Interaction Of Quinidine Research Articles

Quinidine partially blocks mitochondrial voltage-dependent anion channel (VDAC).

Quinidine is an antiarrhythmic drug commonly used for the treatment of cardiac ailments. It affects oxidative phosphorylation, calcium uptake, and ion channels of mitochondria. We have investigated the interaction of Quinidine and mitochondrial voltage-dependent anion channel (VDAC). VDAC was purified from neuronal tissue of Wistar rats and in vitro bilayer electrophysiology experiments were performed on it. 50-mM Quinidine treatment on VDAC leads to a sudden drop in its conductance. The dose of Quinidine leading to a half-maximal current through a single-channel VDAC was calculated using Quinidine at different concentrations. In silico molecular docking studies using Autodock-4.2 software indicate interaction between Quinidine and VDAC. Docking results demonstrate the interaction of Quinidine and VDAC on its Glutamic acid residue (Glu-206 of VDAC). Fluorescence spectroscopy results on Quinidine and Glutamic acidinteraction show an increase in the intensity and wavelength of Quinidine fluorescence, whereas no interaction between Quinidine and Cysteine was observed. This further supports the Glutamic acid and Quinidine interaction. In conclusion, we report Quinidine partially blocks VDAC due to the interaction of Glutamic acid and Quinidine in the channel pore.

Amino acid prodrug of quinidine: An approach to circumvent P-glycoprotein mediated cellular efflux

In the present study, we investigated the effect of large neutral amino acid modification in overcoming P-gp mediated cellular efflux of quinidine. L-isoleucine ester prodrug of quinidine (Ile-quinidine) was synthesized in our laboratory. [14C]-erythromycin was selected as a model substrate to study interaction of quinidine and Ile-quinidine with P-gp. Transport studies were conducted to study translocation kinetics of quinidine and Ile-quinidine in MDCK-MDR1 cells. In cellular accumulation study, uptake rate of [14C]-erythromycin elevated drastically in presence of cyclosporine A and GF 120918. This result indicates that [14C]-erythromycin is an excellent substrate of P-gp. Similarly, uptake rate of [14C]-erythromycin was enhanced significantly in presence of quinidine (25 and 50 μM). However, [14C]-erythromycin uptake rate remained fairly constant in presence of Ile-quinidine (25 μM). Apparent A-B and B-A permeability of quinidine observed in MDCK-MDR1 cells were 1.6 ± 0.2 × 10(-6) and 7.0 ± 0.4 × 10(-6)cm/s, a 4.4-fold difference. Moreover, A-B permeability of quinidine increased dramatically in the presence of cyclosporine A and GF 120918. Apparent permeability values of Ile-quinidine observed from A-B and B-A direction were 4.3 ± 0.9 × 10(-6) and 5.5 ± 0.4 × 10(-6)cm/s, a 1.3-fold difference. Importantly, A-B transport of Ile-quinidine did not change dramatically in the presence of cyclosporine and GF 120918. Based on these results, it was apparent that quinidine displayed higher substrate affinity toward P-gp relative to Ile-quinidine. Chemical or enzymatic hydrolysis of Ile-quinidine resulted in regeneration of low quantities of quinidine during transport studies. Competitive inhibition studies demonstrated that Ile-quinidine was recognized by multiple amino acid transporters such as LAT1, LAT2 and cationic amino acid transporter. In conclusion, chemical modification of quinidine with neutral amino acids results in circumvention of P-gp mediated drug efflux. Hence, amino acid transporter targeted prodrug delivery seems to be a viable strategy for improving drug accumulation in P-gp overexpressing cells.

The effect of digoxin dosage on the digoxin-quinidine interaction in the bile duct-cannulated rat.

Pretreating anaesthetized bile duct-cannulated rats with 9 mg kg-1 quinidine significantly decreased the cumulative biliary excretion of digoxin and its metabolites after 10 or 100 micrograms kg-1 [3H]digoxin, although the effect was more marked in animals receiving the high dose of digoxin. In contrast, however, although quinidine pretreatment raised plasma radioactivity levels by 50-80% in animals given the higher dose of digoxin, no significant effect on circulating plasma levels was observed in rats receiving 10 micrograms kg-1 digoxin. Generally, quinidine had no statistically significant effect on other aspects of digoxin disposition, although with both digoxin doses there were trends towards a reduction in the direct intestinal secretion and urinary excretion of digoxin-derived radioactivity with an increase in tissue levels of radioactivity (apart from the small intestine wall where concentrations were reduced). The radioactivity in the bile after 100 or 10 micrograms kg-1 digoxin comprised about 25 and 33% of digoxin and digoxigenin bis-digitoxoside, respectively, as well as appreciable amounts of the monodigitoxoside and a highly polar component. This metabolite profile was unaffected by quinidine. The influence of cardiac glycoside dosage shown by the present work indicates that the digoxin-quinidine interaction and possibly analogous interactions involving other cardiac glycosides, may not always be readily detectable from plasma concentration data.

