- Celecoxib is a substrate of CYP2D6: Impact on celecoxib metabolism in individuals with CYP2C9*3 variants. [Journal Article]
- DMDrug Metab Pharmacokinet 2018 Jun 19
- Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent Km, ...
Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent Km, Ki, and Vmax of 67.2 μM, 12.6 μM, and 1.33 μM/min, respectively. In human liver microsomes (HLMs), a concentration-dependent inhibition of celecoxib hydroxylation by quinidine was observed after CYP2C9 and CYP3A4 were inhibited. In individual HLMs with variable CYP2D6 activities, a significant correlation was observed between celecoxib hydroxylation and CYP2D6-selective dextromethorphan O-demethylation when CYP2C9 and CYP3A4 activities were suppressed (r = 0.97, P < 0.0001). Molecular modeling showed two predominant docking modes of celecoxib with CYP2D6, resulting in either a substrate or an inhibitor. A second allosteric binding antechamber, which stabilized the inhibition mode, was revealed. Modeling results were consistent with the observed substrate inhibition kinetics. Using HLMs from individual donors, the relative contribution of CYP2D6 to celecoxib metabolism was found to be highly variable and dependent on CYP2C9 genotypes, ranging from no contribution in extensive metabolizers with CYP2C9*1*1 genotype to approximately 30% in slow metabolizers with allelic variants CYP2C9*1*3 and CYP2C9*3*3. These results demonstrate that celecoxib may become a potential victim of CYP2D6-associated drug-drug interactions, particularly in individuals with reduced CYP2C9 activity.
- Chemical proteomics and super-resolution imaging reveal that chloroquine interacts with Plasmodium falciparum PfMRP1 and lipids. [Journal Article]
- ACACS Chem Biol 2018 Sep 12
- It is well established that chloroquine, a quinoline antimalarial, inhibits hemozoin formation in the malaria parasite. Counterintuitively, this archetypal antimalarial is also used in the treatment ...
It is well established that chloroquine, a quinoline antimalarial, inhibits hemozoin formation in the malaria parasite. Counterintuitively, this archetypal antimalarial is also used in the treatment of diseases in which hemozoin biocrystallization does not play a role. Hence, we decided to investigate whether chloroquine possesses binding targets other than Fe(III) protoporphyrin IX in blood stage Plasmodium falciparum parasites and whether these are related to sites of accumulation within the parasite other than the digestive vacuole. A 7-nitrobenz-2-oxa-1,3-diazole (NBD)-labeled fluorescent derivative of chloroquine, especially sensitive to regions outside the digestive vacuole and retaining the antiplasmodial pharmacophore, was synthesized to investigate subcellular localization in the parasite. Super-resolution microscopy revealed association with membranes including the parasite plasma membrane, the endoplasmic reticulum and possibly also the mitochondrion. A drug-labeled affinity matrix was then prepared to capture protein binding targets of chloroquine. SDS-PAGE revealed a single prominent band between 200 and 250 kDa from the membrane-associated fraction. Subsequent proteomic analysis revealed that this band corresponded to P. falciparum multidrug resistance-associated protein (PfMRP1). Intrigued by this finding, we demonstrated pull-down of PfMRP1 by matrices labeled with Cinchona alkaloids quinine and quinidine. While PfMRP1 has been implicated in resistance to quinolines and other antimalarials, this is the first time that these drugs have been found to bind directly to this protein. Based on previous reports, PfMRP1, the only prominent protein found to bind to quinolines in this work, is likely to modulate the activity of these antimalarials in P. falciparum rather than act as a drug target.
- CONTENT OF CATECHOLAMINES IN BLOOD SERUM OF RATS UNDER FLUORIDE INTOXICATION. [Journal Article]
- GMGeorgian Med News 2018 Jul-Aug; (280-281):125-129
- The aim of the research was to determine in the experiment the content of catecholamines in serum of rats exposed to sodium fluoride. The studies were conducted on adult Wistar rats, subjected to ora...
The aim of the research was to determine in the experiment the content of catecholamines in serum of rats exposed to sodium fluoride. The studies were conducted on adult Wistar rats, subjected to oral exposure by means of a probe with aqueous solutions of sodium fluoride (SF) once daily, for 60 days at doses of 1/10, 1/100 and 1/1000 DL50, which correspondingly amounts to 20 mg/kg, 2 mg/kg and 0.2 mg/kg of body weight. Toxification of rats at a dose of 1/100 DL50 for 60 days and at a dose of 1/10 DL50 for 50 days was accompanied by an increase in blood levels of norepinephrine and epinephrine, indicating the hyperactivation of the mediator and hormonal parts of the sympathoadrenal system, and tension of the protective and adaptive reactions of the organism. Prolonged hypercatecholemia may become a pathogenic factor due to intensification of the quinidine route of oxidation of norepinephrine and epinephrine with the formation of reactive radicals and active forms of oxygen. Reduced serum content of catecholamines on the 60th day of oral administration at a dose of 1/10 DL50 reflects, on the one hand, a decrease in their tissue deposit, and, on the other, a decrease in the activity and reserve capacities of the sympathoadrenal system.
