Disopyramide In Plasma Research Articles

個別薬物療法のための血しょう中蛋白非結合型Ｄｉｓｏｐｙｒａｍｉｄｅ濃度測定の有用性

The unbound concentration of disopyramide (DP) in plasma was studied to determine whether or not it is a useful index to assess the effectiveness of DP in anti-arrhythmic therapy. In 20 arrhythmic patients administered DP (Rythmodan®, 100-600 mg/day), there was no correlation between the dose and total or unbound plasma concentration of DP. The values of unbound fraction (fp) of DP in plasma widely varied from 0.25 to 0.57. The fp values were not correlated with the albumin concentration in plasma, but did correlate with the concentration of α1-acid glycoprotein. We further examined the relationship between the total or unbound plasma concentrations of DP and it's effectiveness in 16 of the 20 patients (4 patients had side effects). There was significant difference in the plasma concentrations of DP between the effective group and the ineffective group.However, as the range of the concentration for the two groups overlapped in 75%. the total concentration cannot be used to define the effectiveness. On the other hand, the unbound concentration of DP was greater than 0.8μg/mL in the effective group, whereas it was lower than 0.8μg/mL in the ineffective group.There was no correlation between the unbound concentration of mono-N-dealkyldisopyramide (MND) and the effectiveness. The range of the unbound plasma concentration of MND was 0.1-1.0μg/mL, and no patient developed side effects such as tachycardia or constipation due to the anticholinergic effect. In conciusion, an unbound concentration of DP in plasma of over 0.8μg/mL can be used as an index of the effectiveness of anti-arrhythmic therapy in therapeutic drug monitoring.

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)

Determination of disopyramide in plasma by high-performance liquid chromatography

Disopyramide [4-di-isopropylamino-2-phenyl2-(2-pyridyl)-butyramide] is frequently used in the suppression and prevention of cardiac arrhythmias [I]. Because of the relatively narrow therapeutic index and the intersubject variability in the pharmacokinetics of this drug, monitoring of its concentration in plasma may assist in individualizing the dosage requirements. Chromatographic methods have been developed for the quantitation of disopyramide in biological material; the main method was HPLC [2-I.51 although gas chromatography (GLC) has also been used. However, GLC requires relatively complex and time-consuming sample preparation, including a complicated derivatization. Most HPLC methods with UV monitoring of the eluent at 254 nm [2-4, 9, 10. 131 had poor sensitivity and lacked specificity owing to interference by other drugs. Two of the published HPLC methods required expensive, sophisticated columns and were used for separation of the R and S enantiomers [6, 111 and not for routine measurements in the clinical laboratory. The major disadvantages of some other procedures are the lack of an internal standard, a relatively moderate recovery of about 73% disopyramide or a time-consuming extraction procedure. The extraction of disopyramide from human plasma has been examined and a rapid, selective. accurate and simple HPLC assay has been developed for determining this drug in plasma. The internal standard employed, procaine hydrochloride, is readily available; this substance is structurally dissimilar from disopyramide but has similar solubility and chromatographic and absorptive characteristics.

Comparison between two methods for the determination of the total and free ( R)- and ( S)-disopyramide in plasma using an α 1-acid glycoprotein column

Two different high-performance liquid chromatographic systems for the determination of the total and free ( R)- and ( S)-disopyramide (DP) in plasma and urine were compared. In method I a Nucleosil C 8 column was coupled in series with an α 1-acid glycoprotein column. Method II consisted of two systems; a LiChrosorb Si 60 column was used for the determination of the racemic drug concentration and the R/S ratio was determined on an α 1-acid glycoprotein column. The recovery of ( R)- and ( S)-DP from plasma was >97% in both methods. The precisions of the ( R)- and ( S)-DP determinations in plasma are high with both methods. The relative standard deviations for the determination of the free concentration do not exceed 6.5% at 1.59 μg/ml racemic DP. Method II is preferred as it can also be used to determine the concentration of ( R)- and ( S)-monodesisopropyldisopyramide. It is also easier to avoid disturbances from endogenous compounds in plasma samples with method II than with method I. It was observed that DP was incorporated into urine sediment during storage. A simple ultrasonic treatment of the urine samples was demonstrated to release DP from the sediment.

Distribution of lidocaine and disopyramide in human blood and tissue, a case report of death caused by spinal anesthesia

An 11-year-old girl was anesthetized with hyper-baric solution of lidocaine as spinal anesthesia for an appendectomy in a surgical clinic. Respiratory arrest which occurred soon after the injection, was not discovered for a period of time. Since spontaneous respiration recovered within 2 h of intensive resuscitation, the patient was transferred to a community hospital for intensive care. Ten hours after the spinal anesthesia, she died of cardiac failure. The concentration of lidocaine in the brain was 5 – 10 times more than that in other tissues. The relationship between the possibility of malpractice of spinal anesthesia and tissue distribution of the drug was discussed. In addition to lidocaine, a toxic amount of disopyramide, an antiarrhythmic drug, was detected in the body. The distribution of disopyramide was also estimated, and the pharmacokinetics of disopyramide in plasma and tissues were studied experimentally in rats.