Quinidine interaction with Shab K+ channels: pore block and irreversible collapse of the K+ conductance

Quinidine is a commonly used antiarrhythmic agent and a tool to study ion channels. Here it is reported that quinidine equilibrates within seconds across the Sf9 plasma membrane, blocking the open pore of Shab channels from the intracellular side of the membrane in a voltage-dependent manner with 1:1 stoichiometry. On binding to the channels, quinidine interacts with pore K(+) ions in a mutually destabilizing manner. As a result, when the channels are blocked by quinidine with the cell bathed in an external medium lacking K(+), the Shab conductance G(K) collapses irreversibly, despite the presence of a physiological [K(+)] in the intracellular solution. The quinidine-promoted collapse of Shab G(K) resembles the collapse of Shaker G(K) observed with 0 K(+) solutions on both sides of the membrane: thus the extent of G(K) drop depends on the number of activating pulses applied in the presence of quinidine, but is independent of the pulse duration. Taken together the observations indicate that, as in Shaker, the quinidine-promoted collapse of Shab G(K) occurs during deactivation of the channels, at the end of each activating pulse, with a probability of 0.1 per pulse at 80 mV. It appears that when Shab channels are open, the pore conformation able to conduct is stable in the absence of K(+), but on deactivation this conformation collapses irreversibly.

QUINIDINE-CYCLODEXTRINS INCLUSION COMPLEXES

The complexation behavior of quinidine with four cyclodextrins (CDs)​, namely β-​cyclodextrin (β-​CD)​, hydroxypropyl-​β-​cyclodextrin (HP-​β-​CD)​, methyl-​β-​cyclodextrin (M-​β-​CD) and α-​cyclodextrin (α-​CD) was investigated for the purpose of improving the low aq. soly., stability and side effects of the drug. The aq. soly. of quinidine was increased as a function of CD concn. generating linear AL phase soly. profiles. The interaction was quantified for quinidine-​CDs by detn. of the stability const. using the soly. method at various temps. and the thermodn. parameters were calcd. The results revealed a very strong evidence for mol. interaction between the drug and HP-​β-​CD or M-​β-​CD, suggesting the formation of an equimolar complex. The estd. enthalpies and entropies for the interaction of quinidine with CDs indicate that the interaction is exothermic. The prepd. coevaporates were studied by x-​ray diffractometry, differential scanning calorimetry and IR spectroscopy, in order to investigate the possibility of complexation of the drug with CDs. The relative potency of the CDs to enhance the dissoln. rate of quinidine was in the following order: M-​β-​CD ≥ HP-​β-​CD > α-​CD > β-​CD, which, generally fits the magnitude of the stability const. data of the complexes. The dissoln. profiles of the drug, phys. mixts. of the drug with CDs, as well as, the prepd. complex show higher dissoln. rate of the complex compared with the drug alone or its phys. mixts.

Interactions of quinidine and quinine and (+)- and (−)-pindolol with the organic cation/proton antiporter in renal brush border membrane vesicles

L'elimination renale de cations organiques comme le (+) et le (-) pindolol, la quinine et la quinidine a ete etudiee au niveau de l'antiport cation/proton dans les vesicules membranaires de la bordure en brosse renale. Cette interaction a ete etudiee au niveau de sa stereoselectivite

Quinidine interaction see Ranitidine interaction

Quinidine interaction see Ranitidine interaction

Interaction of quinidine with phospholipids. I. Effect on fluidity and permeability of phosphatidylcholine vesicles.

Interaction of quinidine with phospholipids. I. Effect on fluidity and permeability of phosphatidylcholine vesicles.

