1556/1326.2024.01221
3.1.2 Linearity and LLOQ
Linearity was analyzed by the weighted regression method (1/x2) of peak area ratios of SZJ-1207 to DMP versus actual concentrations. The calibration curves (n = 7) were prepared by spiking blank samples with standard solution of SZJ-1207 and DMP. Final concentrations of the calibration standards were 0.5, 1, 5, 30, 100, 300, 400 ng mL−1 in rat feces, bile and plasma, 20, 40, 100, 400, 2,000, 3,200, 4,000 ng mL−1 in rat urine. The correlation coefficient (n = 3) was found to be >0.99, and within the acceptable limits (Table 2).
The result of linear regression equation and LLOQ determination
| Matrices | Regression equation | Linear Range (ng mL−1) | Correlation coefficient (r) |
| Urine | y = 2.65x+0.272 | 20–4,000 | 0.9943 |
| Feces | y = 0.891x+0.00465 | 0.5–400 | 0.9959 |
| Bile | y = 0.213x+0.00421 | 0.9979 | |
| plasma | y = 0.253x+0.00977 | 0.9958 |
Signal-to-noise ratios of Lower limit of quantification (LLOQ) in all matrices were >5.
3.1.3 Precision and accuracy
The intra-batch and inter-batch precision and accuracy are shown in Table 3. The accuracy and precision of within-batch and between-batch were <15% of the nominal values. This indicated that the method was accurate and precise over the range of the assay.
The results of precision and accuracy
| Matrices | Concentration (ng mL−1) | Intra-batch (n = 6) | Inter-batch (n = 18) | ||
| RE (Accuracy, %) | Precision (RSD, %) | RE (Accuracy, %) | Precision (RSD, %) | ||
| Urine | 60 | −1.6 | 6.7 | −2.2 | 6.2 |
| 300 | 14.9 | 6.2 | 10.0 | 6.9 | |
| 3,000 | −0.11 | 2.6 | −5.1 | 5.1 | |
| Feces | 1.5 | 13.3 | 5.8 | 13.1 | 7.2 |
| 20 | 13.2 | 5.3 | 12.9 | 4.9 | |
| 320 | 7.4 | 3.9 | 4.3 | 4.8 | |
| Bile | 1.5 | −0.41 | 11.4 | 3.9 | 11.6 |
| 20 | 6.9 | 4.4 | 6.5 | 4.8 | |
| 320 | 1.6 | 2.1 | 0.7 | 4.4 | |
| Plasma | 1.5 | −5.7 | 8.8 | −4.4 | 6.8 |
| 20 | 0.5 | 4.4 | 2.1 | 5.3 | |
| 320 | −3.9 | 1.1 | −1.7 | 2.4 | |
3.1.4 Extraction recovery and matrix effect
The extraction recoveries of SZJ-1207 in the low, medium, and high QC samples ranged from 77.9 to 94.6%. The same evaluation was performed on DMP, and no significant peak area differences were detected. Thus, it was demonstrated that the matrix effect was negligible for the assay (Table 4).
Extraction recovery and matrix Effect
| Matrices | Concentration (ng mL−1) | Extraction recovery | Matrix effect | ||
| Mean (%) | RSD (%) | Mean (%) | RSD (%) | ||
| Urine | 60 | 77.9 | 5.9 | 110.7 | 3.4 |
| 300 | 86.3 | 4.2 | – | – | |
| 3,000 | 92.1 | 1.7 | 132.7 | 14.9 | |
| Feces | 1.5 | 88.3 | 5.0 | 98.3 | 6.3 |
| 20 | 89.3 | 5.3 | – | – | |
| 320 | 91.6 | 3.9 | 102.2 | 4.6 | |
| Bile | 1.5 | 94.6 | 7.1 | 104.2 | 6.6 |
| 20 | 79.1 | 4.2 | – | – | |
| 320 | 82.1 | 2.3 | 98.0 | 4.8 | |
| Plasma | 1.5 | 108.0 | 1.6 | 100.2 | 2.6 |
| 20 | 86.2 | 5.8 | – | – | |
| 320 | 85.6 | 1.2 | 96.7 | 2.3 | |
3.1.5 Stability
The stability results of SZJ-1207 under various conditions are listed in Table 5. No significant analyte reduction was observed during the short-term (4 h for excretions, 3 h for plasma), post-treatment (at 4 °C for 24 h in the autosampler), freeze-thaw cycles from −20 °C to 20–25 °C (3 cycles for excretions, 2 cycles for plasma), long-term experiments (−80 °C for 168 d). Ten-fold dilution test indicated that the analytes were stable under the tested conditions.
