The impact of freeze-dried Baiyedancong-Oolong tea aqueous extract containing bioactive compounds on the activities of CYP450 enzymes, the transport capabilities of P-gp and OATs, and transcription levels in mice.

In this study, (-)-epigallocatechin gallate (EGCG) and caffeine extracted from freeze-dried autumn Baiyedancong Oolong tea (FBOT) were orally administered to mice for 7 consecutive days to explore the effects of BOT and its bioactive compounds on the activities and transcription levels of CYP450 enzymes, intestinal effluence transporter P-gp, and renal ingestion Organic Anion Transporters (OATs). Concurrently, EGCG and caffeine enhanced the activities of CYP3A, CYP2E1, and CYP2C37 in the liver of mice, while impairing the transport capabilities of P-gp and OATs. Reduced levels of MDR1 encoding P-gp transcription in the small intestine and renal OAT1 and OAT3 revealed that transcription was involved in the regulation of CYP450, P-gp, and OATs. The reduced transcription level of liver CYP2E1 suggested that CYP2E1 activity may have been elevated due to alternative mechanisms, but not through transcription. The absorption, metabolism, and excretion of drugs may be influenced by the daily consumption or high-dose administration of BOT and its related products, in which EGCG and caffeine may make great contributions.

Discovery of novel third generation P-glycoprotein inhibitors bearing an azo moiety with MDR-reversing effect.

P-glycoprotein (P-gp)-caused multidrug resistance (MDR) is a crucial factor in the cancer chemotherapy failure. Herein, a total of twenty two azo-containing WK-X-34 (WK34, a third generation P-gp inhibitor) derivatives were synthesized as novel P-gp inhibitors. Biological evaluation revealed that compound 7i effectively reversed P-gp-mediated MDR in K562/A02 cells, with a higher reversal fold (RF) value than WK34 (142.79 vs. 64.41). Further investigation indicated that 7i dose-dependently inhibited P-gp function, without affecting its expression. CETSA results illustrated that 7i could obviously improve P-gp stability, suggesting its high affinity with P-gp. Molecular docking analysis revealed that 7i fit well into P-gp's binding pocket, thus displaying potent reversal effect on P-gp-mediated tumor MDR Optical properties evaluation confirmed that azo-containing 7i can undergo reversible changes in the cis and trans configurations under the irradiation of 365 nm and 520 nm wavelength of light. Notably, the configuration change of azo might affect the MDR-reversal potency, and cis-7i has a lower RF value than trans-7i (122.70 vs. 142.79), suggesting that development of photoswitchable P-gp inhibitors might be a novel strategy to reduce the systemic toxicity caused by indiscriminate inhibition of P-gp by traditional inhibitors. Collectively, 7i, as a novel P-gp inhibitor, warranted further investigation.

Construction of cytochrome P450 3A and P-glycoprotein knockout rats with application in rivaroxaban-verapamil interactions.

Cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), as important metabolic enzymes and transporters, participate in the biological transformation and transport of many substances in the body. CYP3A and P-gp are closely related, with very high substrate overlap and regulation similarity, making it particularly difficult to investigate the function of one or the other individually in vivo. Rivaroxaban and verapamil are commonly used together to treat nonvalvular atrial fibrillation in clinical practice. However, this combination therapy can increase systemic exposure to rivaroxaban and the risk of major bleeding and intracranial hemorrhage. In this study, Cyp3a1/2 and Mdr1a/b quadruple gene knockout (qKO) rat model was generated and characterized for the first time. CYP3A1/2 and P-gp are completely absent in this novel rat model. Then, the qKO rat model was applied for the evaluation of the drug-drug interactions (DDI) between rivaroxaban and verapamil. The results demonstrated that CYP3A and P-gp were jointly and selectively involved in the pharmacokinetic interactions between rivaroxaban and verapamil. This study may provide useful information for understanding the role of CYP3A and P-gp in rivaroxaban-verapamil therapy and predicting the potential interaction between CYP3A and P-gp.

High-throughput screening of the natural STK11 agonist dauricine: a biphenylisoquinoline alkaloid exerting anti-NSCLC effects and reversing gefitinib resistance.

