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European Journal of Medicinal Chemistry Jul 2024Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly...
Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC = 28 nM) and CYP3A4 (IC = 223 nM) inhibitory activities with low absorption potential (P (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.
Topics: Cytochrome P-450 CYP3A; Humans; Animals; ortho-Aminobenzoates; Drug Design; ATP Binding Cassette Transporter, Subfamily B, Member 1; Mice; Cytochrome P-450 CYP3A Inhibitors; Structure-Activity Relationship; Molecular Structure; Models, Molecular; Rats; Dose-Response Relationship, Drug; Paclitaxel; Male
PubMed: 38762918
DOI: 10.1016/j.ejmech.2024.116492 -
European Journal of Pharmaceutics and... Jul 2024P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration...
P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.
Topics: Female; Animals; Drug Resistance, Neoplasm; Breast Neoplasms; Humans; Mice; Drug Resistance, Multiple; Liposomes; Cell Line, Tumor; Mice, Inbred BALB C; Antineoplastic Agents; Apoptosis; Drug Delivery Systems; Xenograft Model Antitumor Assays; Mice, Nude; MCF-7 Cells; Peptide Fragments; Doxorubicin; ATP Binding Cassette Transporter, Subfamily B, Member 1; Collagen Type IV
PubMed: 38759900
DOI: 10.1016/j.ejpb.2024.114327 -
Frontiers in Pharmacology 2024The therapeutic effect of chemotherapy and targeted therapy are known to be limited by drug resistance. Substantial evidence has shown that ATP-binding cassette (ABC)...
The therapeutic effect of chemotherapy and targeted therapy are known to be limited by drug resistance. Substantial evidence has shown that ATP-binding cassette (ABC) transporters P-gp and BCRP are significant contributors to multidrug resistance (MDR) in cancer cells. In this study, we demonstrated that a clinical-staged ATR inhibitor ceralasertib is susceptible to P-gp and BCRP-mediated MDR. The drug resistant cancer cells were less sensitive to ceralasertib compared to the parental cells. Moreover, ceralasertib resistance can be reversed by inhibiting the drug efflux activity of P-gp and BCRP. Interestingly, ceralasertib was able to downregulate the level of P-gp but not BCRP, suggesting a potential regulation between ATR signaling and P-gp expression. Furthermore, computational docking analysis predicted high affinities between ceralasertib and the drug-binding sites of P-gp and BCRP. In summary, overexpression of P-gp and BCRP are sufficient to confer cancer cells resistance to ceralasertib, underscoring their role as biomarkers for therapeutic efficacy.
PubMed: 38756373
DOI: 10.3389/fphar.2024.1400699 -
Bioorganic & Medicinal Chemistry Letters Aug 2024Using an electrochemical C(sp)-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to...
Using an electrochemical C(sp)-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to compare with the parent compounds. Improvements were observed in membrane permeability, P-gp liability, and inhibitory effects on hERG and Na1.5 channels, accompanied with a trend of decreased aqueous solubility and microsomal stability. It was also revealed that α-fluorination reduced the basicity of tropane nitrogen atom for about 1000-fold.
Topics: Humans; Tropanes; Halogenation; Solubility; Structure-Activity Relationship; Ether-A-Go-Go Potassium Channels; Cell Membrane Permeability; Animals; Molecular Structure; ATP Binding Cassette Transporter, Subfamily B, Member 1
PubMed: 38754562
DOI: 10.1016/j.bmcl.2024.129798 -
Journal of Drug Targeting May 2024The worldwide HIV cases were 39.0 million (33.1-45.7 million) in 2022. Due to genetic variations, HIV-1 is more easily transmitted than HIV-2 and favours CD4 + T... (Review)
Review
The worldwide HIV cases were 39.0 million (33.1-45.7 million) in 2022. Due to genetic variations, HIV-1 is more easily transmitted than HIV-2 and favours CD4 + T cells and macrophages, producing AIDS. Conventional HIV drug therapy has many drawbacks, including adherence issues leading to resistance, side effects that lower life quality, drug interactions, high costs limiting global access, inability to eliminate viral reservoirs, chronicity requiring lifelong treatment, emerging toxicities, and a focus on managing infections. Conventional dosage forms have bioavailability issues due to intestinal P-glycoprotein (P-gp) efflux, which can reduce anti-retroviral drug efficacy and lead to resistance. Use of phyto-constituents with P-gp regulating actions has great benefits for semi-synthetic modification to create formulations with greater bioavailability and reduced toxicity, which improves drug effectiveness. Lipid-based nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers, polymer-based nanocarriers, and inorganic nanoparticles may inhibit P-gp efflux. Employing potent P-gp inhibitors within nanocarriers as a Trojan horse approach can enhance the intracellular accumulation of anti-retroviral drugs (ARDs), which are substrates for efflux transporters. This technique increases oral bioavailability and offers lower-dose options, boosting HIV patient compliance and lowering costs. Molecular docking of the inhibitor with P-gp may anticipate optimum binding and function, allowing drug efflux to be minimised.
