Data

Podophyllum Resin: A Global Look at Key Buyers

Podophyllum resin, extracted from the Mayapple plant, is a potent ingredient with significant applications in the pharmaceutical and medical industries. Its potent anti-cancer and anti-viral properties have fueled substantial global demand, making it a sought-after commodity. For suppliers and exporters, identifying reputable and high-volume buyers is crucial for navigating this lucrative market.

Key Podophyllum Resin Buyers by Region:

Europe: Germany, France, and the UK remain leading importers, driven by established pharmaceutical and research institutions. Companies like WDT Chemie GmbH and Sanofi occupy prominent positions.
North America: The US is a major hub, with buyers like Spectrum Chemical and Lonza Corporation dominating the market. Canada also shows promising growth, with Apotex Inc. emerging as a key player.
Asia: China and Japan are witnessing a surge in demand, fueled by expanding healthcare sectors and rising disposable incomes. Companies like Shanghai Yuanye Biotechnology and Mitsubishi Chemical Corporation are major players.
Emerging Markets: Brazil, India, and Turkey are exhibiting dynamic market growth, presenting exciting opportunities for exporters. Local pharmaceutical companies and distributors are actively seeking reliable suppliers.
Market Trends and Insights:

Stringent regulations: Governments are implementing stricter controls on Podophyllum resin due to its potent nature. Exporters must comply with relevant regulations and certifications.
Sustainability concerns: Ethical sourcing and sustainable harvesting practices are increasingly important for buyers. Highlighting responsible sourcing practices can attract eco-conscious partners.
Technological advancements: New extraction and purification methods are improving resin quality and yield. Embracing such advancements can provide a competitive edge.

Finding Your Ideal Podophyllum Resin Buyer:

Trade data platforms: Utilize resources like Volza.com and Panjiva to access import/export data and identify potential buyers.
Industry events and conferences: Attending relevant trade shows and conferences allows you to network directly with potential partners.
B2B matchmaking platforms: Leverage online platforms like Alibaba and EC21 to connect with buyers worldwide.

The global Podophyllum resin market offers immense potential for suppliers and exporters. By understanding key buyer locations, market trends, and utilizing valuable B2B resources, you can effectively connect with reputable partners and build long-term success in this dynamic sector.

CENTRAL DE DROGAS S A DE C V
CHEMO SA DE CV
DROCERSA S A DROCERSA
BIODEAL LAB LTD
MANSOOR DAYA CHEMICALS LTD
BIODEAL LABORATORIES LTD
CDR8311251R8 CENTRAL DE DROGAS SA DE CV
HINDUSTAN PHARMACEUTICALS

Pregnant women may experience anxiety and depression during pregnancy due to physiological, psychological and other changes [1-2]. Studies have shown that depression during pregnancy can cause many adverse effects on the health of pregnant women and fetuses, such as fetal cardiovascular malformations, pulmonary hypertension, and premature birth [3]. Women with moderate to severe depression during pregnancy require drug treatment [4-5]. Selective serotonin reuptake inhibitor (SSRI) is a new type of antidepressant, including fluoxetine (FXT), sertraline (SERT), citalopram , paroxetine, fluvoxamine, etc. [6], of which FXT and SERT are both the first-line antidepressants recommended by the “Chinese Guidelines for the Prevention and Treatment of Depressive Disorders (Second Edition)”, and they are also the most commonly used SSRI antidepressants in women with depression during pregnancy. Depression drugs [7-10]. Some studies have pointed out that FXT can be metabolized to norfluoxetine (NFXT) with antidepressant activity in vivo [9]. At present, the safety of SSRIs for depression in pregnancy is not yet clear. In recent years, studies have found that compared with fetuses delivered by women during normal pregnancy, women who use FXT during pregnancy have more obvious adverse outcomes, mainly heart disease. Malformation (including atrioventricular septal defect, atrioventricular valve defect or atrioventricular valve insufficiency, etc.), the incidence rate is 1.18% to 1.60%, which is higher than the incidence rate of fetal heart malformation delivered by women during normal pregnancy (0.40% to 1.00%) [11-12]. Therefore, it is particularly important to detect the concentrations of FXT, NFXT, and SERT.