Stability of SZJ-1207 under different conditions
| Matrices | Concentration (ng mL−1) | Short-term (Room Temperature) | Post-preparation (4 °C, 24 h) | Freeze-thaw Cycles | Long-term (−80 °C, 168 d) | ||||
| RE (%) | RSD (%) | RE (%) | RSD (%) | RE (%) | RSD (%) | RE (%) | RSD (%) | ||
| Urine | 60 | −2.3 | 8.1 | −0.42 | 5.2 | −12.5 | 8.0 | −6.2 | 9.2 |
| 3,000 | −9.9 | 6.5 | −9.0 | 3.2 | −14.1 | 3.0 | −11.2 | 5.5 | |
| Feces | 1.5 | 11.9 | 7.7 | 13.1 | 9.5 | 14.0 | 3.6 | 11.1 | 8.7 |
| 320 | 6.0 | 6.9 | 2.9 | 3.7 | 4.5 | 3.4 | 9.9 | 3.1 | |
| Bile | 1.5 | 1.0 | 4.9 | 12.4 | 13.3 | 1.0 | 12.6 | −4.7 | 8.5 |
| 320 | −2.9 | 3.3 | −5.6 | 2.9 | −4.5 | 4.6 | −6.9 | 3.1 | |
| Plasma | 1.5 | 1.6 | 3.8 | 5.2 | 2.7 | −5.4 | 3.8 | −11.0 | 2.2 |
| 320 | 10.1 | 7.5 | 8.8 | 3.0 | 7.7 | 0.9 | 6.7 | 1.3 | |
3.2 Pharmacokinetic study of SZJ-1207 in rats
The average plasma concentration-time curves of SZJ-1207 are shown in Fig. 5, and the main pharmacokinetic parameters are shown in Table 6. As shown in Fig. 5, SZJ-1207 exhibited pharmacokinetic characteristics of extremely rapid absorption and elimination in rats.
Main pharmacokinetic parameters of SZJ-1207 in rats (mean ± SD, n = 6)
| Dose | Gender | t1/2 | Tmax | Cmax | AUC(0-t) | AUC(0-∞) | Vd/(F) | CL/(F) | MRT(0-t) |
| mg kg−1 | (h) | (h) | (μg L−1) | (μg L−1 h) | (μg L−1 h) | (L kg−1) | (L h−1 kg−1) | (h) | |
| 0.5 (ig) | ♂ | 2.24 ± 1.65 | 0.17 ± 0.0 | 141.00 ± 37.32 | 87.47 ± 16.20* | 98.00 ± 13.71* | 15.99 ± 11.31 | 5.16 ± 0.67* | 1.86 ± 1.38 |
| ♀ | 1.49 ± 1.93 | 0.20 ± 0.05 | 73.50 ± 12.73 | 45.55 ± 8.48 | 48.24 ± 11.78 | 18.86 ± 21.28 | 10.75 ± 2.35 | 1.31 ± 1.48 | |
| All | 1.86 ± 1.65 | 0.18 ± 0.03 | 107.25 ± 44.60 | 66.51 ± 25.71 | 73.12 ± 29.56 | 17.42 ± 15.32 | 7.96 ± 3.42 | 1.59 ± 1.31 | |
| 1.5 (ig) | ♂ | 2.90 ± 0.16 | 0.14 ± 0.05 | 417.33 ± 70.73* | 244.74 ± 29.59* | 264.63 ± 36.88* | 23.92 ± 2.41* | 5.74 ± 0.78* | 1.94 ± 0.31 |
| ♀ | 3.08 ± 0.65 | 0.14 ± 0.05 | 249.00 ± 16.70 | 136.30 ± 13.94 | 147.25 ± 19.00 | 45.02 ± 4.60 | 10.31 ± 1.44 | 1.87 ± 0.70 | |
| All | 2.99 ± 0.44 | 0.14 ± 0.05 | 333.17 ± 103.02 | 190.52 ± 62.89 | 205.94 ± 69.44 | 34.47 ± 12.01 | 8.03 ± 2.71 | 1.90 ± 0.49 | |
| 4.5 (ig) | ♂ | 2.15 ± 0.46 | 0.14 ± 0.05 | 1,490.0 ± 395.09 | 748.58 ± 189.53 | 768.19 ± 206.47 | 18.72 ± 4.49 | 6.17 ± 1.73 | 1.02 ± 0.54 |
| ♀ | 4.68 ± 3.22 | 0.20 ± 0.05 | 704.67 ± 141.80 | 469.70 ± 143.81 | 502.20 ± 182.09 | 65.60 ± 53.71 | 9.67 ± 2.96 | 1.47 ± 0.87 | |
