Protein Binding Of Disopyramide Research Articles

Protein binding of disopyramide--displacement by mono-N-dealkyldisopyramide and variation with source of alpha-1-acid glycoprotein.

The binding of disopyramide to human serum proteins and human alpha-1-acid glycoprotein (AAG) was determined over a wide drug concentration range. Addition of 3.7 X 10(-6) mol litre-1 mono-N-dealkyldisopyramide caused a 20-100% increase in disopyramide free fraction. The disopyramide free fraction in AAG solutions prepared from various commercially available sources of alpha-1-acid glycoprotein varied up to 2.5 fold at corresponding disopyramide concentrations. Pronounced differences in the calculated binding constants (affinity and capacity) were observed among the commercially available AAG preparations. These findings suggest that binding studies should be performed in appropriately harvested human serum or plasma to avoid possible artifacts associated with the use of commercial preparations of alpha-1-acid glycoprotein for binding studies.

Nomogram for estimating plasma unbound disopyramide concentrations in patients with varying plasma alpha 1-acid glycoprotein concentrations.

Since plasma protein binding of disopyramide (DP)--a class IA antiarrhythmic widely used in the prevention and treatment of various types of cardiac arrhythmias--is not only saturable within the therapeutic range but also altered under various pathophysiological conditions, the interpretation of total DP concentrations, Ctotal, measured during routine therapeutic drug monitoring (TDM) is often complicated. To circumvent this problem, we attempted to establish a comprehensive nomogram that allows estimation of unbound DP concentrations (Cu) based upon Ctotal of the drug and plasma concentration of alpha 1-acid glycoprotein (AAG), a major DP-binding protein. The nomogram was formulated with use of the in vitro binding data retrieved from 103 subjects categorized into 10 different groups each with a different mean concentration of AAG (range: 0.14-1.54 g/L). Data analysis, using a binding model assuming one specific binding site and nonspecific binding(s), revealed that alterations in plasma DP binding are attributable mainly to those in the capacity, Bmax, rather than affinity, ka, constant of the specific binding site. In addition, plasma AAG concentration correlated significantly (r = 0.90, p < 0.001) with the Bmax value over the range 0.09-2.28 g/L. For this reason, we substituted Bmax calculated by the regression equation as a function of AAG and the overall mean ka and nonspecific binding parameter values for the respective individual variables of the binding model, so that Cu of each plasma sample was estimated from the corresponding data on Ctotal and plasma AAG levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered Alpha-1-acid Glycoprotein Concentration and Free Fraction of Disopyramide in Patients with Heart Disease.

Alpha-1-acid glycoprotein (AAG) concentration and protein binding of disopyramide (DSP) in serum were measured in patients with heart disease. An increase in AAG (121±45mg/dl, mean±SD) was fbund in padents with heart failure as compared with healthy controls (73±14) and with cardiac patients without heart failure (78±12). The free fraction of DSP (0.35±0.12) was decreased in patients with heart failure as compared with control (0.56±0.11) and with patients without heart failure (0.47±0.15). The values of the heart failure patients returned to the level of cardiac patients with out heart failure (89±23 mg/dl and 0.48±0.07) with recovery from the decompensated stage. These findings suggest that the free concentration of DSP should be monitored frequently in cardiac patients, especially in patients with congestive heart failure.

Enantioselective steady-state kinetics of unbound disopyramide and its dealkylated metabolite in man

Disopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration. There was enantioselective clearance of unbound disopyramide (0.39 l.h-1.kg-1 for R-disopyramide and 0.58 l.h-1.kg-1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective. The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity. The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h-1.kg-1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.

Plasma protein binding of disopyramide in pregnant and postpartum women, and in neonates and their mothers

Plasma protein binding of disopyramide in pregnant and postpartum women, and in neonates and their mothers

Plasma protein binding of disopyramide is significantly lower

Plasma protein binding of disopyramide is significantly lower

Concentration-response relationships of disopyramide in patients with ventricular tachycardia.

