Current Drug Metabolism - Volume 23, Issue 14, 2022

Background: Cycloastragenol (CAG) is a sapogenin derived from the main bioactive constituents of Astragali Radix (AR). However, the current research on CAG metabolism in vivo and in vitro is still inadequate, and the metabolite cluster is incomplete due to incomplete analysis strategy. Objective: The objective of this study was to screen and identify the metabolic behavior of CAG in vivo and in vitro. Methods: A simple and rapid analysis strategy based on UHPLC-Q-Exactive Orbitrap mass spectrometry combined with data-mining processing technology was developed and used to screen and identify CAG metabolites in rat body fluids and tissues after oral administration. Results: As a result, a total of 82 metabolites were fully or partially characterized based on their accurate mass, characteristic fragment ions, retention times, corresponding Clog P values, and so on. Among the metabolites, 61 were not been reported in previous reports. These metabolites (6 metabolites in vitro and 91 in vivo) were generated through reactions of hydroxylation, glucuronidation, sulfation, hydrogenation, hydroxylation, demethylation, deisopropylation, dehydroxylation, ring cleavage, and carboxyl substitution and their composite reactions, and the hydroxylation might be the main metabolic reaction of CAG. In addition, the characteristic fragmentation pathways of CAG were summarized for the subsequent metabolite identification. Conclusion: The current study not only clarifies the metabolite cluster-based and metabolic regularity of CAG in vivo and in vitro, but also provides ideas for metabolism of other saponin compounds.

Purpose: Physiological changes during pregnancy can affect antiretroviral drug processes and further influence drug efficacy and safety. Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict PK in pregnant women. The objective of this study was to establish a PBPK modeling of tenofovir disoproxil fumarate (TDF) in pregnant women, to provide a reference for the clinical use of TDF. Methods: A full PBPK modeling of tenofovir (TFV) and TDF following i.v. and p.o. administration was developed using the simulation software PK-Sim®. The modeling was then extrapolated to pregnant women based on pregnancy- related physiological parameters in Mobi® Simulator. The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between predicted and observed values of PK parameters (Cmax, tmax, AUC0-∞) to evaluate the accuracy of PBPK modeling. Results: The developed PBPK modeling successfully predicted the TDF disposition in the non-pregnant population, wherein the MFE average and GMFE of all predicted PK parameters were within a 1.5-fold error range, and more than 96.30% of the predicted drug concentration values were within a 2-fold error range of the measured values. After the extrapolation of these models to the third trimester of pregnancy, the scaling anatomy/physiology and hepatic intrinsic clearance made the pregnant population PBPK modeling meet the standard requirement of 0.5 < MFE and GMFE value < 2. It was more appropriate to simulate the in vivo process of low-dose TDF in pregnant women. Conclusion: The non-pregnant population PBPK modeling of TDF established in our study can be extrapolated to pregnant women. Our study provides a reference for realizing clinical personalized medication for pregnant women.

Introduction and Aim: Vitamin D is the name given to a group of lipid-soluble steroidal substances of physiological importance in the body, especially in bone metabolism. The active form of vitamin D is believed to have immunomodulatory effects on immune system cells, especially T lymphocytes, as well as on the production and action of several cytokines and on the expression of potent antimicrobial peptides in epithelial cells that line the respiratory tract, playing an important role in protecting the lung from infections. The aim of this study was to assess vitamin D levels in patients with COVID-19 in healthcare service and to verify that these levels are adequate to protect the progression of this infection. Methods: The aim of this observational study was to evaluate the serum concentration of vitamin D in 300 patients suspected of being infected with COVID-19, treated at Basic Health Units (BHUs) and at the Hospital Complex in the municipality of São Bernardo do Campo. Results: 294 patients were included, 195 (66%) of which tested positive for COVID-19 and 99 (34%) negative for COVID-19. Among the patients in the positive group, 163 patients were in the mild group (84%); 22 patients in the moderate group (11%); 8 patients in the severe group (4%), and 2 patients in the deceased group (1%). Conclusion: For the patients in this study, no association was observed for the protective factor of vitamin D against COVID-19 infection, and its role in controlling the clinical staging of the disease was not verified.