In the evaluation of drug safety during pregnancy, fetal drug exposure is often used as the theoretical basis and important reference for risk assessment, and the placental barrier is the most important material exchange channel between the fetus and the mother [13]. Therefore, the study of the placental penetration rate of drugs and the determination of the speed and degree of drug penetration through the placenta can be used as one of the methods of drug safety evaluation during pregnancy, and also an important basis and supplement for the content of drug safety evaluation during pregnancy. At present, there are no relevant reports on the study of placental permeability of FXT, NFXT and SERT in my country. Our research group has successfully established a human placental perfusion model in the early stage, and studied the placental permeability of drugs [14]. On this basis, in this study, an ultra-fast liquid chromatograph-mass spectrometer/mass spectrometer (UFLC-MS/MS) method was used to establish a method for the determination of FXT, NFXT and SERT in human placental perfusate. The method of this study investigated the placental penetration rate of the above components, aiming to provide a basis for safe drug use during pregnancy.

1 material

1.1 Main instruments

The main instruments used in this study are API 3200TM triple quadrupole tandem mass spectrometer and equipped with electrospray ionization (ESI), nitrogen source, Analyst Software 1.5.2 quantitative processing software (AB SCIEX, USA), LC- 20AD type liquid chromatography system and equipped with LC-20AD XR type high pressure pump, SIL-20A type autosampler, CTO-20AC type column oven, DGU-20A3 type online degasser (Japan Shimadzu company), XPE105 type Electronic analytical balance (Mettler Toledo, Switzerland), SB3222 ultrasonic instrument [Branson Ultrasound (Shanghai) Co., Ltd.], Elix type water purifier (Merck Millipore, USA), XH-B vortex mixer (Jiangyan) City Kangjian Medical Equipment Co., Ltd.), 5804R low-temperature high-speed desktop centrifuge, pipette (German Eppendorf company), etc.

1.2 Main Drugs and Reagents

Fluoxetine hydrochloride reference substance (batch number 100513-201602, purity 99.3%), sertraline hydrochloride reference substance (batch number 100702-202103, purity 99.8%), glyburide reference substance (internal standard, batch number 100135-201806, purity 99.8%), antipyrine reference substance (positive control, batch number 100506-202003, purity > 99.9%) were purchased from China National Institute for Food and Drug Control; norfluoxetine hydrochloride reference substance (batch number 10716, purity 99.0%) It was purchased from Santa Cruz Biotechnology Company in the United States; low molecular weight dextran (batch number P1054729) was purchased from Shanghai Adamas Reagent Co., Ltd.; Sodium Chloride Injection (Guoyao Zhunzi H19994067, batch number S1709062, specification 100 mL: 0.9 g) was purchased from Shanghai Baibai Special Medical Products Co., Ltd.; Krebs-Ringer buffer (containing glucose 1.8 g/L, magnesium chloride 0.047 g/L, potassium chloride 0.34 g/L, sodium chloride 7.0 g/L, disodium hydrogen phosphate 0.1 g/L, Sodium dihydrogen phosphate 0.18 g/L, batch No. 11801060) was purchased from Beijing Soleibao Technology Co., Ltd.; Sodium Bicarbonate Injection (National Medicine Zhunzi H41021050, batch No. 11807201, specification 10 mL: 0.5 g) was purchased from Suicheng Pharmaceutical Co., Ltd. Co., Ltd.; Penicillin Sodium for Injection (Guoyao Zhunzi H13020657, batch number F7032124, specification 800,000 units) was purchased from Huabei Pharmaceutical Co., Ltd.; Heparin sodium injection (Guoyao Zhunzi H32020612, batch number 51809105, specification 2 mL: 12 500 units) It was purchased from Jiangsu Wanbang Biochemical Pharmaceutical Co., Ltd.; bovine serum albumin (BSA) dry powder (batch number 0306C272) was purchased from VWR Life Science Company, USA; formic acid, acetonitrile, and methanol were all chromatographically pure, and water was ultrapure water.