| All | 3.42 ± 2.48 | 0.17 ± 0.05 | 1,097.3 ± 505.48 | 609.14 ± 214.42 | 635.19 ± 227.02 | 42.16 ± 42.68 | 7.92 ± 2.90 | 1.25 ± 0.69 | |
| 1.5 (iv) | ♂ | 1.53 ± 0.38 | 0.08 ± 0.00 | 873.67 ± 57.57* | 359.88 ± 41.37* | 365.26 ± 38.07* | 9.20 ± 2.95 | 4.14 ± 0.41* | 0.81 ± 0.34* |
| ♀ | 2.47 ± 2.73 | 0.08 ± 0.00 | 646.33 ± 24.19 | 229.55 ± 14.68 | 231.55 ± 15.98 | 22.29 ± 23.62 | 6.50 ± 0.46 | 0.37 ± 0.07 | |
| All | 2.00 ± 1.82 | 0.08 ± 0.00 | 760.00 ± 130.63 | 294.72 ± 76.59 | 298.42 ± 77.75 | 15.75 ± 16.67 | 5.32 ± 1.35 | 0.59 ± 0.32 |
Compared with females, * indicates p < 0.05.
After ig administration of 0.5, 1.5 and 4.5 mg kg−1 of SZJ-1207, AUC and Cmax both increased with dose. Cmax were 107.25 ± 44.60, 333.17 ± 103.02, and 1097.33 ± 505.48 μg L−1. AUC(0-t)were 66.51 ± 25.71, 190.52 ± 62.89, 609.14 ± 214.42 μg L−1 h. AUC(0-∞)were 73.12 ± 29.56, 205.94 ± 69.44, 635.19 ± 227.02 μg L−1 h. Linear regression of the logarithm of Cmax, AUC(0-t) and AUC(0-∞) values against the logarithm of the administered doses showed that the 90% confidence intervals of the slopes (β) were 0.88–1.22, 0.85–1.17 and 0.82–1.16, respectively (Fig. 6). The strict 90% confidence interval criteria required that the intervals be entirely within the intervals for Cmax (0.84, 1.16) and AUC (0.90, 1.10), respectively, and thus no clear conclusion could be drawn. The absolute bioavailability of 1.5 mg kg−1 SZJ-1207 in rats given by ig was 64.64%.
The average plasma concentration-time curves of SZJ-1207 in rats
Citation: Acta Chromatographica 37, 2; 10.1556/1326.2024.01221
Linear relationship between pharmacokinetic parameters and dose
Citation: Acta Chromatographica 37, 2; 10.1556/1326.2024.01221
Comparing pharmacokinetic parameters between different genders, it was found that SZJ-1207 had higher exposure levels and lower clearance rate in male rats. Especially, there were significant differences between genders in AUC and CL at doses of both 0.5 and 1.5 mg kg−1 (p < 0.05) and in Cmax at a dose of 1.5 mg kg−1 (p < 0.05). The absence of gender-stratified informations for many medications raises the concerns that gender differences in pharmacokinetics may be widespread and of clinical significance [17]. These may be primarily due to the expression differences of hepatic metabolic enzymes between genders, resulting in differences of drug metabolism and drug exposure in vivo. Thus, the gender differences of SZJ-1207 reflected in this study should be paid attention to.