BACKGROUND: Serine / threonine kinase 11 (STK11) deletion and downregulation caused cancer progression, and were widely associated with drug resistance. Accurate screening of natural small molecules about anti-cancer and anti-drug resistance is the key to the development and utilization of natural product application, which could promote traditional Chinese medicine in the treatment of cancer. Dauricine, which is derived from the rhizome of Menispermum dauricum DC., has certain potential but unexplored mechanism for the treatment of cancer. PURPOSE: The aim of this study was to screen and validate the role and mechanism of natural STK11 agonists with anti-drug resistance from plants in the treatment of NSCLC. METHODS: A lentiviral STK11 overexpression cell model was employed for the screening of natural STK11 agonists. The efficacy of dauricine in the treatment of NSCLC was validated on PC-9 and HCC827 cells. In vivo validation of dauricine activity was performed using nude mouse models equipped with PC9 xenografts. To investigate the anti-resistant effects of dauricine, gefitinib-resistant PC9 cell models were constructed. RESULTS: As a natural agonist of STK11, it causes the activation of the STK11/AMPK pathway and inhibits the growth of PC-9 cells. Dauricine synergises the inhibitory effect with gefitinib on PC9. The up-regulation of STK11 protein expression by dauricine was demonstrated in vitro and in vivo, while restoring the sensitivity of PC9 / GR to gefitinib by down-regulating the protein expression of Nrf2 and Pgp. CONCLUSION: Dauricine, a natural agonist of STK11, effectively inhibited NSCLC, and its combination treatment with gefitinib reversed drug-resistant NSCLC.

Modulation of Multidrug Resistance Transporters by Food Components and Dietary Supplements: Implications for Cancer Therapy Efficacy and Safety.

The aim of this review is to explore how diet and dietary supplements influence the activity of key multidrug resistance (MDR) transporters-MRP2, BCRP, and P-gp. These transporters play a crucial role in drug efflux from cancer cells and significantly affect chemotherapy outcomes. This review focuses on how dietary phytochemicals, such as catechins and quercetin, impact the expression and function of these transporters. Both in vitro and in vivo experiments were examined to assess changes in drug bioavailability and intracellular drug accumulation. The findings show that certain dietary components-such as catechins, flavonoids, resveratrol, curcumin, terpenoids, sterols, and alkaloids-can either inhibit or induce MDR transporter activity, thus influencing the effectiveness of chemotherapy. These results highlight the importance of understanding diet-drug interactions in cancer therapy to improve treatment outcomes and reduce side effects. In conclusion, dietary modifications and supplements should be carefully considered in cancer treatment plans to optimize therapeutic efficacy.

In Vivo Detection of Multidrug-Resistance Related Proteins in Locally Advanced Breast Cancer Using 99mTc-MIBI SPECT/CT Imaging: Correlation with Clinical Outcomes.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) is widely used for treating locally advanced Breast cancer (LABC). However, development of multidrug resistance (MDR) is the main underlying factor for chemoresistance. Technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) is a substrate for MDR. This study aimed to analyze the relationship between expression of MDR-related proteins (P-gp and Bcl-2) and 99mTc-MIBI uptake and retention in BC tumor cells, pathologic response to NACT, disease free survival (DFS) and overall survival (OS). METHODS: prospective analysis recruited 31 patients with LABC who received NACT between January 2019 and March 2020. 99mTc-MIBI planar and SPECT/CT imaging was conducted before and after NACT. Qualitative and quantitative analyses were performed, pre and post-NACT early and delayed lesion to non-lesion (LNL) ratios, and retention index (RI) of 99mTc-MIBI were calculated. Expression of P-gp and Bcl-2 in tumor cells was determined by immunohistochemistry. RESULTS: Quantitively, inter-reader ICC for SPECT/CT based quantification was consistently higher than that of planar images. Post-NACT LNL ratios were significantly higher in patients with pathologic persistent disease (PPD). A change in RI between pre- and post-NACT scans demonstrated a significant association with DFS with a hazard ratio of 0.7 (95%CI: 06-1.0). Qualitatively, SPECT/CT was significantly more accurate compared to planar imaging in identifying residual viable tumor (81% compared to 57%).  Her2neu positivity and high post-operative Bcl-2 and P-gp were associated with worse DFS. A significant association was found between increased expression of post-NACT Bcl-2 and PPD, advanced tumor stage and poor OS. CONCLUSION: 99mTc-MIBI SPECT/CT based qualitative evaluation of BC response to NACT is more accurate than planar imaging. Post-NACT MIBI retention is positively correlated with P-gp and Bcl-2 expression. 99mTc-MIBI SPECT/CT may predict MDR development. High post-NACT Bcl-2 expression is significantly associated with advanced tumor stage and OS. High post-NACT P-gp expression has a worse impact on pathologic response and DFS.

