Aims
The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 ...(CYP2J2), CYP‐independent mechanisms, and P‐glycoprotein (P‐gp) and breast cancer resistance protein (Bcrp) (ABCG2).
Methods
The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P‐gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.
Results
Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co‐administered with midazolam was slightly decreased by 11% (95% confidence interval CI −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P‐gp inhibitor; 34% increase 95% CI 23%, 46%), clarithromycin (strong CYP3A4/moderate P‐gp inhibitor; 54% increase 95% CI 44%, 64%) and fluconazole (moderate CYP3A4, possible Bcrp ABCG2 inhibitor; 42% increase 95% CI 29%, 56%). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P‐gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase 95% CI 136%, 182% for a 400 mg once daily dose) and ritonavir (153% increase 95% CI 134%, 174%).
Conclusions
Results suggest that rivaroxaban may be co‐administered with CYP3A4 and/or P‐gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P‐gp and Bcrp (ABCG2) inhibitors (mainly comprising azole‐antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi‐pathway inhibitors of rivaroxaban clearance and elimination.
Objectives This review discusses the limitations and applications of the everted gut sac model in studying drug absorption, metabolism, and interaction.
Key findings The mechanism of drug ...absorption, interaction and the effect of factors such as age, sex, species, chronic therapy, and disease state on drug absorption have been summarized. The experimental conditions and their effects on the outcomes of trials have been discussed also.
Summary The everted sac model is an efficient tool for studying in‐vitro drug absorption mechanisms, intestinal metabolism of drugs, role of transporter in drug absorption, and for investigating the role of intestinal enzymes during drug transport through the intestine.
Objective
Overexpression of the drug transporter P‐glycoprotein (P‐gp) is thought to be involved in drug‐resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission ...tomography (PET) and the P‐gp substrate radiotracer (R)‐11Cverapamil (VPM) together with the third‐generation P‐gp inhibitor tariquidar (TQD) to evaluate P‐gp function in individuals with drug‐resistant epileptogenic developmental lesions.
Methods
Twelve healthy controls (7 male, median age 45, range 35‐55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM‐PET scans before and 60 minutes after a 30‐minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM‐K1, was estimated from the first 10 minutes of dynamic data using a single‐tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls.
Results
At baseline, SPM voxel‐based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls (P < .048). This was accentuated following P‐gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls (P < .002).
Significance
This study provides further evidence of P‐gp overactivity in patients with drug‐resistant epilepsy, irrespective of the type of lesion. Identifying P‐gp overactivity as an underlying contributor to drug‐resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P‐gp overactivity.
Introduction
Hyperprolactinaemia, a common adverse effect of antipsychotic drugs, is primarily linked to blockade of dopamine D2 receptors in the pituitary gland. Certain antipsychotic drugs, such ...as, for example risperidone and paliperidone, are more likely to induce hyperprolactinaemia compared to others. This effect is probably caused by a relatively high blood/brain concentration ratio, a consequence of being a substrate of P‐glycoprotein. Genetic variants of P‐glycoprotein with changed functional activity might influence the potential of risperidone and paliperidone to cause hyperprolactinaemia as the altered blood/brain concentration ratio would lead to a reduced therapeutic drug level within essential brain areas making dose adaptations necessary. This increases exposure of dopamine D2 receptors within the pituitary gland.
Aims
To investigate possible associations between MDR1/ABCB1 gene polymorphisms and antipsychotic drug‐induced hyperprolactinaemia in Russian patients with schizophrenia and to determine possible differences between risperidone/paliperidone and other antipsychotics.
Methods
In total, 446 patients with schizophrenia were included from 3 psychiatric hospitals in Siberia. Blood samples were obtained in a cross‐sectional study design for DNA extraction and prolactin measurement. Associations between hyperprolactinaemia and 8 MDR1/ABCB1 gene‐polymorphisms were assessed using logistic regression analysis accounting for covariates. The analysis was repeated in a patient subgroup using risperidone or paliperidone.