In addition, a small increase in SZJ-1207 concentration was observed at the end of the elimination phase in the plasma concentration-time curve. It is hypothesized that enterohepatic circulation of SZJ-1207 led to drug reabsorption into blood.
3.3 Excretion study in rats
The results are shown in Tables 7 and 8. Only a small portion of unchanged SZJ-1207 was excreted via the renal, fecal and biliary routes. And the cumulative excretion rates were 1.89 ± 1.08%, 8.46 ± 4.82% and 0.179 ± 0.118%, respectively. The total excretion of SZJ-1207 was less than 20% of the administered dose. It was promoted that most of SZJ-1207 was metabolized in rats and further studies should be carried out to clarify how SZJ-1207 is disposed in vivo.
Excretion characteristics of SZJ-1207 via urine and bile
| Time (h) | Urine excretion (μg) | Urine excretion rate (%) | Bile excretion (μg) | Bile excretion rate (%) |
| Mean ± SD (n = 6) | Mean ± SD (n = 6) | |||
| 0–0.5 | 1.80 ± 1.60 | 0.523 ± 0.468 | 0.261 ± 0.224 | 0.0711 ± 0.0619 |
| 0.5–1 | 1.60 ± 0.963 | 0.466 ± 0.271 | 0.166 ± 0.0976 | 0.0448 ± 0.0253 |
| 1–3 | 0.636 ± 0.153 | 0.188 ± 0.0391 | 0.160 ± 0.0461 | 0.0432 ± 0.0115 |
| 3–6 | 0.358 ± 0.134 | 0.107 ± 0.0421 | 0.0534 ± 0.0479 | 0.0143 ± 0.0125 |
| 6–12 | 1.22 ± 0.602 | 0.373 ± 0.201 | 0.0187 ± 0.0246 | 0.00502 ± 0.00653 |
| 12–24 | 0.773 ± 0.200 | 0.231 ± 0.0631 | 0.00328 | 0.000877 |
| Total | 6.39 ± 3.65 | 1.89 ± 1.08 | 0.662 ± 0.440 | 0.179 ± 0.118 |
Excretion characteristic of feces
| Time (h) | Feces excretion (μg) | Feces excretion rate (%) |
| Mean ± SD (n = 6) | ||
| 0–2 | 0.156 ± 0.128 | 0.0465 ± 0.0376 |
| 2–4 | 0.324 ± 0.242 | 0.0941 ± 0.0676 |
| 4–6 | 2.32 ± 2.33 | 0.665 ± 0.647 |
| 6–12 | 21.7 ± 10.3 | 6.51 ± 3.19 |
| 12–24 | 3.80 ± 2.80 | 1.14 ± 0.874 |
| Total | 28.3 ± 15.7 | 8.46 ± 4.82 |
4 Conclusion
In this study, sensitive, robust, and reliable UPLC-MS/MS methods were established and validated for determination of SZJ-1207 in different matrices. The methods successfully applied to quantitation of the compound in rat plasma, feces, urine, and bile samples.
SZJ-1207 presented pharmacokinetic characteristics of extremely rapid absorption and elimination in rats. Compared with in female rats, SZJ-1207 showed higher exposure levels and lower clearance rate in male rats. The bioavailability of 1.5 mg kg−1 SZJ-1207 in rats given by ig was 64.64%. To improve pharmacokinetic properties of this compound, pharmaceutic approches could be employed to prolong its residence time in vivo and to improve its druggability.
SZJ-1207 exhibited lower levels in excretion samples, indicating that it underwent extensive metabolism in rats. So, structure modification could be another means to promote its druggability.
Acknowledgements
This work was supported by Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province (2019E10021), Medical and Health Science and Technology Program of Zhejiang Provincial Health Commission of China (2022KY725, 2021KY633) and Zhejiang Provincial Key R&D Program of China (2022C03097).
Abbreviations
| DMP | deacylmetaplexigenin |
| LLOQ | lower limit of quantification |
| CHM | Chinese herbal medicine |
| MTBE | Methyl tert-butyl ether |
| ig | intragastrically administration |
| NA | not applicable |
| RSD | relative standard deviation |
| RE | relative error |
| h | hour |
| min | minute |
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