Digoxin quinidine interaction: A pharmacokinetic study in the isolated perfused rat liver

Digoxin-quinidine interaction was studied in the experimental model of isolated perfused rat liver. Neither digoxin nor quinidine were toxic to the isolated rat liver. The clearance of digoxin and quinidine by the liver was directly related to the rate of bile flow and the size of the initial dose of digoxin. In the presence of quinidine, after initial doses of digoxin of 0.5 and 1 μg, the concentration of digoxin in the perfusate was increased 2.5 and 3-fold. Its excretion in the bile was reduced by 45% and 20.5%, respectively (all comparisons, p<0.01). Digoxin concentration in the liver tissue was calculated and found to be appreciably elevated in the presence of quinidine. A reduction of about 30% (p<0.05) in the excretion of quinidine in the bile was observed in the presence of digoxin. Thus, a competition of digoxin and quinidine for biliary excretion was demonstrated as an underlying cause for digoxin-quinidine interaction in the isolated perfused rat liver.

Interactions of quinidine and lidocaine with rat brain and heart muscarinic receptors

We have studied the effect of quinidine and lidocaine on binding to rat brain and cardiac muscarinic receptors. Both drugs had a higher affinity to brain stem and cardiac receptors, as compared with cerebral cortex, coinciding with the distribution of high-affinity agonist binding sites in the above tissues. The effects of the drugs on muscarinic antagonist and agonist binding did not fit simple competition to one receptor site, suggesting either preferential binding to high affinity agonist binding sites, or allosteric interactions. Batrachotoxin, which opens voltage sensitive sodium channels, had an opposite effect on agonist binding. The possibility of allosteric interactions between the muscarinic receptors and a site analogous to the sodium channel is discussed.

Quinidine is a competitive antagonist at alpha 1- and alpha 2-adrenergic receptors.

Although quinidine is known to have antiadrenergic effects in the cardiovascular system, the precise mechanism by which it exerts these effects is not well defined. We asked whether quinidine binds directly to adrenergic receptors. Radioligand-binding assays were used to identify alpha 1-adrenergic receptors [( 3H]prazosin-binding sites) on membranes prepared from rat heart and kidney, alpha 2-adrenergic receptor [( 3H]yohimbine-binding sites) on human platelets and rat kidney membranes, and beta-adrenergic receptors [( 125I]iodocyanopindolol-binding sites) on rat heart and kidney membranes. Although it did not effectively compete for binding to beta-adrenergic receptors, quinidine competed for binding to alpha 1- and alpha 2-adrenergic receptors and yielded equilibrium dissociation constants of 0.3-3 microM. Two other antiarrhythmic agents, lidocaine and procainamide, did not compete for binding to alpha-adrenergic receptors. Further experiments demonstrated that the interactions of quinidine with the cardiac alpha 1- and platelet alpha 2-adrenergic receptors were competitive and reversible. We conclude that that antiadrenergic actions of quinidine can be explained by occupancy and competitive blockade of alpha 1- and alpha 2-adrenergic receptors.

Quinidine and propranolol binding to very low and low density lipoproteins of human plasma.

The interaction of quinidine (Q) and propranolol (P) with human very low density lipoproteins (VLDL) and low density lipoproteins (LDL) was determined by ultrafiltration in phosphate buffer (pH 7.4) for Q and in phosphate and Tris buffers (pH 7.4-7.5) for P, respectively. The Scatchard plots of Q are curved and were best described by a model assuming two independent classes of binding sites on lipoproteins. When working with P, the Scatchard plots were also nonlinear, but positive cooperativity was observed for the VLDL fraction in phosphate buffer and apparently also for the LDL fraction in Tris buffer. These nonlinear curves were described by the model used for Q, excluding any data falling in the cooperating region. The binding parameters, primary (K1) and secondary (K2) affinity constants and the number of sites in each class of independent binding sites, were generated by a computer program. The results of this in vitro study suggest that drug binding (and possibly distribution) to lipoproteins may be affected by the nature and concentration of some ions present in serum.