Genetic diversity, stress tolerance and phytobeneficial potential in rhizobacteria of Vachellia tortilis subsp. raddiana.

BACKGROUND: Soil bacteria often form close associations with their host plants, particularly within the root compartment, playing a significant role in plant growth and stress resilience. Vachellia tortilis subsp. raddiana, (V. tortilis subsp. raddiana)a leguminous tree, naturally thrives in the harsh, arid climate of the Guelmim region in southern Morocco. This study aims to explore the diversity and potential plant growth-promoting (PGP) activities of bacteria associated with this tree. RESULTS: A total of 152 bacterial isolates were obtained from the rhizosphere of V. tortilis subsp. raddiana. Rep-PCR fingerprinting revealed 25 distinct genomic groups, leading to the selection of 84 representative strains for further molecular identification via 16 S rRNA gene sequencing. Seventeen genera were identified, with Bacillus and Pseudomonas being predominant. Bacillus strains demonstrated significant tolerance to water stress (up to 30% PEG), while Pseudomonas strains showed high salinity tolerance (up to 14% NaCl). In vitro studies indicated variability in PGP activities among the strains, including mineral solubilization, biological nitrogen fixation, ACC deaminase activity, and production of auxin, siderophores, ammonia, lytic enzymes, and HCN. Three elite strains were selected for greenhouse inoculation trials with V. tortilis subsp. raddiana. Strain LMR725 notably enhanced various plant growth parameters compared to uninoculated control plants. CONCLUSIONS: The findings underscore the potential of Bacillus and Pseudomonas strains as biofertilizers, with strain LMR725 showing particular promise in enhancing the growth of V. tortilis subsp. raddiana. This strain emerges as a strong candidate for biofertilizer formulation aimed at improving plant growth and resilience in arid environments.

Inhibition of P-Glycoprotein Asymmetrically Alters the In Vivo Exposure Profile of SGC003F: A Novel Guanylate Cyclase Stimulator.

As a novel guanylate cyclase stimulator, SGC003F is being developed for the treatment of heart failure with a reduced ejection fraction (HFrEF). This study aimed to assess the effect of P-glycoprotein (P-gp) inhibition on SGC003F exposure in vivo, comparing plasma and tissue levels, and evaluating the role of P-gp in the small intestine, blood-brain barrier (BBB), and kidney in impacting the tissue exposure. Tariquidar, a P-gp inhibitor, was added to monolayer transport assays to observe the changes in the transmembrane characteristics of SGC003F. Rats were given SGC003F with tariquidar via various routes to measure plasma, tissue, urine, and fecal concentrations. The inclusion of tariquidar significantly altered the pharmacokinetics of SGC003F. In LLC-PK1-MDR1 cells, tariquidar reduced the efflux ratio of SGC003F from 6.56 to 1.28. In rats, it enhanced the plasma AUC by 3.05 or 1.61 times, increased the Cmax by 2.13 or 1.07 times, and notably improved bioavailability from 46.4% to 95%. Additionally, co-administration with tariquidar led to a decrease in fecal excretion and an increase in tissue exposure, with only a moderate effect on the partition ratios in the small intestine and brain. P-gp inhibition impacts SGC003F exposure, with plasma levels not fully reflecting tissue levels. P-gp in the small intestine and BBB affects SGC003F's pharmacokinetics, warranting further clinical drug-drug interaction (DDI) studies.

Candidate antibody reference reagents for Chlamydia trachomatis serology.