The protein binding of disopyramide is altered when concentration is increased within the therapeutic range. A wide range of free concentrations may be produced at a given total concentration. The present study assessed whether intracardiac electrophysiologic responses to disopyramide related better to free or to total concentration. Intravenous infusions of disopyramide were evaluated in 17 patients with inducible sustained ventricular tachycardia. The first maintenance infusion produced total serum concentrations of 11.7 +/- 2 mumols/L, and no significant increase occurred at higher-dose infusions. However, free concentrations during the first and second maintenance infusions were significantly different at 5.3 +/- 1 mumols/L and 6.8 +/- 1 mumols/L, respectively. Free fraction also increased significantly, from 45% +/- 8% to 50% +/- 7%. Overall change in QTc interval and ventricular tachycardia cycle length correlated with free concentration but not with total concentration. This study showed that some intracardiac measurements correlate with free concentration but that none correlate with total concentration.

Inhibitory effect of free fatty acids on plasma protein binding of disopyramide in haemodialysis patients.

The plasma (or serum) protein binding of disopyramide (DSP) in five haemodialysis patients was studied using an ultrafiltration technique. There was an increase in the free fraction of DSP in the plasma on dialysis days in comparison to the levels on interdialysis days, which was associated with an elevation of the free fatty acid levels in the plasma together with the increase of the free fraction of DSP. The inhibitory effect of free fatty acids on DSP binding in an in vitro study was enhanced in proportion to their concentrations, and was shown to be due to competition at one binding site by experiments with oleic acid as a representative displacer. Certain endogenous organic acids, such as indoxyl sulphate, 2-hydroxyhippuric acid and hippuric acid, which are characteristically elevated in chronic renal failure, scarcely affected the protein binding of DSP. The findings indicate that free DSP should be monitored in patients with elevated plasma free fatty acid levels, such as those on haemodialysis therapy.

Quantitative and qualitative binding characteristics of disopyramide in serum from patients with decreased renal and hepatic function.

Protein binding of disopyramide, binding capacities, affinity constants and serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in five groups of patients. A: young healthy volunteers (n = 8); B: elderly patients with minor symptoms of ischaemic heart disease (n = 9); C: patients with cirrhosis of the liver and normal values of coagulation factors (II, VII and X), albumin and immunoglobulin G (n = 8); D: patients with cirrhosis and at least two abnormal of the previously mentioned values (n = 9) and E: eleven patients with severely impaired renal function. Subfractions of AAG (Fr1, Fr2 and Fr3) were determined by affinoimmunoelectrophoresis. AAG concentration was significantly (P less than 0.005) elevated in group E patients and decreased (P less than 0.025) in group D patients. Fr2 is probably associated with the high affinity, first binding site of disopyramide to AAG. Earlier observations of a reduced qualitative binding of disopyramide in patients with cirrhosis can be explained by a significant decrease in Fr2 (P less than 0.001) in group D patients. The protein binding of disopyramide in patients with uraemia was significantly increased due to a significant (P less than 0.005) increase in AAG concentration in spite of a smaller (P less than 0.025) affinity constant. Suggestions for therapeutic drug monitoring based on total serum concentrations are given.

慢性腎不全患者におけるＤｉｓｏｐｙｒａｍｉｄｅの蛋白結合に関する研究

慢性腎不全患者におけるＤｉｓｏｐｙｒａｍｉｄｅの蛋白結合に関する研究

Plasma free fatty acids and protein binding of disopyramide during haemodialysis.

The binding of disopyramide (DSP) to plasma (or serum) proteins was determined using an ultrafiltration technique in three patients undergoing haemodialysis. An increase in the free fraction (FF) of DSP during dialysis occurred together with elevation of the free fatty acid (FFA) level in plasma. The effect of FFA on protein binding in vitro was examined using DSP- and FFA-spiked solutions containing human alpha 1-acid glycoprotein and serum albumin. The FF of DSP rose in proportion to increasing FFA levels, supporting the in vivo observations. The findings suggest that the free concentration of DSP should be routinely monitored, especially in haemodialysis patients.

The pharmacokinetics and protein binding of disopyramide in pigs.