2 Methods and results

2.1 Preparation of the solution

2.1.1 Mixed reference substance stock solution Precisely weigh 2.79 mg of fluoxetine hydrochloride reference substance, 2.80 mg of norfluoxetine hydrochloride reference substance, and 2.79 mg of sertraline hydrochloride reference substance, dissolve with methanol and make up to volume to obtain FXT , NFXT, SERT mass concentration of 50.0 μg/mL mixed reference stock solution, stored at -30 ℃ for future use.

2.1.2 Standard curve working solution, quality control working solution and internal standard working solution Take the mixed reference substance stock solution under “2.1.1” and dilute with methanol step by step to make FXT, NFXT and SERT with mass concentrations of 5 respectively. 000, 2 500, 1 250, 500, 250, 125, 50.0 ng/mL series of standard curve working solutions. In addition, take the mixed reference substance stock solution under “2.1.1” and dilute it with methanol to prepare a series of quality control working solutions with the mass concentrations of FXT, NFXT and SERT of 4 500, 2 500 and 150 ng/mL, respectively. Accurately weigh 150 mg of the internal standard reference substance, dissolve it with acetonitrile and make up to volume to prepare the internal standard stock solution with a mass concentration of 3.00 mg/mL, and store it at -30 ℃; when using, take 80.0 μL of the above internal standard stock solution , add 300 mL of acetonitrile to dilute, and mix to obtain the internal standard working solution with a mass concentration of 800 ng/mL.

2.1.3 Take 500 mL of Krebs-Ringe buffer from blank placental perfusate and drug-containing placental perfusate, add 4 mL of 5% sodium bicarbonate injection, 2 mL of heparin sodium injection, and 0.48 g of penicillin sodium for injection, and mix well. , add BSA 15.0 g, stir well, and dissolve. The solution was divided into 2 parts, and 7.5 g of low-molecular-weight dextran was added to one of them, and the mixture was fully stirred to obtain the placental perfusate on the daughter side (containing about 30 g/L of low-molecular-weight dextran, that is, blank placental perfusate). Add 2.1 g of low-molecular-weight dextran to the other part and stir well to obtain the maternal side placental perfusate (containing about 8.4 g/L of low-molecular-weight dextran).

2.1.4 Standard curve sample solution Take 180 μL of blank placental perfusate under “2.1.3”, and add 20 μL of series standard curve working solution under “2.1.2” to obtain FXT, NFXT, and SERT mass concentrations, respectively Standard curve sample solutions of 500, 250, 125, 50.0, 25.0, 12.5, 5.00 ng/mL.

2.1.5 Quality control sample solution Take 180 μL of blank placental perfusate under “2.1.3”, add 20 μL of serial quality control working solution under “2.1.2”, and obtain FXT, NFXT, and SERT mass concentrations of 450, 250, 15.0 ng/mL QC sample solutions.

2.2 Sample processing

2.2.1 Standard curve sample solution and quality control sample solution Take 200 μL each of the standard curve sample solution under “2.1.4” and the quality control sample solution under “2.1.5”, and add the internal standard under “2.1.2” The working solution was 800 μL, vortexed and mixed, centrifuged at 14 000 r/min for 8 min, and the supernatant was taken for analysis.

2.2.2 Placental perfusate sample Take 180 μL of the placental perfusate sample under “2.1.3”, add 20 μL of methanol, mix well, add 800 μL of the internal standard working solution under “2.1.2”, vortex and mix well, Centrifuge at 14 000 r/min for 8 min, and take the supernatant for injection analysis.