Chlamydia trachomatis (Ct) serology is an important tool for monitoring infection and disease burden but there are currently no formal reference reagents to harmonize results reporting. Our objective was to develop a panel of candidate reference reagents with reactivity against the major outer membrane protein (MOMP) and virulence factor (pgp3) antigens. Plasma packs from females (20-40 years old) were screened against MOMP and pgp3 antigens and selected positive and negative samples pooled to create a panel of candidate antibody reference reagents that were tested in two laboratories. Antigen specificity and internal quality assurance were also evaluated. Suitable candidate materials have been selected to produce Ct reference reagents.

A study of PGP 9.5 immunohistochemical labeling on formalin-fixed paraffin embedded tissues for epidermal nerve fiber density testing.

There have been several methods established for immunohistochemical labeling of the PGP 9.5 antigen in human tissue for the assessment of epidermal nerve fiber density, none of which uses neutral-buffered formalin as the preferred fixative for paraffin-embedded tissue. The literature maintains that formalin-fixed paraffin embedded tissues are unable to be used for this purpose and that other fixatives must be used due to the cross-linkages caused by formalin fixation. This study was undertaken to develop a standardized method for the use of formalin-fixed paraffin embedded tissues for immunohistochemical labeling and assessment of epidermal nerve fiber density. Formalin-fixed paraffin embedded tissues from the punch biopsies of patients suspected to have small fiber neuropathy were prepared for immunohistochemical labeling using heat-induced epitope retrieval for one hour at 92°C. The tissues were then stained with a polyclonal rabbit anti-human PGP 9.5 primary antibody. The resulting stains were then evaluated by a licensed pathologist who counted the number of epidermal nerve fibers stained and recorded the epidermal length in millimeters. Human foreskin was used as the tissue control in these studies. Satisfactory immunohistochemical labeling of epidermal nerve fibers was achieved from formalin-fixed paraffin embedded tissues through the use of heat-induced epitope retrieval. The authors of this paper have concluded that formalin-fixed paraffin embedded tissues may be used to achieve satisfactory immunohistochemical labeling for the assessment of epidermal nerve fiber density.

The role of efflux transporters in cytotoxicity and intracellular concentration of chlorpyrifos and chlorpyrifos oxon in human cell lines.

In this study, we investigated the role of two efflux transporters, p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in the cytotoxicity and intracellular accumulation of the organophosphate pesticide chlorpyrifos (CPF) and its active metabolite, CPF-oxon (CPFO), in a human-derived liver cell line (HepG2) and kidney epithelial cell line (HK-2). The cytotoxicity to CPF and CPFO differed between cell lines where HK-2 had lower IC50 values which could be attributed to lower basal expression and inducibility of metabolizing enzymes, transporters, and nuclear receptors in HK-2 cells. In HepG2 cells, co-exposure of CPF with a specific inhibitor of either P-gp or BCRP enhanced the cytotoxicity of CPF while co-exposure of CPFO with VRP enhanced the cytotoxicity of CPFO, suggesting the role of these transporters in the elimination CPF and CPFO. Inhibition of efflux transporters did not affect the cytotoxicity of CPF and CPFO in HK-2 cells. Co-incubation of CPF with P-gp and BCRP inhibitors increased the intracellular concentration of CPF in HepG2 cells suggesting that both transporters play a role in limiting the cellular accumulation of CPF in HepG2 cells. Our results provide evidence that inhibition of efflux transporters can enhance CPF-induced toxicity through enhanced cellular accumulation and raises additional questions regarding how pesticide-transporter interactions may influence toxicity of mixtures containing pesticides and other environmental chemicals.

Characterization of the Synergistic Effect of Fungal Isolates in Suppressing Ganoderma boninense and Enhancing Oil Palm Growth.