The pharmacokinetics of disopyramide were investigated in 5 pigs. Disopyramide was administered as intravenous bolus injections at different doses and as intravenous infusions at different rates. By measuring the free and total concentrations in plasma of parent compound and desisopropyldisopyramide (the main metabolite in humans) and the amounts excreted in urine it was found that disopyramide had a concentration dependent protein binding and that free and total concentrations could be described by a two-compartment model with a t1/2, beta of approximately 2 hours. The free concentrations were found to be more valuable for estimating the kinetic parameters. The total clearance of disopyramide in the pig was found to approximately 3 ml/min./kg which is about 3 times greater than in man. In contrast to humans the free clearance in the pig increased with declining concentration. Apart from this the kinetics of disopyramide in the pig were very similar to those in man. In conclusion the pig could be a relevant model for studying the pharmacokinetics in humans.

Protein Binding of Disopyramide and Elevated Alpha-1-Acid Glycoprotein Concentrations in Serum Obtained from Dialysis Patients and Renal Transplant Recipients

A rapid ultrafiltration technique was used to measure the free (unbound) fraction of disopyramide in serum obtained from 14 normal volunteers, 6 chronic hemodialysis patients, and 10 renal transplant recipients. The disopyramide-free fraction varied more than tenfold at a corresponding total (free plus bound) serum disopyramide concentration of 3 micrograms/ml and was related to the concentration of an acute-phase protein, alpha-1-acid glycoprotein (AAG), in patient serum. Moreover, disopyramide-free fraction values were nearly twofold lower than normal in serum specimens obtained from those renal patients and transplant recipients with corresponding AAG serum concentrations greater than 100 mg/100 ml. AAG concentrations varied tenfold in patient serum and were on average nearly three times higher than AAG concentrations in normal volunteer serum. These findings suggested that the free fraction of disopyramide and possibly other drugs which bind extensively to AAG may be lower, and the interpatient variability in drug binding may be much more pronounced in serum obtained from hemodialysis patients and transplant recipients than previously recognized.

Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man.

The pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, disopyramide, were investigated in 12 volunteers who took 300 mg doses of 3 different capsule preparations and an aqueous oral solution of the drug at 1-week intervals. Concentrations of drug unbound to plasma proteins were measured by a sensitive immunoenzyme assay after ultrafiltration of plasma samples taken serially after dosing. QT interval was measured on serial ECG recordings with correction for changes in heart rate. Unbound concentrations of disopyramide were modelled by an open one-compartment pharmacokinetic model with a zero-order absorption rate and a lag time. There was no significant difference in parameter estimates between the four preparations, except for the lag time, which was significantly shorter for the solution preparation. The saturable protein binding of disopyramide was described by a hyperbolic model including a specific binding site and additional nonspecific binding. The pharmacodynamic relationship between unbound drug concentration and QT prolongation was fit by a simple linear model. This fit was better using unbound concentration of the drug than using total concentrations.

Intravenous Disopyramide in Acute Myocardial Infarction

We studied the haemodynamic and pharmacokinetic effects of intravenous disopyramide phosphate in 12 patients (average age, 59 years) with proven transmural myocardial infarction, whose symptoms began less than 12 h prior to the study. The aim was to assess the effects of intravenous disopyramide (2 mg/kg given over 5 min) on cardiac index (CI), left ventricular filling pressure (LVFP), heart rate (HR), mean systemic arterial blood pressure (BP), and systemic vascular resistance (SVR) for 60 min after administration of the drug. Both total and free concentrations of disopyramide in the plasma were also measured. A significant elevation (p less than 0.01) of LVFP (estimated indirectly as pulmonary artery end-diastolic pressure) occurred and persisted through the 1-h evaluation period. There was a small but significant (p = 0.02) initial fall in CI and a rise in SVR (p = 0.05). No significant changes occurred in HR or BP. Serum concentrations of disopyramide reached recommended therapeutic concentrations. There was no significant correlation of the changes in cardiac variables from pretreatment values with total serum concentrations, but the free concentration of disopyramide in plasma correlated better with cardiac effect, and the relationships of the free concentration of disopyramide to the changes in LVFP and in SVR from pretreatment values were significant (p less than 0.05). In two patients studied in detail, there was evidence of dose-dependent protein binding of disopyramide.