Altered protein binding of disopyramide in plasma from patients with cancer and with inflammatory disease.

Protein binding of disopyramide (D) was studied in eight patients with cancer, seven with inflammatory diseases, and seven healthy subjects. Plasma samples containing concentrations of 0.2-12.0 micrograms/ml were ultrafiltered, and the free fractions were measured with fluorescence polarization immunoassay. The mean free fractions at D concentrations ranging from 1.0 to 6.0 micrograms/ml were significantly less in patients with cancer (p less than 0.01) and those with inflammatory diseases (p less than 0.05) than in healthy subjects. Patients with cancer had a greater (p less than 0.05) D binding than those with inflammatory diseases. A multiple regression analysis revealed a significant contribution of plasma alpha 1-acid glycoprotein (AAG) (r = -0.79, p less than 0.01), but not of albumin (r = -0.096), to the overall variability in D binding at 3.0 micrograms/ml. The mean capacity constant in the two patient groups was similar, but significantly (p less than 0.01) greater than in the healthy group. Nonspecific D binding was greater in cancer patients (p less than 0.01) compared to the other two groups. Our results suggest that (a) therapeutic range of D measured as total drug concentration in patients with cancer and with inflammatory diseases would be greater than previously thought, and (b) unidentified component(s) (other than AAG and albumin) might contribute to the greater D binding in cancer patients compared to other study groups.

Measurement of plasma disopyramide as a guide to paediatric use

We have studied the relationship between age, daily dose, plasma concentration and clinical efficacy of disopyramide in a group of paediatric patients. Twelve children with ventricular and 3 with supraventricular arrhythmias were treated with oral disopyramide. The initial dose was 3–6 mg/kg per day. This was adjusted until a pre-dose plasma concentration > 2 mg/l was achieved. Seven patients were judged to have responded to the treatment on clinical criteria. No symptoms or signs of toxicity were observed. In some of the children the dose of disopyramide required to achieve a plasma concentration > 2 mg/l was greatly in excess of the normal adult dose. Generally the youngest children required the highest dose, but the variation was wide. The dose could not be predicted from the age, the body weight or the surface area of the patient. In children high doses of disopyramide may be needed to achieve effective plasma concentrations of the drug; such doses are not associated with adverse effects. Measurement of the plasma concentration is necessary to guard against premature termination of therapy.

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.

Plasma Protein Binding of Disopyramide by Equilibrium Dialysis and Ultrafiltration

An ultrafiltration technique, using Ultrafree Anticonvulsant Drug Filters, was compared to equilibrium dialysis for the determination of disopyramide plasma protein binding. Mean total recovery of drug was 92.4% for ultrafiltration compared with 98.4% for equilibrium dialysis. At initial plasma concentrations spanning the therapeutic range (2-8 micrograms/ml), the percentage binding of disopyramide was concentration dependent for both methods (78-38%). Initial experiments with ultrafiltration (1 ml of plasma) indicated a small (0.14%) but variable loss of total plasma protein in the ultrafiltrate (0.1-ml volume). In ultrafiltration, percentage binding of disopyramide was similar at 22 and 37 degrees C, whereas in equilibrium dialysis, binding was significantly (p less than 0.001) greater (1.4-2.7%) at 22 than at 37 degrees C. Percentage binding for plasma (1-ml volume), assessed at ultrafiltrate volumes of approximately 0.1 and 0.25 ml, was found to be significantly (p less than 0.05) different, but in practical terms the mean difference was less than 1% at any of the concentrations studied and was therefore of little consequence. Absolute values for percentage disopyramide bound by ultrafiltration and equilibrium dialysis were very similar, irrespective of the temperature. However, when these values were related in the usual way to the starting plasma drug concentration for ultrafiltration or to the final dialysed plasma concentration, ultrafiltration gave results that were consistently greater than those with equilibrium dialysis. Reasons for these differences and their implications are discussed.

Absorption and antidysrhythmic activity of oral disopyramide phosphate after acute myocardial infarction.