The globally vital oil palm, a major oil producer, confronts productivity challenges due to Ganoderma boninense (Gb), causing output decline. Chemical control efforts have proven ineffective, prompting exploration of microbial-based biocontrol. While single fungal biocontrol research exists, the impact of employing multiple biocontrols concurrently to combat Ganoderma and enhance oil palm growth remains uncharted. This study examined four soil-derived fungal isolates for their ability to antagonize Gb PER71 in vitro. Molecular identification categorized them as Talaromyces spp. and Penicillium sp. Moreover, all isolates were revealed to have at least three plant growth-promoting (PGP) traits and were shown to have phosphoric hydrolase, ester hydrolase, peptide hydrolase, and glycosidase activities which are essential for plant growth. Furthermore, the synergistic evaluation of fungal isolates was tested against Gb PER71. One out of six combinations of fungal isolates showed a synergistic effect in vitro, and two showed a synergistic effect in planta. The application of single and combined fungal isolates tested in planta also suppressed Gb PER71 and enhanced oil palm growth compared to control groups. The findings indicate the promising potential of these isolates as biocontrol agents (BCAs) and bioformulations against Gb in oil palm cultivation.

PGPR isolated from hot spring imparts resilience to drought stress in wheat (Triticum aestivum L.).

Drought is a major abiotic stress that occurs frequently due to climate change, severely hampers agricultural production, and threatens food security. In this study, the effect of drought-tolerant PGPRs, i.e., PGPR-FS2 and PGPR-VHH4, was assessed on wheat by withholding water. The results indicate that drought-stressed wheat seedlings treated with PGPRs-FS2 and PGPR-VHH4 had a significantly higher shoot and root length, number of roots, higher chlorophyll, and antioxidant enzymatic activities of guaiacol peroxidase (GPX) compared to without PGPR treatment. The expression study of wheat genes related to tryptophan auxin-responsive (TaTAR), drought-responsive (TaWRKY10, TaWRKY51, TaDREB3, and TaDREB4) and auxin-regulated gene organ size (TaARGOS-A, TaARGOS-B, and TaARGOS-D) exhibited significantly higher expression in the PGPR-FS2 and PGPR-VHH4 treated wheat under drought as compared to without PGPR treatment. The results of this study illustrate that PGPR-FS2 and PGPR-VHH4 mitigate the drought stress in wheat and pave the way for imparting drought in wheat under water deficit conditions. Among the two PGPRs, PGPR-VHH4 more efficiently altered the root architecture to withstand drought stress.

Trichoderma produces methyl jasmonate-rich metabolites in the presence of Fusarium, showing biostimulant activity and wilt resistance in tomatoes.

Bioactive secondary metabolites from fungi, including Trichoderma, are an excellent source of plant biostimulants. Although production of novel biostimulants from known microbes is critical, challenging them may produce novel bioactive compounds. With this hypothesis, the study used live Fusarium chlamydosporum (FOL7) culture as the inducer during T. harzianum (IF63) growth in broth. Plate assays and gas chromatography-mass spectrometry (GC-MS) analysis were used to characterise the metabolites. Microscopy, pot experiments and, biochemical estimations of the defence-related enzymes in tomato plants established the biostimulant activity of the induced Trichoderma metabolites. Fungal crude metabolites (FCM) obtained from IF63+FOL7 extracts (TF.ex) showed increased antimicrobial activity. TF.ex at 50 µg mL-1, inhibited the FOL7 growth by 68.33% compared to the Trichoderma alone extract. Scanning electron microscopy (SEM) revealed morphological disruption of FOL7 mycelia by TF.ex. GC-MS analysis of the extracts revealed the presence of approximately 64 compounds, of which at least 13 were detected explicitly in TF.ex. Methyl (3-oxo-2-pentylcyclopentyl) acetate (Methyl dihydrojasmonate), a lipid functionally related to jasmonic acid, was the major metabolite (∼21%) present in TF.ex. Tomato seed dressing with TF.ex promoted plant growth and induced systemic resistance against FOL7 compared to alone Trichoderma and Fusarium extracts. The TF.ex treatment increased the superoxide dismutase (33%) and catalase activity by 2.5-fold in tomato plants. The study concludes that fungal secondary metabolites may be modulated by providing appropriate challenges to produce effective metabolite-based biostimulants for agricultural applications.

Effect of midostaurin on the pharmacokinetics of P-gp, BCRP, and CYP2D6 substrates: assessing potential drug-drug interactions in healthy participants : Brief title: Drug-drug interaction of midostaurin.