- Poststroke emotionalism with dacrystic (Crying) episodes - making a case for risperidone. [Case Reports]
- AAAnn Afr Med 2018 Jul-Sep; 17(3):156-158
- Emotionalism is the abnormal expression of emotions like crying and laughing and could follow stroke, traumatic brain injury, multiple sclerosis and amyotrophic lateral sclerosis. Emotionalism has be...
Emotionalism is the abnormal expression of emotions like crying and laughing and could follow stroke, traumatic brain injury, multiple sclerosis and amyotrophic lateral sclerosis. Emotionalism has been known to respond therapeutically to different classes of drugs including tricyclic antidepressants like imipramine, Selective Serotonin Reuptake Inhibitors (SSRI) like sertraline and citalopram, anticonvulsants like lamotrigine, dopamine precursors like levodopa and NMDA receptor antagonists like dextromethorphan. Classical antipsychotics are hardly prescribed for emotionalism alone without psychotic features. In this case report, an eighty year old woman with a dominant fronto-temporal infarctive stroke with right faciohemiparesis presented with frequent crying (dacrystic) episodes after a month of onset of stroke and who did not satisfy DSM IV criteria for depression nor had other psychotic features. Serial trial of SSRIs and dextromethorphan/quinidine could not help until risperidone, an antipsychotic was introduced with resolution of crying episodes. The response to risperidone after trial of SSRIs and dextromethorphan/quinidine which are considered the gold standard for post-stroke emotionalism (PSE), could be another therapeutic dimension in the management of emotionalism in general and PSE in particular.
- Lack of response to quinidine in KCNT1-related neonatal epilepsy. [Journal Article]
- EEpilepsia 2018 Sep 04
- CONCLUSIONS: Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.
- Action potential clamp characterization of the S631A hERG mutation associated with short QT syndrome. [Journal Article]
- PRPhysiol Rep 2018; 6(17):e13845
- The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss- and gain-of-function hERG mutations are associated, respectively, with long and short QT s...
The hERG potassium channel is critical to normal repolarization of cardiac action potentials (APs) and loss- and gain-of-function hERG mutations are associated, respectively, with long and short QT syndromes, pathological conditions that can lead to arrhythmias and sudden death. hERG current (IhERG ) exhibits uniquely fast inactivation involving conformational changes to the channel pore. The S631A hERG pore mutation was originally engineered to interrogate hERG channel inactivation, but has very recently been found in a family with short QT syndrome (SQTS). Accordingly, this study characterized the effects of the S631A mutation on IhERG profile during ventricular, atrial, and Purkinje fiber (PF) AP waveforms, using patch clamp recording from hERG expressing HEK 293 cells at 37°C. Under conventional voltage clamp, the current-voltage (I-V) relation for IhERG exhibited a marked right-ward shift in the region of negative slope at positive membrane potentials. Under ventricular AP clamp, the S631A mutation resulted in augmented IhERG , which also peaked much earlier during the AP plateau than did wild-type (WT) IhERG . Instantaneous I-V relations showed a marked positive shift in peak repolarizing current during the ventricular AP in the S631A setting, while the instantaneous conductance-voltage relation showed an earlier and more sustained rise in S631A compared to WT IhERG conductance during ventricular repolarization. Experiments with atrial and PF APs in each case also showed augmented and positively shifted IhERG in the S631A setting, indicating that the S631A mutation is likely to accelerate repolarization in all three cardiac regions. Ventricular AP clamp experiments showed retained effectiveness of the class Ia antiarrhythmic drug quinidine (1 μmol/L) against S631A IhERG . Quinidine is thus likely to be effective in reducing excessively fast repolarization in SQTS resulting from the S631A hERG mutation.
- CYP3A but not P-gp plays a relevant role in the in vivo intestinal and hepatic clearance of the delta-specific phosphoinositide-3 kinase inhibitor leniolisib. [Journal Article]
- BDBiopharm Drug Dispos 2018 Sep 01
- This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) on the single dose pharmacokinetics of leniolisib. In order to diffe...