Results
We did not observe an association between any of the 8 single nucleotide polymorphisms and the prevalence of antipsychotic‐induced hyperprolactinaemia in the total patient population. However, in the risperidone/paliperidone subgroup, the single nucleotide polymorphism rs2032582 (G2677T) was found to be negatively associated with risperidone/paliperidone‐induced hyperprolactinaemia.
Conclusion
This study revealed a significant association between the ABCB1 gene polymorphism rs2032582 (G2677T) and risperidone/paliperidone‐induced hyperprolactinaemia.
Drug resistance in multiple myeloma Robak, Pawel; Drozdz, Izabela; Szemraj, Janusz ...
Cancer treatment reviews,
11/2018, Letnik:
70
Journal Article
Recenzirano
•Plasma cell myeloma (PCM) is an incurable hematologic disease characterized by the clonal proliferation of malignant plasma cells.•New targeted drugs including proteasome inhibitors, ...immunomodulatory drugs and monoclonal antibodies can prolong the survival of patients with PMM.•Several aspects of the mechanisms associated with the acquisition of resistance to available drugs have been investigated in recent years.•The better understanding of the pathways and protein expression involved in PMM drug resistance and the development of novel therapeutic strategies are important goals for further progress in the treatment of PMM.•This review gives a critical overview of the role of cellular, microenvironmental and molecular mechanisms of drug resistance in PMM.
Multiple myeloma (MM, plasma cell myeloma) is a malignant hematologic disease characterized by the clonal proliferation of malignant plasma cells. The treatment of MM has changed dramatically in recent years, with the introduction of new drugs into therapeutic strategies, both in the front line setting and in relapsed refractory disease. However, most patients eventually relapse and often demonstrate multiple drug resistance. Therefore there is still an urgent and unmet need to define the molecular mechanisms of resistance for available drugs in order to enhance the use of existing treatments and design more effective therapies. Genetic abnormalities are well known to play a central role in MM resistance to available drugs, and epigenetic aberrations mainly affecting the patterns of DNA methylation and histone modifications of genes, especially tumor suppressors, can be involved in the resistance mechanism. Moreover, defects in the mechanisms of apoptosis, senescence and DNA repair could also contribute to drug resistance. In addition, mutations or alterations in the expression of the drug target can influence response to therapy. Achieving a better understanding of the pathways and protein expression involved in MM drug resistance and the development of novel therapeutic strategies are important goals for further progress in the treatment of MM. This review gives a critical overview of the role of cellular, microenvironmental and molecular mechanisms of drug resistance in MM.
P‐glycoprotein (P‐gp) is an efflux transporter at the blood–brain barrier (BBB) that hinders brain access of substrate drugs and clears endogenous molecules such as amyloid beta (Aβ) from the brain. ...As biometals such as copper (Cu) modulate many neuronal signalling pathways linked to P‐gp regulation, it was hypothesised that the bis(thiosemicarbazone) (BTSC) Cu‐releasing complex, copper II glyoxal bis(4‐methyl‐3‐thiosemicarbazone) (CuIIGTSM), would enhance P‐gp expression and function at the BBB, while copper II diacetyl bis(4‐methyl‐3‐thiosemicarbazone) (CuIIATSM), which only releases Cu under hypoxic conditions, would not modulate P‐gp expression. Following treatment with 25–250 nM CuII(BTSC)s for 8–48 h, expression of P‐gp mRNA and protein in human brain endothelial (hCMEC/D3) cells was assessed by RT‐qPCR and Western blot, respectively. P‐gp function was assessed by measuring accumulation of the fluorescent P‐gp substrate, rhodamine 123 and intracellular Cu levels were quantified by inductively coupled plasma mass spectrometry. Interestingly, CuII(ATSM) significantly enhanced P‐gp expression and function 2‐fold and 1.3‐fold, respectively, whereas CuII(GTSM) reduced P‐gp expression 0.5‐fold and function by 200%. As both compounds increased intracellular Cu levels, the effect of different BTSC backbones, independent of Cu, on P‐gp expression was assessed. However, only the Cu‐ATSM complex enhanced P‐gp expression and this was mediated partly through activation (1.4‐fold) of the extracellular signal‐regulated kinase 1 and 2, an outcome that was significantly attenuated in the presence of an inhibitor of the mitogen‐activated protein kinase regulatory pathway. Our findings suggest that CuII(ATSM) and CuII(GTSM) have the potential to modulate the expression and function of P‐gp at the BBB to impact brain drug delivery and clearance of Aβ.