PURPOSE: Midostaurin, approved for FLT3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is mainly metabolized by cytochrome P450 (CYP) 3A4. Midostaurin exhibited potential inhibitory effects on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion-transporting polyprotein 1B1, and CYP2D6 in in vitro studies. This study investigated the pharmacokinetic (PK) effects of midostaurin on P-gp (digoxin), BCRP (rosuvastatin) and CYP2D6 (dextromethorphan) substrates in healthy adults. METHODS: This was an open-label, single-sequence, phase I clinical study evaluating the effect of single-dose midostaurin (100 mg) on the PK of digoxin and rosuvastatin (Arm 1), and dextromethorphan (Arm 2). Participants were followed up for safety 30 days after last dose. In addition, the effect of midostaurin on the PK of dextromethorphan metabolite (dextrorphan) was assessed in participants with functional CYP2D6 genes in Arm 2. RESULTS: The effect of midostaurin on digoxin was minor and resulted in total exposure (AUC) and peak plasma concentration (Cmax) that were only 20% higher. The effect on rosuvastatin was mild and led to an increase in AUCs of approximately 37-48% and of 100% in Cmax. There was no increase in the primary PK parameters (AUCs and Cmax) of dextromethorphan in the presence of midostaurin. The study treatments were very well tolerated with no occurance of severe adverse events (AEs), AEs of grade ≥ 2, or deaths. CONCLUSION: Midostaurin showed only a minor inhibitory effect on P-gp, a mild inhibitory effect on BCRP, and no inhibitory effect on CYP2D6. Study treatments were well tolerated in healthy adults.

Studies on pharmacokinetic properties and intestinal absorption mechanism of sanguinarine chloride: in vivo and in situ.

Sanguinarine (SAN) is an alkaloid with multiple biological activities, mainly extracted from Sanguinaria canadensis or Macleaya cordata. The low bioavailability of SAN limits its utilization. At present, the nature and mechanism of SAN intestinal absorption are still unclear. The pharmacokinetics, single-pass intestinal perfusion test (SPIP), and equilibrium solubility test of SAN in rats were studied. The absorption of SAN at 20, 40, and 80 mg/L in different intestinal segments was investigated, and verapamil hydrochloride (P-gp inhibitor), celecoxib (MPR2 inhibitor), and ko143 (BCRP inhibitor) were further used to determine the effect of efflux transporter proteins on SAN absorption. The equilibrium solubility of SAN in three buffer solutions (pH 1.2, 4.5 and 6.8) was investigated. The oral pharmacokinetic results in rats showed that SAN was rapidly absorbed (Tmax=0.5 h), widely distributed (Vz/F = 134 L/kg), rapidly metabolized (CL = 30 L/h/kg), and had bimodal phenomena. SPIP experiments showed that P-gp protein could significantly affect the effective permeability coefficient (Peff) and apparent absorption rate constant (Ka) of SAN. Equilibrium solubility test results show that SAN has the best solubility at pH 4.5. In conclusion, SAN is a substrate of P-gp, and its transport modes include efflux protein transport, passive transport and active transport.

In Vivo Activity of Intestinal P-Glycoprotein and Hepatic Organic Anion Transporters Polypeptide in Pregnancy and Postpartum.

This study investigates the influence of pregnancy on the in vivo activity of the intestinal P-glycoprotein (P-gp) and hepatic organic anion transporters polypeptide (OATP/BCRP) using, respectively, fexofenadine and rosuvastatin as probe drugs. Eleven healthy participants were investigated during the third trimester of pregnancy (Phase 1, 28 to 38 weeks of gestation) and in the postpartum period (Phase 2, 8 to 12 weeks postpartum). In both phases, after administration of a single oral dose of fexofenadine (60 mg) and rosuvastatin (5 mg), serial blood samples were collected for up to 24 h. Rosuvastatin and fexofenadine in plasma were analyzed by LC-MS/MS using previously validated methods. The pharmacokinetic parameters of fexofenadine and rosuvastatin (Phoenix WinNonLin software) with normal distribution (Shapiro-Wilk test) are presented as geometric mean and 90% confidence interval. Phases 1 and 2 were compared using the t test (P < .05). Fexofexadine AUC0-24 values do not differ (P-value: .0715) between Phase 1 (641.9 ng h/mL [500.6-823.1]) and Phase 2 (823.8 ng h/mL [641.5-1057.6]) showing that pregnancy (third trimester) does not alter intestinal P-gp activity. However, rosuvastatin AUC0-24 values are higher (P-value: .00005) in Phase 1 (18.7 ng h/mL [13.3-26.4]) when compared to Phase 2 (9.5 ng h/mL [6.7-13.4]), suggesting inhibition of OATP1B1/OATP1B3 transporters. In conclusion, pregnancy assessed during the third trimester does not alter the intestinal P-gp activity but reduces the activity of hepatic OATP1B1/OATP1B3 transporters. Therefore, adjustments in dosage regimens may be necessary for drugs with low therapeutic index, substrates of the OATP1B1/OATP1B3 transporters, administered during the third trimester of pregnancy.