2.3 Chromatographic and mass spectrometry conditions

2.3.1 Chromatographic conditions SynergiTM Hydro-RP 80A LC (50 mm×2 mm, 4 μm) was used as the chromatographic column, and water (containing 0.1% formic acid, A)-acetonitrile (containing 0.1% formic acid, B) was used as the mobile phase. Gradient elution (0~1.00 min, 2%B; 1.00~2.00 min, 2%B→90%B; 2.00~3.00 min, 90%B; 3.00~3.10 min, 90%B→2%B; 3.10~ 4.00 min, 2% B); the flow rate was 0.70 mL/min; the column temperature was 40 °C; the injection volume was 5 μL.

2.3.2 Mass spectrometry conditions The ion source was ESI, the detection mode was positive ion mode, and scanning was performed in multiple reaction monitoring (MRM) mode; the ion source voltage was 5 000 V; the ionization temperature was 600 °C; (gas1, N2) pressure is 414 kPa; auxiliary gas (gas2, N2) pressure is 345 kPa; collision gas pressure is 83 kPa; The mass spectrometry parameters of FXT, NFXT, SERT and internal standard are shown in Table 1, and their mass spectra are shown in Figure 1.

2.4 Methodological investigation

2.4.1 Specificity investigation Take blank placental perfusate, standard curve sample solution and drug-containing placental perfusate under item “2.1” respectively, and process them according to the method under item “2.2” (blank placental perfusate does not need to add internal standard), Then press the chromatographic and mass spectrometry conditions under “2.3” to inject and analyze, and record the chromatogram. The results showed that the buffer, low molecular weight dextran and other substances in the placental perfusate did not interfere with the determination of each drug, indicating that the method has good specificity. The results are shown in Figure 2.

2.4.2 Examination of linear relationship Take the standard curve sample solution under “2.1.4”, process it according to the method under “2.2”, and then inject and analyze it according to the chromatographic and mass spectrometry conditions under “2.3”, and record the peak area. Linear regression was performed with the mass concentration of the component to be tested (x, ng/mL) as the abscissa and the ratio of the peak area of ​​the component to be tested to the internal standard peak area (y) as the ordinate (with a weight of 1/x). The results show that the regression equation of FXT is y=0.003 88x+0.001 15 (r=0.991 2), NFXT is y=0.003 86x+0.002 52 (r=0.993 9), and SERT is y=0.005 59x+0.031 4 (r= 0.994 8), the linear range of detection mass concentration of FXT, NFXT and SERT was 5.00-500 ng/mL, and the lower limit of quantification was 5.00 ng/mL.

2.4.3 For the precision and accuracy test, take the standard curve solution with a mass concentration of 5.00 ng/mL (ie the lower limit of quantification) under item “2.1.4” and a mass concentration of 450, 250, and 15.0 ng under item “2.1.5” /mL of quality control sample solution, 5 copies each, processed according to the method under “2.2” within 1 day, and then injected and analyzed according to the chromatographic and mass spectrometry conditions under “2.3” to examine the intra-day precision; After the methods under “2.2” were processed, samples were injected and analyzed according to the chromatographic and mass spectrometry conditions under “2.3” to examine the inter-day precision. The measured mass concentration was compared with the theoretical mass concentration, and the relative error (RE) was used to examine the accuracy. The results showed that the intra-day and inter-day RSD of each sample were not higher than 14.0%, and the RE was -9.6% to 14.7%, indicating that the precision and accuracy of the method were good [15]. The results are shown in Table 2.

2.4.4 For the stability test, take the quality control sample solutions with mass concentrations of 450, 250, and 15.0 ng/mL under item “2.1.5”, respectively, freeze and store at -30 ℃ for 8 d, and freeze and thaw repeatedly (-30 ℃ ~ room temperature) for 3 times and then processed according to the method under “2.2”, and then injected and analyzed according to the chromatographic and mass spectrometry conditions under “2.3”, and the peak area was recorded. The measured mass concentration was compared with the theoretical mass concentration, and the RE was used to examine the accuracy. Each sample was operated in parallel 6 times. The results show that the RSD of each sample is not higher than 11.5%, and the RE is -4.0% to 11.0%, indicating that the samples have good stability under the above conditions. The results are shown in Table 3.