Impaired enzyme induction by rifampicin in the elderly [letter

British Journal of Clinical PharmacologyVolume 17, Issue 5 p. 595-597 Free Access Impaired enzyme induction by rifampicin in the elderly [letter] Y Twum-Barima, Y Twum-BarimaSearch for more papers by this authorT Finnigan, T FinniganSearch for more papers by this authorAI Habash, AI HabashSearch for more papers by this authorRD Cape, RD CapeSearch for more papers by this authorSG Carruthers, SG CarruthersSearch for more papers by this author Y Twum-Barima, Y Twum-BarimaSearch for more papers by this authorT Finnigan, T FinniganSearch for more papers by this authorAI Habash, AI HabashSearch for more papers by this authorRD Cape, RD CapeSearch for more papers by this authorSG Carruthers, SG CarruthersSearch for more papers by this author First published: May 1984 https://doi.org/10.1111/j.1365-2125.1984.tb02397.xCitations: 36AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References Adelman, R. C. (1975). Impaired hormonal regulation of enzyme activity during ageing. Fed. Proc., 34, 179– 181. Ahmad, D., Mathur, P., Ahuja, S., Henderson, R. & Carruthers, S. G. (1979). Rifampicin-quinidine interaction. Br. J. dis. Chest, 73, 409– 410. Crooks, J., O'Malley, K. & Stevenson, I. H. (1976). Pharmacokinetics in the elderly. Clin. Pharmacokin., 1, 280– 296. Cusack, B., Kelly, J. G., Lavan, J., Noel, J. & O'Malley, K. (1980). Theophylline kinetics in relation to age: The importance of smoking. Br. J. clin. Pharmac., 10, 109– 114. Eichelbaum, M. & Spannbrucker, N. (1977). Rapid and sensitive method for the determination of antipyrine in biological fluids by high-pressure liquid chromatography. J. Chromatogr., 140, 288– 292. Gelehrter, T. D. (1976). Enzyme induction. New Engl. J. Med., 294, 522– 526, 589–595, 646–651. Greenblatt, D. J., Sellers, E. M. & Shader, R. I. (1982). Drug disposition in old age. New Engl. J. Med., 306, 1081– 1088. Kato, R. & Takanaka, A. (1968). Effect of pheno-barbital on electron transport system, oxidation and reduction of drugs in liver microsomes of rats of different age. J. Biochem. (Tokyo), 63, 406– 408. Kato, R., Vassanelli, P., Frontino, G. & Chiesara, E. (1964). Variation in the activity of liver microsomal drug-metabolising enzymes in rats in relation to age. Biochem. Pharmac., 13, 1037– 1051. Kroboth, F. J., Kroboth, P. D. & Logan, T. (1983). Phenytoin-theophylline quinidine interaction. New Engl. J. Med., 308, 725. Marshall, W. J. (1978). Enzyme induction by drugs: its relevance to clinical biochemistry. Ann. clin. Biochem., 15, 55– 64. O'Malley, K., Crooks, J., Duke, E. & Stevenson, I. H. (1971). Effect of age and sex on human drug metabolism. Br. med. J., 3, 607– 609. Salem, S. A. M., Rajjayabun, P., Shepherd, A. M. M. & Stevenson, I. H. (1978). Reduced induction of drug metabolism in the elderly. Age Ageing, 7, 68– 73. Twum-Barima, Y. & Carruthers, S. G. (1981). Quinidine-rifampicin interaction. New Engl. J. Med., 304, 1466– 1469. Urbano, A. M. (1983). Phenytoin-quinidine interaction in a patient with recurrent ventricular tachyarrhythmias. New Engl. J. Med., 308, 225. Citing Literature Volume17, Issue5May 1984Pages 595-597 ReferencesRelatedInformation

An electrophysiologic study of the digoxin--quinidine interaction.

To study the electrophysiologic mechanisms responsible for the digitalis-quinidine interaction, 27 mongrel dogs were given either quinidine alone, digoxin alone, or digoxin followed by the digoxin-quinidine combination, via the oral route for sufficient time to permit accumulation of steady-state plasma levels. As anticipated, digoxin levels increased significantly in the presence of quinidine (P less than 0.05). Whereas digoxin alone had no significant effect on the ECG, quinidine alone prolonged the Q-T interval (P less than 0.05), and the combination prolonged both the QRS complex and the Q-T interval (P less than 0.05). Digoxin alone had no significant effect on the Purkinje fiber transmembrane potential, whereas quinidine reduced action potential (AP) amplitude and maximum upstroke velocity (Vmax) significantly. The combination significantly reduced AP amplitude Vmax, and maximum diastolic potential and prolonged AP reduced AP amplitude, Vmax, and maximum diastolic potential and prolonged AP duration. The changes induced by the drug combination appeared to be the sum of changes induced by each drug alone.

Quinidine-digoxin interaction: evidence for involvement of an extrarenal mechanism.

The influence of quinidine 750mg per day for one week on serum digoxin concentration (SDC) was evaluated in digitalized anuric patients on chronic haemodialysis. During quinidine administration the SDC increased markedly, from 0.84 +/- 0.37 to 1.58 +/- 0.72 ng/ml (p less than 0.01), a comparable effect ot that reported previously in patients with normal renal function. Neither in vitro nor in vivo did quinidine alter the serum protein binding of digoxin. The increase in SDC in anuric patients indicates a decrease in the extrarenal clearance of digoxin, which means that mechanisms other than of renal origin are also involved in the interaction of quinidine and digoxin. There was great interindividual variability in the extent of the quinidine-induced rise in SDC. Regardless of the state of renal function, careful monitoring of digitalized patients seems mandatory once quinidine treatment is initiated.