Airway extracellular LTA4H concentrations are governed by release from liver hepatocytes and changes in lung vascular permeability.

Leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme, with dual activities critical in defining the scale of tissue inflammation and pathology. LTA4H classically operates intracellularly, primarily within myeloid cells, to generate pro-inflammatory leukotriene B4. However, LTA4H also operates extracellularly to degrade the bioactive collagen fragment proline-glycine-proline to limit neutrophilic inflammation and pathological tissue remodeling. While the dichotomous functions of LTA4H are dictated by location, the cellular source of extracellular enzyme remains unknown. We demonstrate that airway extracellular LTA4H concentrations are governed by the level of pulmonary vascular permeability and influx of an abundant repository of blood-borne enzyme. In turn, blood LTA4H originates from liver hepatocytes, being released constitutively but further upregulated during an acute phase response. These findings have implications for our understanding of how inflammation and repair are regulated and how perturbations to the LTA4H axis may manifest in pathologies of chronic diseases.

P-glycoprotein-mediated herb-drug interaction evaluation between Tenacissoside G and paclitaxel.

P-glycoprotein (P-gp)-mediated herb-drug interactions (HDIs) may impact drug efficacy and safety. Tenacissoside G (Tsd-G), a major active component of Marsdenia tenacissima, exhibits anticancer activity. To analyze the effect of Tsd-G on the pharmacokinetics of paclitaxel (PTX), researchers selected 30 Sprague-Dawley (SD) rats, randomized into a solvent control group, a verapamil positive control group, and 20, 40, and 60 mg/kg Tsd-G groups. After seven consecutive days of intraperitoneal injection of verapamil or Tsd-G, a single dose of 6 mg/kg PTX was injected intravenously. Plasma samples were collected at different time points, and proteins were precipitated using a methanol-acetonitrile solution. An ultrahigh-performance liquid chromatography-tandem mass spectrometry method was developed, with docetaxel as an internal standard, and quantified using positive ion multiple reaction monitoring (MRM) mode. This analytical method's specificity, accuracy, precision, recovery, matrix effect, and sample stability meet the requirements for biological sample determination. After Tsd-G administration in rats, the mean residence time of PTX was significantly prolonged. And Tsd-G can stably bind to P-gp by forming hydrogen bonds and inhibiting the expression of P-gp in rat liver. Although the metabolites of PTX were not detected in this study, the above results still indicate the existence of HDIs between Tsd-G and PTX, and P-gp may be the main target to mediate HDIs.

Innovative Approaches to Optimize Clinical Transporter Drug-Drug Interaction Studies.

Of the 450 cell membrane transporters responsible for shuttling substrates, nutrients, hormones, neurotransmitters, antioxidants, and signaling molecules, approximately nine are associated with clinically relevant drug-drug interactions (DDIs) due to their role in drug and metabolite transport. Therefore, a clinical study evaluating potential transporter DDIs is recommended if an investigational product is intestinally absorbed, undergoes renal or hepatic elimination, or is suspected to either be a transporter substrate or perpetrator. However, many of the transporter substrates and inhibitors administered during a DDI study also affect cytochrome P450 (CYP) activity, which can complicate data interpretation. To overcome these challenges, the assessment of endogenous biomarkers can help elucidate the mechanism of complex DDIs when multiple transporters or CYPs may be involved. This perspective article will highlight how creative study designs are currently being utilized to address complex transporter DDIs and the role of physiology-based -pharmacokinetic (PBPK) models can play.