PubMed: 38748868
DOI: 10.1080/1061186X.2024.2356751 -
Journal of Pharmaceutical and... Aug 2024Scutebarbatine B (SBT-B) is a neo-clerodane diterpenic compound isolated from Scutellaria barbata D. Don (S. barbata), which has been reported to exhibit inhibitory...
Identification of Scutebarbatine B metabolites in rats using UHPLC-Q-Orbitrap-MS/MS and exploration of its mechanism of reversal multidrug resistance in breast cancer by network pharmacology and molecular docking studies.
Scutebarbatine B (SBT-B) is a neo-clerodane diterpenic compound isolated from Scutellaria barbata D. Don (S. barbata), which has been reported to exhibit inhibitory P-glycoprotein (P-gp) property in MCF-7/ADR cells. However, its metabolism and molecular mechanism of reversal multidrug resistance (MDR) in breast cancer remains unclear. This study investigated the metabolite profile of SBT-B in rats by UHPLC-Q-Orbitrap-MS/MS, and explored its mechanism of reversal MDR through network pharmacology and molecular docking studies. A total of 16 Phase I metabolites and 2 Phase II metabolites were identified, and 18 metabolites were all newly discovered metabolites as novel compounds. The metabolic pathway of SBT-B mainly includes oxidization, reduction, hydrolysis, acetylation and glycination. Meanwhile, network pharmacology analyses showed that SBT-B mainly regulated p27 phosphorylation during cell cycle progression, p53 signaling pathway, influence of Ras and Rho proteins on G1 to S Transition. Molecular docking studies revealed that SBT-B exhibits the potential to inhibit P-gp expression by selectively binding to GLN721 and ALA981 residue sites at the interface of P-gp. In addition, SBT-B exhibits moderate binding affinity with CDK2 and E2F1. This study illustrated the major metabolic pathways of SBT-B in vivo, clarified detailed information on SBT-B metabolites in rats, and uncovered the potential mechanism of SBT-B reversal MDR in breast cancer, providing new insights for the development of P-gp inhibitors.
Topics: Animals; Molecular Docking Simulation; Female; Tandem Mass Spectrometry; Rats; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Humans; Chromatography, High Pressure Liquid; Rats, Sprague-Dawley; Breast Neoplasms; Network Pharmacology; MCF-7 Cells; Diterpenes, Clerodane; Scutellaria; ATP Binding Cassette Transporter, Subfamily B, Member 1
PubMed: 38744199
DOI: 10.1016/j.jpba.2024.116207 -
Antimicrobial Agents and Chemotherapy May 2024Ivermectin (IVM) could be used for malaria control as treated individuals are lethal to blood-feeding , resulting in reduced transmission. Tafenoquine (TQ) is used to...
Ivermectin (IVM) could be used for malaria control as treated individuals are lethal to blood-feeding , resulting in reduced transmission. Tafenoquine (TQ) is used to clear the liver reservoir of and as a prophylactic treatment in high-risk populations. It has been suggested to use ivermectin and tafenoquine in combination, but the safety of these drugs in combination has not been evaluated. Early derivatives of 8-aminoquinolones (8-AQ) were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein (P-gp) blood brain barrier (BBB) transporter. Thus, there is concern that co-administration of these drugs could be neurotoxic. This study aimed to evaluate the safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine (CQ) in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine and ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed . Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3''--demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques; therefore, this combination could be considered for evaluation in human trials.
PubMed: 38742896
DOI: 10.1128/aac.00181-24 -
Heliyon May 2024P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) multidrug resistance (MDR) transporters are localized at the luminal surface of the blood-brain barrier...
Hypoxia modulates P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) drug transporters in brain endothelial cells of the developing human blood-brain barrier.