Influence of volume shifts on drug binding during equilibrium dialysis: correction and attenuation.

A time-dependent volume shift from buffer to plasma, which occurs during equilibrium dialysis, decreased the protein binding of disopyramide and its capacity constant, and had no effect on the binding association constant. The volume-dependent decrease in disopyramidine binding may be corrected for by use of a derived equation. Inclusion of dextran, 2.5% (w/v), and use of a thick, low molecular weight cutoff membrane was the most effective technique in attenuating the volume shift. The plasma (serum) protein binding of the basic drugs lidocaine, disopyramide, propranolol, and diazepam was decreased when protein was diluted to 88% or less of its undiluted concentration as a consequence of the volume shift. The protein binding of clofibrate, a highly bound acid drug, was more sensitive to volume shifts than the four basic drugs. Correction of drug binding for volume shifts was reasonably successful for most drugs. The highest binding measured for all drugs was associated with the lowest volume shift.

Effect of age and plasma concentrations of albumin and alpha 1-acid glycoprotein on protein binding of disopyramide.

British Journal of Clinical PharmacologyVolume 16, Issue 3 p. 344-345 Free Access Effect of age and plasma concentrations of albumin and alpha 1-acid glycoprotein on protein binding of disopyramide. DW Holt, DW HoltSearch for more papers by this authorAM Hayler, AM HaylerSearch for more papers by this authorGF Healey, GF HealeySearch for more papers by this author DW Holt, DW HoltSearch for more papers by this authorAM Hayler, AM HaylerSearch for more papers by this authorGF Healey, GF HealeySearch for more papers by this author First published: September 1983 https://doi.org/10.1111/j.1365-2125.1983.tb02175.xCitations: 16AboutPDF 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 onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume16, Issue3September 1983Pages 344-345 ReferencesRelatedInformation

Determination of disopyramide and mono-N-desisopropyl-disopyramide in serum by gas-liquid chromatography with nitrogen-selective detection

A rapid, reliable assay is described for the quantitation of disopyramide (DP) and its metabolite, mono-N-desisopropyl-disopyramide (MNDP), in serum using p-chloro-disopyramide as the internal standard and aqueous standards for calibration. The procedure involves extraction of the serum sample with diethyl ether, derivatization of MNDP with acetic anhydride, and gas-liquid Chromatographic analysis with nitrogen-selective detection. The accuracy of the procedure is97.8 ± 10.3 (SD)% for DP over the concentration range, 0.25–10.00 μg/ml ( n = 37), and 99.6 ± 10.2 (SD)% for MNDP over the concentration range, 0.50–5.00 μg/ml ( n = 18). The within-day coefficient of variation is less than 8% for DP and 12% for MNDP. The lower limit of quantitative sensitivity is 0.25 μg/ml for DP and 0.50 μg/ml for MNDP, and the lower limit of detection is 0.6 ng and 1.6 ng, respectively, for DP and MNDP. This assay has been used to determine the time-course of DP and MNDP and the protein binding of DP (without requiring an in vitro protein binding curve) in the serum obtained from patients and laboratory animals during DP administration.

The influence of blood collection technique on serum and plasma protein binding of disopyramide.

Serum and plasma disopyramide (D) protein binding was compared after blood was collected from four normal subjects in various Vacutainer tubes. The fraction of disopyramide bound to proteins in control serum and plasma was drug concentration dependent and correlated well with the capacity factor (N) associated with a high affinity protein binding site. D free fraction increased 60% at a postequilibrium concentration of 2 micrograms/ml in plasma following exposure of blood to green-top Vacutainer stoppers due to a 60% reduction in the affinity constant associated with the high affinity protein binding site. Heparin and EDTA had no effect on the plasma protein binding of D. These results suggest a competitive inhibition of disopyramide binding to alpha 1-acid-glycoprotein following contact of blood with rubber Vacutainer stoppers.