2.4.5 Extraction recovery rate and matrix effect investigation Take the quality control sample solutions with mass concentrations of 450, 250, and 15.0 ng/mL under item “2.1.5”, and 6 replicates for each mass concentration, according to the method under item “2.2” After treatment, inject and analyze according to the chromatographic and mass spectrometry conditions under “2.3”, and record the peak area A. Take the blank placental perfusate under item “2.1.3” and process it according to the method under item “2.2”, take 180 μL of supernatant as blank matrix, add 4 500, 2 500, 150 ng/ml under item “2.1.2” Each of 20.0 μL of the quality control working solution of mL, with 6 parallel copies of each mass concentration, was injected and analyzed according to the chromatographic and mass spectrometry conditions under “2.3”, and the peak area B was recorded. Take 180 μL of water to replace the blank placental perfusate, and prepare the quality control sample solutions with mass concentrations of 450, 250, and 15.0 ng/mL according to the method under “2.1.5”. After the method is processed, the sample is injected and analyzed according to the chromatographic and mass spectrometry conditions under “2.3”, and the peak area C is recorded. Extraction recovery = A/B × 100%, matrix effect = B/C × 100%. The results showed that the average extraction recovery of FXT was 63.7%-88.8% (RSD≤16.2%), the average matrix effect was 73.9%-76.1% (RSD≤20.0%); the average extraction recovery of NFXT was 79.4%-112.0% (RSD≤15.0%), the average matrix effect was 95.4%~119.0% (RSD≤13.9%); the average extraction recovery of SERT was 83.7%~101.0% (RSD≤13.2%), and the average matrix effect was 96.3%~108.0 % (RSD≤12.9%); the average extraction recovery of the internal standard was 92.1% (RSD=12.3%), and the average matrix effect was 90.1% (RSD=11.0%). The results are shown in Table 4.

2.4.6 Residual effect investigation Take 180 μL of blank placental perfusate under item “2.1.3”, prepare a sample solution with a mass concentration of 500.0 ng/mL according to the method under item “2.1.4”, and process according to the method under item “2.2” Then, press the chromatographic and mass spectrometry conditions under “2.3” to inject and analyze. Take an appropriate amount of blank placental perfusate, prepare a sample solution with a mass concentration of 0 ng/mL according to the method under “2.1.4”, and measure it with the same method to investigate the residual effect of the method. Each sample was measured 5 times in parallel. The results showed that there were no obvious chromatographic peaks in the chromatogram of blank placental perfusate.

2.5 Detection of placental permeability

2.5.1 Placenta Inclusion and Exclusion Criteria The inclusion criteria for placenta in this study were: (1) fresh placenta delivered by vaginal delivery or cesarean section; (2) fresh placenta delivered at term (37-41 weeks gestation) (3) Placenta with intact structure and no obvious damage to the placental lobules, and intact fetal membranes and amniotic membranes; (4) Placenta delivered by women during pregnancy without underlying diseases. The exclusion criteria were: (1) placenta that had been artificially removed; (2) placenta that required pathological examination at the judgment of a physician; (3) placenta delivered by women with underlying metabolic diseases or infectious diseases during pregnancy; (4) delivery Placenta older than 10 min.

2.5.2 Establishment of placenta source and perfusion model Before obtaining the placenta, the pregnant women or their family members have obtained the informed consent, and signed the placenta disposition notice with them. This research protocol was approved by the hospital ethics committee, and the ethics code is (2016) Lunshen L No. 5-1. The placenta provided by the Obstetrics and Gynecology Department of the First Affiliated Hospital of Kunming Medical University from March 2017 to September 2020 was selected, and a placental perfusion model was established as follows: According to the structure and functional characteristics of the placenta, the placenta just delivered was collected, and one piece of the placenta was selected. Complete placental villus lobules, establish bidirectional circulation of maternal and fetal sides (daughter-faces), and use placental perfusate containing target substances to replace human blood circulation to perfuse the placental lobules according to the experimental design, simulating the blood flow of mother and fetus in the real uterus and internal environment for the study of various nutrient and drug exchanges between mother and fetus [9, 16-18]. The schematic diagram of the bidirectional circulation perfusion model of a single placental lobule is shown in Figure 3.