P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) multidrug resistance (MDR) transporters are localized at the luminal surface of the blood-brain barrier (BBB). They confer fetal brain protection against harmful compounds that may be circulating in the peripheral blood. The fetus develops in low oxygen levels; however, some obstetric pathologies such as pre-eclampsia, placenta accreta/previa may result in even greater fetal hypoxic states. We investigated how hypoxia impacts MDR transporters in human fetal brain endothelial cells (hfBECs) derived from early and mid-stages of pregnancy. Hypoxia decreased BCRP protein and activity in hfBECs derived in early pregnancy. In contrast, in hfBECs derived in mid-pregnancy there was an increase in P-gp and BCRP activity following hypoxia. Results suggest a hypoxia-induced reduction in fetal brain protection in early pregnancy, but a potential increase in transporter-mediated protection at the BBB during mid-gestation. This would modify accumulation of various key physiological and pharmacological substrates of P-gp and BCRP in the developing fetal brain and potentially contribute to the pathogenesis of neurodevelopmental disorders commonly associated with hypoxia.
PubMed: 38737275
DOI: 10.1016/j.heliyon.2024.e30207 -
BMC Complementary Medicine and Therapies May 2024Cepharanthin alone or in combination with glucocorticoid (GC) has been used to treat chronic immune thrombocytopenia (ITP) since the 1990s. Cepharanthine (CEP) is one of...
Cepharanthine synergistically promotes methylprednisolone pharmacodynamics against human peripheral blood mononuclear cells possibly via regulation of P-glycoprotein/glucocorticoid receptor translocation.
BACKGROUND
Cepharanthin alone or in combination with glucocorticoid (GC) has been used to treat chronic immune thrombocytopenia (ITP) since the 1990s. Cepharanthine (CEP) is one of the main active components of Cepharanthin. The purpose of this study was to investigate the effects of CEP on GC pharmacodynamics on immune cells and analyse the possible action mechanism of their interactions.
METHODS
Peripheral blood mononuclear cells (PBMCs), T lymphocytic leukemia MOLT-4 cells and daunorubicin resistant MOLT-4 cells (MOLT-4/DNR) were used to evaluate the pharmacodynamics and molecular mechanisms. Drug pharmacodynamics was evaluated by WST-8 assay. P-glycoprotein function was examined by rhodamine 123 assay. CD4CD25Foxp3 regulatory T cells and Th1/Th2/Th17 cytokines were detected by flow cytometry. P-glycoprotein expression and GC receptor translocation were examined by Western blot.
RESULTS
CEP synergistically increased methylprednisolone (MP) efficacy with the suppressive effect on the cell viability of PBMCs. 0.3 and 1 μM of CEP significantly inhibited P-glycoprotein efflux function of CD4 cells, CD8 cells, and lymphocytes (P<0.05). 0.03~3 μM of CEP also inhibited the P-glycoprotein efflux function in MOLT-4/DNR cells in a concentration-dependent manner (P<0.001). However, 0.03~3 μM of CEP did not influence P-glycoprotein expression. 0.03~0.3 μM of CEP significantly increased the GC receptor distribution from the cytoplasm to the nucleus in a concentration-dependent manner in MOLT-4/DNR cells. The combination did not influence the frequency of CD4, CD4CD25 and CD4CD25Foxp3 T cells or the secretion of Th1/Th2/Th17 cytokines from PBMCs. In contrast, CEP alone at 1 μM decreased the percentage of CD4 T cell significantly (P<0.01). It also inhibited the secretion of IL-6, IL-10, IL-17, TNF-α, and IFN-γ.
CONCLUSIONS
CEP synergistically promoted MP pharmacodynamics to decrease the cell viability of the mitogen-activated PBMCs, possibly via inhibiting P-glycoprotein function and potentiating GC receptor translocation. The present study provides new evidence of the therapeutic effect of Cepharanthin alone or in combination with GC for the management of chronic ITP.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzodioxoles; Benzylisoquinolines; Drug Synergism; Leukocytes, Mononuclear; Methylprednisolone; Receptors, Glucocorticoid
PubMed: 38734604
DOI: 10.1186/s12906-024-04489-z -
Journal of Clinical Medicine Apr 2024: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the...
: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). : A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and , and SNP while on two different dabigatran doses (110 and 150 mg BID). : A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different and genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44-111) ng/mL in patients with the heterozygous genotype vs. 127 (85-147) ng/mL in the wild-type CC genotype vs. 110 (47-159) ng/mL in the mutant trait TT genotype ( = 0.048). In patients with the genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 ( = 0.042). : heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.
PubMed: 38731074
DOI: 10.3390/jcm13092545