Quinidine interaction see Digoxin

Quinidine interaction see Digoxin

Effect of quinidine on the digoxin receptor in vitro.

To investigate the basis for a clinically important digitalis-quinidine interaction that is characterized by increases in serums digoxin concentrations when quinidine is administered to digoxin-treated patients, we have studied in vitro the interaction of quinidine with the digoxin receptor. Evidence has been obtained that quinidine is capable of decreasing the affinity for digoxin of cardiac glycoside receptor sites on purified Na,K-ATPase and on intact human erythrocyte membranes. As others have shown, quinidine is capable of inhibiting Na,K-ATPase activity, and evidence has been obtained in the current study that, while quinidine can reduce the affinity of the enzyme for digoxin, it is also capable of acting together with digoxin in inhibiting enzyme activity to a degree greater than the inhibitory effect of digoxin alone. The concentrations of digoxin and quinidine used in this study were considerably greater than their therapeutic serum concentrations. Nevertheless, these observations are consistent with the hypothesis that the increases in serum digoxin concentrations and the decreases in volumes of digoxin distribution observed clinically when quinidine is administered to digoxin-treated patients may reflect, at least in part, a decrease in the affinity of tissue receptors for digoxin. The possibility must also be considered that enhanced cardiac effects of digoxin may occur clinically as the result of an augmentation, by quinidine, of digoxin effects, which more than compensates for the modest reduction in digoxin binding.

In vitro Interaction of Quinidine with Kaolin and Pectin

The adsorption of quinidine onto kaolin was studied as a function of pH in aqueous solutions in which the ionic strength was adjusted to 0.1. The interaction of quinidine with pectin also was investigated in water and in phosphate buffer; the buffer pH and ionic strength were adjusted to 6.5 and 0.1, respectively. The in vitro results indicated that quinidine was adsorbed onto kaolin. At the highest concentration studied, the extent of adsorption increased from 3.64 mg of quinidine adsorbed/g of adsorbent at pH 2.4 to an average of 5.81 mg/g in the pH 5.5-7.5 range. In the presence of electrolytes, the interaction of quinidine with pectin was relatively small (3-13% bound) as compared to studies performed in water (66-90% bound). The data indicate that some quinidine may be adsorbed when this drug is administered concurrently with kaolin-pectin preparations.

Effects of interaction of quinidine and beta-blocking agents on some cardiodynamic and hemodynamic parameters of normal individuals

The effects of association of two isomers of butidrine with quinidine were studied in 31 normal individuals. A series of cardiodynamic and hemodynamic parameters were considered. In general, interaction of the beta-blocking agents with quinidine gave effects inferior to those which would result from the sum of the single drug's administration. This “negative” interaction was particularly evident in regard to deformation time, isometric contraction time, and ET TT index. The significance and the importance of this phenomenon, which was partly observed in pharmacologic experiments on the isolated rabbit heart, is discussed.

Interactions of quinidine and potassium on atrioventricular transmission.

The effects of quinidine and its interactions with potassium (K) on atrio-ventricular (A-V) conduction were studied in isolated, perfused rabbit hearts, utilizing microelectrode techniques. Quinidine gluconate (10 mg/liter) was added to perfusion fluid containing either normal [K + ] (4.5 mEq/liter), low [K + ] (1.5 mEq/liter), or high [K + ] (7.5 mEq/liter). The following observations were made: (A) The marked prolongation of A-V conduction time produced by quinidine was antagonized by low K + and enhanced by high K + concentration. (B) Quinidine or high K + concentration prolonged the A-V interval by slowing intra-atrial and His-Purkinje-ventricular conduction. (C) Low K + concentration depressed conduction in the N region of the A-V node. (D) Lowering K + concentration in the presence of quinidine shortened the A-V interval by enhancing His-Purkinje-ventricular conduction. (E) Quinidine and high K + concentration increased the action potential amplitude in the nodal and the node-His regions of the A-V node while low K + concentration showed opposite effects. Hence, different regions of the A-V conducting system were selectively influenced by these agents. A-V conduction in the presence of low K + and quinidine depends upon the net results of their antagonism within individual fiber types. The importance of these interrelationships in pharmacologic approach to A-V conduction disturbances is stressed.