Background: Erzhi formula (EZF) is a traditional Chinese medicine prescription, which has been widely used in the treatment of osteoporosis and premature ovarian failure. Objective: To enhance curative effects, the other two herbal medicines, including Spatholobi Caulis (SC) and Achyranthes bidentata Blume (ABB), were added into the original EZF formula to obtain two new Jiawei-EZF (JW-EZF) preparations. To clarify the effect of the compatibility of herbs for original formulas, the chemical constituents and bioactive compounds in vivo were detected. Methods: An efficient and sensitive targeted and untargeted UHPLC/ESI-Q-Orbitrap MS method, together with mass defect filter and precursor ion list, was established firstly for the profiling of different EZF formulas. Furthermore, eleven absorbed compounds (apigenin, luteoloside, luteolin, oleuropein, wedelolactone, acteoside, specnuezhenide, 11-methyloleoside, ecliptasaponin A, formononetin, and β-ecdysone) were simultaneously quantified in rat plasma. Results: A total of 124, 162, and 177 compounds were identified or tentatively identified in EZF, JW-3-EZF (EZF+SC) and JW-4-EZF (EZF+SC+ABB), respectively. 110 compounds were found to be common constituents in the three formulas. Moreover, 66 prototypes were unambiguously identified in the rats' plasma after oral administration of the three formulas using the same strategy. 11 out of the 66 absorbed components were simultaneously quantitated in the pharmacokinetic (PK) study. Compared to the original EZF, the plasma AUC(0-24h) and AUC(0-∞) of apigenin, 11-methyloleoside, luteolin, luteoloside, wedelolactone, and acteoside were found to be significantly increased after oral administration of JW-3-EZF, and plasma AUC(0-24h) and AUC(0-∞) of apigenin, wedelolactone, and acteoside, were also found to be significantly increased after JW-4-EZF administration. Conclusion: The combined qualitative and quantitative methods were used to provide a potential approach to the characterization and quality control of the Traditional Chinese Medicine (TCM) and its preparations.

Background: Filifolium sibiricum flavonoids dropping pill (FSFp), a unique Chinese Filifolii sibirici herba extract preparation, has the potential as an alternative therapy against S. aureus infection (SA) and antiinfection. However, its chemical composition and in vivo metabolism characteristics remain unknown, which limits its clinical application. Methods: Here, we aimed to understand the in vitro and in vivo material basis of FSFp. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to identify chemicals in FSFp as well as its phase I and phase II reaction metabolites in plasma, urine and feces. Results: A total of 38 chemicals were characterized in FSFp, including 22 flavonoids, 10 organic acids, 3 chromones, 1 aromatic ketone, 1 coumarin, and 1 ligan. After analysis of the drugged bio-samples, a total of 21 compounds were found in urine, and 16 of them were found in feces, but only one was found in plasma. In addition, 56 FSFp-related metabolites were characterized, of which 56 were in urine, 4 in feces, and 8 in plasma. Conclusion: This is the first comprehensive research of FSFp on chemical constituents and metabolic profiles. It was expected that this study would offer reliable support for further investigation of FSFp.

Background: Propofol is the most commonly used general anesthetic drug in many countries, including Jordan. However, there is a wide variation in the propofols' dose and response among the patients. Genetic variation in the cytochrome (CYP) 2B6 gene affects propofol metabolism and might affect propofol dose and response. Aims: This study aimed to determine the influence of major genetic alleles of the CYP2B6 gene, CYP2B6*2A, *6A, *3, *4A, and *5A, on the required propofol dose and response among Jordanian Arabic patients attending The University of Jordan Hospital. Methods: A total of 155 patients were administrated propofol. The propofol response was evaluated by monitoring the time to reach the bispectral index of 60 (BIS60) for every patient. The CYP2B6 genetic variants were genotyped by polymerase chain reaction followed by restriction through specific enzymes for CYP2B6 variants. Results: It is found that patients with variant CYP2B6*2A and *4A alleles required significantly (P < 0.05) lower propofol doses, while patients with variant CYP2B6*6A, *3, and *5A alleles required higher propofol doses in comparison with patients carrying the wild CYP2B6 alleles. Patients with variant CYP2B6*2A and *3 alleles needed a significantly (P < 0.05) shorter while patients with variant CYP2B6*5A allele needed longer time of BIS60 than patients with wild CYP2B6*2A, *3, and *5A alleles. Conclusion: It is concluded that CYP2B6 genetic variants affect propofol dose and can explain, at least partly, the inter-individual variation in the propofol response. Further clinical studies with a larger sample size are needed to confirm the findings of this study.