This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P-gp, the potential interaction with quinidine, a strong inhibitor of P-gp but not CYP3A, was studied as well. Using a fixed-sequence, 3-way crossover design, twenty healthy male subjects received single oral doses of 10 mg leniolisib during 3 phases separated by a washout: (1) leniolisib alone, (2) 200 mg itraconazole once daily for 9 days plus leniolisib on day 5, and (3) 300 mg quinidine administered 1 hour before and 3 hours after leniolisib. Itraconazole increased leniolisib oral drug exposure (AUCinf) by on average 2.1 fold, whereas peak drug concentration (Cmax) was less impacted (1.25 fold). The terminal elimination half-life (T1/2) of leniolisib was also increased by ~2 fold. Neither oral AUCinf nor Cmax or T1/2 was found to be altered by quinidine. These findings suggest that the interaction with itraconazole occurred mainly systemically through inhibition of CYP3A, and corroborate our in vitro findings that leniolisib is neither a sensitive CYP3A substrate nor a relevant in vivo substrate for intestinal or hepatic P-gp. Assuming itraconazole levels achieved complete inhibition of CYP3A, the fractional contribution of CYP3A to the overall disposition of leniolisib is estimated to be about 50%. Concomitant use of leniolisib with strong inhibitors of CYP3A as well as strong and moderate inducers of CYP3A is best avoided.
- Additional evidence for a therapeutic effect of dextromethorphan/quinidine on bulbar motor function in persons with ALS: A quantitative speech analysis. [Journal Article]
- BJBr J Clin Pharmacol 2018 Aug 28
- CONCLUSIONS: These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech.
- P-glycoprotein protein expression versus functionality at the blood-brain barrier using immunohistochemistry, microdialysis and mathematical modeling. [Journal Article]
- EJEur J Pharm Sci 2018 Aug 23; 124:61-70
- A proper understanding of P-gp mediated transport (functionality) at the blood-brain barrier (BBB) and beyond is needed to interpret, understand and predict pharmacokinetic (PK)- pharmacodynamic (PD)...
A proper understanding of P-gp mediated transport (functionality) at the blood-brain barrier (BBB) and beyond is needed to interpret, understand and predict pharmacokinetic (PK)- pharmacodynamic (PD) relationships of CNS drugs that are substrates of P-gp, especially since P-gp functionality may be different in different conditions. Often, P-gp expression is taken as a biomarker of transporter functionality. The aim of our study was to investigate whether brain capillary protein expression of P-gp is associated with changes in P-gp mediated drug efflux at the BBB. Status Epilepticus (SE) was induced by kainate in male rats. During 3-5 weeks post SE, hippocampal P-gp expression was determined using immunohistochemistry, while BBB P-gp functionality was assessed by microdialysis of quinidine, in absence and presence of the P-gp blocker tariquidar. The data were analyzed using Non-linear Mixed Effect Modeling implemented in NONMEM. Following SE, changes in brain capillary P-gp expression were observed. However, no relation between BBB P-gp protein expression and BBB P-gp mediated drug efflux was found. This warrants a critical view on the interpretation of reported changes in BBB P-gp expression as a biomarker of BBB P-gp functionality.
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- Microsecond MD simulations of human CYP2D6 wild-type and five allelic variants reveal mechanistic insights on the function. [Journal Article]
- PlosPLoS One 2018; 13(8):e0202534
- Characterization of cytochrome P450 2D6 (CYP2D6) and the impact of the major identified allelic variants on the activity of one of the most dominating drug-metabolising enzymes is essential to increa...
Characterization of cytochrome P450 2D6 (CYP2D6) and the impact of the major identified allelic variants on the activity of one of the most dominating drug-metabolising enzymes is essential to increase drug safety and avoid adverse reactions. Microsecond molecular dynamics simulations have been performed to capture the dynamic signatures of this complex enzyme and five allelic variants with diverse enzymatic activity. In addition to the apo simulations, three substrates (bufuralol, veliparib and tamoxifen) and two inhibitors (prinomastat and quinidine) were included to explore their influence on the structure and dynamical features of the enzyme. Our results indicate that the altered enzyme activity can be attributed to changes in the hydrogen bonding network within the active site, and local structural differences in flexibility, position and shape of the binding pocket. In particular, the increased (CYP2D6*53) or the decreased (CYP2D6*17) activity seems to be related to a change in dynamics of mainly the BC loop due to a modified hydrogen bonding network around this region. In addition, the smallest active site volume was found for CYP2D6*4 (no activity). CYP2D6*2 (normal activity) showed no major differences in dynamic behaviour compared to the wild-type.