P‐glycoprotein (P‐gp) expressed at the blood–brain barrier (BBB) acts as a gatekeeper regulating the transport of molecules into and out of the brain. Two similar copper complexes, CuII(ATSM) and CuII(GTSM), have opposite modulatory effects on the expression and function of this efflux transporter that is responsible for keeping the brain a protected sanctuary as well as to clear unwanted molecules like amyloid beta (Aβ) from the brain. This involves the activation of MAPK signalling and MDR1 promoter regions regulating P‐gp. This has implications for enhancing brain drug delivery and clearance of Aβ in Alzheimer's disease.
Carbonic anhydrase XII (CAXII) is a membrane‐tethered ectoenzyme involved in intracellular pH regulation and overexpressed across various types of human cancer. Because CAXII inhibition shows ...antitumor activity in vitro, it is thought that the enzyme is mandatory for maximum tumor growth, above all under hypoxic conditions. Recently, it has been shown that CAXII is co‐expressed along with the P‐glycoprotein (P‐GP) on many tumor cells and that both proteins physically interact. Of interest, blocking CAXII activity also decreases P‐GP activity in cancer cells both in vitro and in vivo. Previously, we have reported on the development of a monoclonal antibody, termed 6A10, which specifically and efficiently blocks human CAXII activity. Here, we demonstrate that 6A10 also indirectly reduces P‐GP activity in CAXII/P‐GP double‐positive chemoresistant cancer cells, resulting in enhanced chemosensitivity as revealed by enhanced accumulation of anthracyclines and increased cell death in vitro. Even more important, we show that mice carrying human triple‐negative breast cancer xenografts co‐treated with doxorubicin (DOX) and 6A10 show a significantly reduced number of metastases. Collectively, our data provide evidence that the inhibition of CAXII with 6A10 is an attractive way to reduce chemoresistance of cancer cells and to interfere with the metastatic process in a clinical setting.
What's new?
Through the reversible hydratation of carbon dioxide, carbonic anhydrases (CAs) produce bicarbonate, a critical mediator of pH homeostasis. In human cancers, however, certain forms of CA are overexpressed and may provide a survival advantage for hypoxic tumor cells in acidic tumor environments. Here, using a monoclonal antibody, 6A10, the authors show that inhibition of cancer‐associated CAXII enhances chemosensitivity in resistant cancer cells. In an orthotopic breast cancer mouse model, co‐treatment with 6A10 and doxorubicin had no inhibitory effect on primary tumor growth. In tumor‐bearing animals, however, co‐treatment with the drugs significantly reduced the number of lung metastases.
A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) V10O286– (V10), H6V14O38(PO4)5− ...(V14), V15O36Cl6− (V15) and V18O42I7− (V18) as inhibitors of three major multidrug resistance‐linked ABC transporters: P‐glycoprotein (P‐gp), ABCG2 and MRP1. All of the POVs selectively inhibited P‐gp. V10 and V18 were the two most promising compounds, with IC50 values of transport inhibition of 25.4 and 22.7 µm, respectively. Both compounds inhibited P‐gp ATPase activity, with the same IC50 value of 1.26 µm. V10 and V18 triggered different conformational changes in the P‐gp protein with time‐dependent inhibition, which was confirmed using the synthesized salt of V10 with rhodamine B, RhoB‐V10. The hydrophilic nature of POVs supports the hypothesis that these compounds target an unusual ligand‐binding site, opening new possibilities in the development of potent modulators of ABC transporters.
One of the main challenges in cancer treatment is the resistance mediated by P‐glycoprotein (P‐gp). We described polyoxovanadates (POVs) as new selective P‐gp inhibitors. The two best compounds were V10O286– (V10) and V18O42(I)7− (V18). These compounds were not transported, inhibited the ATPase activity and triggered different protein conformational changes. In addition, compound RhoB‐V10 confirmed the time‐dependent intracellular accumulation of POVs.
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