RESULTS:
1 - 4 of 4 for ""Quinidine""
Probing Multidrug Resistance P-glycoprotein Transporter Activity with SPECT Radiopharmaceuticals
Multidrug resistance (MDR) mediated by overexpression of MDR1 (ABCB1) P-glycoprotein (Pgp) is one of the best characterized transporter-mediated barriers to successful chemotherapy in cancer patients and is also a rapidly emerging target in the progression of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Therefore molecular imaging probes capable of imaging noninvasively Pgp and closely related transporter activities in tissues as well as tumors would be expected to contribute to personalized medicine. Interrogation of Pgp-mediated transport activity in vivo via noninvasive SPECT imaging could be beneficial for stratification of patient populations likely to benefit from a given therapeutic treatment assist in the management of chemotherapy and aid the study of neurodegenerative diseases.
N,N-bis(Cyclohexanol)amine Aryl Esters: The Discovery of a New Class of Highly Potent Inhibitors of ransporter-Dependent Multidrug Resistance (MDR)
Multidrug resistance (MDR) is a kind of acquired resistance of microorganisms and cancer cells to chemotherapeutic drugs that are characterized by different chemical structure and different mechanism of action. Classic MDR is due to a lower intracellular concentration of cytotoxic drugs that is associated with accelerated efflux of the chemotherapeutic drugs and is the consequence of the over expression of transporter proteins that act as extrusion pumps. Pglycoprotein (P-gp/ABCB1) is the most important and studied member of such proteins belonging to the ATP Binding Cassette (ABC) superfamily of transporters that use ATP as energy source. Inhibition of the functions of P-gp and other ABC proteins could represent a way to circumvent appearance of MDR in cancer cells and the most classical pharmacological strategy is the administration of agents able to modulate the P-gp function. On the basis of the known characteristics of the recognition site of P-gp we have designed a new class of P-gp-mediated MDR reverters. These compounds are flexible molecules carrying a basic nitrogen atom flanked at properly modulated distance by two aromatic moieties; most of them possess MDR inhibitory activity on anthracycline-resistant erytroleukemia K562 cells. By applying the frozen analog approach to that series of very flexible MDR reverters we identified a new series of NN-bis(cyclohexanol)amine aryl esters that show very interesting MDR-reversing properties. Among them compound 15d that consistently shows low nanomolar potency and high efficacy in all the tests used appears as a new pharmacological tool for P-gp studies and a promising lead for the development of potent efficient and safe MDR reverters.
Impact of Impurities on IC50 Values of P450 Inhibitors
During early drug discovery the synthetic pathways for test compounds are not well defined and impurities in the test compounds are inevitable. Compounds undergo serial screening tests at this stage to assess their biological activities and drug-like properties. Impurities in the test compounds can produce false positive results and therefore complicate the interpretation of data. P450 inhibition is one of the screens used in the early drug discovery process to assess the potential of drug-drug interactions caused by the inhibition of P450 enzymes. The impact of impurities on P450 inhibition has not been investigated. In this study the impact of impurities on CYP2D6 IC50 values was evaluated using model compounds. Cimetidine was chosen as the test compound. Quinidine fluoxetine fluvoxamine and ibuprofen were chosen to represent impurities as they inhibit CYP2D6 to varying degrees. The IC50 values of these model impurities for CYP2D6 were 0.11 μM 0.98 μM 13.4 μM and >100 μM respectively. Impurities with potent CYP2D6 inhibition such as quinidine can significantly decrease the apparent IC50 value for the mixture. With the addition of only 2% quinidine to cimetidine (mol/mol) the apparent IC50 value of cimetidine decreased from 98 μM to 4.4 μM. With the addition of 10% quinidine the apparent IC50 decreased to 1.04 μM. Such a significant decrease in apparent IC50 values can produce a false alert and cause the inappropriate elimination of good compounds at an early stage. Impurities with low inhibitory potential such as fluvoxamine and ibuprofen did not cause a significant change in apparent IC50 values. An impurity can have a similar effect on the IC50 values for inhibition of other biological activities. The effect of an impurity on apparent IC50 values can be predicted by using a simulation curve if the potency of the impurity is characterized.
A Simplified Protocol Employing Elacridar in Rodents: A Screening Model in Drug Discovery to Assess P-gp Mediated Efflux at the Blood Brain Barrier
In the present study we have developed a simple time and cost effective in vivo rodent protocol to screen the susceptibility of a test compound for P-glycoprotein (P-gp) mediated efflux at the blood brain barrier (BBB) during early drug discovery. We used known P-gp substrates as test compounds (quinidine digoxin and talinolol) and elacridar (GF120918) as a chemical inhibitor to establish the model. The studies were carried out in both mice and rats. Elacridar was dosed intravenously at 5 mg/kg 0.5 h prior to probe substrate administration. Plasma and brain samples were collected and analyzed using UPLC-MS/MS. In the presence of elacridar the ratio of brain to plasma area under the curve (B/P) in mouse increased 2 4 and 38-fold respectively for talinolol digoxin and quinidine; whereas in rat a 70-fold increase was observed for quinidine. Atenolol a non P-gp substrate exhibited poor brain penetration in the presence or absence of elacridar in both species (B/P ratio ~ 0.1). Elacridar had no significant effect on the systemic clearance of digoxin or quinidine; however a trend towards increasing volume of distribution and half life was observed. Our results support the utility of elacridar in evaluation of the influence of P-gp mediated efflux on drug distribution to the brain. Our protocol employing a single intravenous dose of elacridar and test compound provides a cost effective alternative to expensive P-gp knockout mice models during early drug discovery.