In this study, 31 placental perfusion models were successfully established, of which 15 were perfused with FXT and NFXT, 10 were perfused with SERT, and 6 were perfused with antipyrine (positive control, since antipyrine is a small-molecule lipophilic compound, it is not Binding to proteins, it can be transported across the placenta by passive diffusion, and can be used as a positive control in placental perfusion experiments to evaluate whether the model is successful or not, and can also be used to analyze whether there are differences in different laboratory data [14]).

2.5.3 Determination of placental permeability In the perfusion experiment of FXT, the maternal side placental perfusate under item “2.1.3” was taken, and fluoxetine hydrochloride reference substance and norfluoxetine hydrochloride reference substance were added to make FXT and NFXT. The initial mass concentration of the maternal placental perfusate was 160 ng/mL; in the SERT perfusion experiment, the maternal placental perfusate under item “2.1.3” was taken, and the sertraline hydrochloride reference substance was added to make the SERT in the perfusion experiment. The initial mass concentration of the maternal placental perfusate was 100 ng/mL. Antipyrine was added to the above single drug-containing placental perfusate to make its mass concentration 100 μg/mL. A single placental lobule bidirectional closed circulation perfusion process lasted for 180 minutes, and the perfusion samples of the daughter side placenta and the mother side placental perfusion were taken at 0, 10, 20, 30, 45, 60, 90, 120, 150, and 180 minutes, respectively. Each 0.5 mL liquid sample was used to analyze the mass concentration of FXT, NFXT, SERT and the positive control antipyrine (for the antipyrine mass concentration detection method and its methodological verification, please refer to the published literature of our research group [14, 19] ]), use Graphpad Prism 12.0 software to draw the concentration-time curve, and calculate the placental permeability according to the formula: placental permeability=CF/CM×100%[20]. In the formula, CF represents the drug concentration at each sampling point of the daughter placental perfusate sample, and CM represents the initial drug concentration of the maternal side placental perfusate sample. The results showed that the average placental permeability of the daughter-side placental perfusate samples and the maternal-side placental perfusate samples was (37.68±5.87)% after antipyrine perfusion for 3 hours, which was consistent with the results reported in previous studies [(36.62 ±5.08)%] are basically consistent, indicating that the model functions well [14, 16-17, 21]. After 3 h of perfusion, the average placental penetration rates of FXT, NFXT, and SERT were (8.74±1.67)%, (10.70±4.81)%, and (5.90%±1.25)%, respectively, indicating that FXT, NFXT and SERT can It was detected in the lateral placental perfusion model that the above three drugs could penetrate the placenta. The results are shown in Figure 4 and Figure 5.

3 Discussion

The research group compared the response of FXT, NFXT and SERT under ESI positive and negative ion scanning respectively. It was found that the response values ​​of the three in the positive ion mode were all about 10 times that of the negative ion mode, so the detection mode was selected as the positive ion mode. Compared with mobile phase systems such as methanol-5 mmol ammonium acetate solution, when water (containing 0.1% formic acid)-acetonitrile (containing 0.1% formic acid) was used as mobile phase, the mass spectral response was stronger and the background noise was reduced, so the choice of Water (containing 0.1% formic acid)-acetonitrile (containing 0.1% formic acid) was used as the mobile phase. The research group also compared the effects of isocratic and gradient elution on the chromatographic retention and sensitivity of the components to be tested. The results show that the chromatographic peaks obtained by gradient elution have good peak shape and high sensitivity, so gradient elution is selected; The physical and chemical properties and structures of the components were finally determined by the gradient elution procedure under “2.3.1”. In addition, our research group also compared different flow rates. The results found that when the flow rate was 0.5 mL/min, the peak rate of the component to be tested was too slow; when the flow rate was 1.0 mL/min, the peak rate was accelerated. , but its ionization effect is poor, which affects the ionization and quantitative analysis of the components to be tested, so the final selection flow rate is 0.70 mL/min. Through the optimization of the chromatographic and mass spectrometry conditions, the chromatographic and mass spectrometry conditions under “2.3” were finally determined, and the rapid detection of the components to be detected (detection time <4 min) was realized.

At present, the correlation between drug exposure and potential risk is a more concerned issue in clinical application, and it is also an important reference for drug safety and risk assessment [8]. Drug placental penetration rate is a direct evaluation index of drug exposure. Drugs with high placental penetration rate will have higher fetal exposure. If the drug has risks to the growth and development of the fetus, it is likely to cause adverse fetal outcomes, such as stillbirth, Preterm birth, low body mass, etc. [9]. Gentile et al [22] pointed out that SSRI exposure can cause changes in fetal respiratory activity, cardiac blood flow, epigenetic changes, corticotropin-releasing hormone changes, etc., but the study did not consider the effects of dose differences. Mulder et al [23] monitored the link between SSRI exposure and fetal activity by B-ultrasound and found that compared with healthy people or pregnant women using low-dose SSRIs, those who used conventional doses or higher doses had better fetal sleep Affected, the number of fetal movements increased, but there was no difference between the different SSRIs. Rurak et al [24] found that, compared with before administration in the morning, peak concentrations of SSRIs could cause an increase in fetal heart rate and a decrease in cerebral arterial blood flow.

Due to moral and ethical constraints, it is difficult to carry out human-based drug-placental transfer studies. Most of them are based on animal models, and then the experimental results are extrapolated to humans. However, due to differences in species, the conclusions may be controversial. The extracorporeal circulation perfusion model of human placenta is currently recognized as a classic method for the study of material placental permeability in the world, and it is also one of the more widely used models [9, 16-18]. This model can intuitively study the degree of drug-placental transfer under the premise of complete placenta. Its advantages include: (1) The acquisition of the placenta has been signed by the pregnant woman, and it is handed over to the hospital for processing after delivery, and there is no ethics. (2) Compared with primary trophoblast cells, the placenta is easier to obtain; (3) The perfusion model is non-invasive, and is closer to the physiological environment of the human body than the monolayer model, etc., and can be used to study the placenta. Metabolism, hormone and enzyme production and release and other behaviors [18].

In this study, referring to the "Guidelines for Psychiatric Therapeutic Drug Monitoring" [25] and related literature [26], with 160 ng/mL FXT, NFXT or 100 ng/mL SERT as the maternal drug concentration, a human placental perfusion model was established and ex vivo circulation was performed. perfusion studies. The results showed that the average placental penetration rates of FXT, NFXT, and SERT were (8.74±1.67)%, (10.70±4.81)%, and (5.90%±1.25)%, respectively, after perfusion for 3 hours, indicating that FXT, NFXT, and SERT were Can pass through the placenta. This result is in line with the results of small in vivo studies (when pregnant women were given a daily dose of 20 mg of FXT, the cord blood/maternal concentration ratio of FXT to NFXT was 32% to 74% and 12% to 92% [9,27] ), which may be related to the shorter perfusion time, while FXT, NFXT, and SERT are widely distributed in the body and have a certain degree of tissue accumulation [28]. The results of placental permeability study showed that FXT and SERT only penetrated the placenta in a small amount, and compared with FXT, the permeability of SERT was lower, so SERT was more preferred in clinical practice. Due to the lack of research on the mechanism of abnormal fetal development caused by FXT and SERT at home and abroad, it is necessary to further investigate the effects of the above drugs on fetal development in order to clarify the safety of their application during pregnancy.

In conclusion, the established UFLC-MS/MS method is easy to operate, with high sensitivity and accuracy, and can be used to determine the concentrations of FXT, NFXT and SERT in human placental perfusate. FXT, NFXT, and SERT can all penetrate the placenta, but the placental penetration rate of SERT is lower.

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