1 In a prophylactic, double-blind, randomized placebo-controlled trial of oral disopyramide phosphate, initiated within 12 h of suspected acute myocardial infarction (MI), antidysrhythmic effect was evaluated. The loading dose was 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh 85 kg, respectively. After each loading dose and a maintenance dose on one of days 4-7, 2 and 6 h venous blood samples were obtained for determination of plasma disopyramide and mono-N-dealkylated disopyramide (MND) concentrations (expressed herein as levels), by a technique incorporating fluorescence photometry and thin layer chromatography. Of 121 patients entering the trial, 101 had confirmed acute MI and of these, 12 on active drug were recalled during convalescence and restudied after a loading dose. 2 In acute MI patients on disopyramide phosphate, an important degree of antidysrhythmic effect was observed (on active drug and placebo, 19% v 37%, respectively (P = 0.047), received lignocaine for `warning arrhythmias'), even though in the first 6 h post-loading dose, disopyramide and MND levels were low and variable. 3 Disopyramide levels 2 h post-loading dose were lower in acute MI than in non-MI patients (P = 0.004), and similarly in the limited within patient study corresponding levels after acute MI were lower than during convalescence (P = 0.013). At 6 h post-loading dose, the levels had increased in acute MI patients but decreased in non-MI patients, this change being significantly different (P = 0.048). A similar significant difference existed in the limited within patient data available during acute MI and convalescence (P = 0.002). 4 Acute MI patients on active drug developing `warning arrhythmias' had lower post-loading dose, 2 and 6 h levels than in those without `warning arrhythmias' (P = 0.012 and P = 0.0002, respectively). 5 One patient who developed renal insufficiency developed excessive disopyramide levels. 6 On any given dose, there was no significant correlation between disopyramide level and body weight. 7 In acute MI patients given oral disopyramide phosphate (a) there was marked interindividual variation in the ensuing drug and metabolite levels, (b) absorption of disopyramide into the circulation was delayed, (c) prophylactic antidysrhythmic activity was present at levels of about 1.5 mg/l which is about half the minimal level recommended hitherto, (d) disopyramide accumulated in renal insufficiency, (e) elaborate dosage adjustments based on body weight are not useful.

Plasma disopyramide concentrations following a 300-mg oral loading dose in acute myocardial infarction.

Plasma disopyramide concentrations were measured in 19 patients with suspected myocardial infarction (MI) following an oral loading dose of 300 mg. Infarction was confirmed in 17 patients. In 10 patients blood samples were collected frequently over a period of 6 h, and in the remaining nine, blood samples were collected for 60 h whilst they were receiving a maintenance dose of 100 mg six hourly. There was a wide variation in the absorption of the drug, and only 8 patients achieved plasma concentrations in the range 2-4 mg/L within one hour of ingestion; 8 of the patients on maintenance therapy were within this range 24 h following the start of therapy. Although only 2 noninfarct patients were observed, they achieved the highest plasma disopyramide concentrations--above the therapeutic range--within 1 h of receiving the loading dose. Narcotic analgesia was associated with poor absorption of the drug, but this does not exclude severity of infarction or vomiting after the loading dose from contributing to the wide variation in plasma concentrations in the early stages following the loading dose. It is concluded that this regime is unsuitable for prophylactic use in acute MI.

The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide.

Disopyramide exhibits saturable binding to plasma proteins in the therapeutic plasma concentration range. Because of this property, controversy exists in the literature regarding the pharmacokinetic properties of the drug. The purposes of this study were to reassess the pharmacokinetic properties of disopyramide in humans, taking into consideration both total and unbound concentrations and to use disopyramide as a model compound to study the effect of drug binding on the renal clearance of both total and unbound drug. A single intravenous dose of disopyramide (1.5 mg/kg) was administered to eight normal volunteers. Blood and urine samples were collected for 36 h. Total concentrations of disopyramide in plasma and urine were determined by high pressure liquid chromatography. Binding of disopyramide to plasma proteins was determined by equilibrium dialysis. In all subjects the binding of disopyramide to plasma proteins was saturable, but there were considerable differences in binding between subjects. The volume of distribution, total body clearance, and renal clearances of both total and unbound drug were calculated. Because only the total body clearance and renal clearance of unbound compound are not dependent upon unbound fraction (alpha), these are the only parameters which can be reported without qualification as to the concentration. The mean +/-DS total body clearance of unbound drug in the eight subjects was 5.40 +/- 2.80 ml/min/kg. About 50% of this was due to renal elimination. A statistically significant negative correlation of the renal clearance of total disopyramide with time was observed in seven of eight subjects, whereas a significant correlation between the renal clearance of unbound disopyramide and time was observed in only one subject. This suggests that the renal clearance of unbound disopyramide is independent of alpha, while the renal clearance of total disopyramide is dependent upon alpha.

Determination of unbound fraction of disopyramide in plasma: A comparison of equilibrium dialysis, ultrafiltration through dialysis membranes and ultrafree anticonvulsant drug filters

A simple, rapid ultrafiltration technique for determination of free drug concentration in plasma is described and compared with equilibrium dialysis and ultrafiltration through dialysis membranes. When used for disopyramide protein binding studies, this method requires only 1 ml of plasma and up to 20 samples may be filtered simultaneously in 20–40 min. Commercially available Ultrafree anticonvulsant drug filters are used, these are attached to 2 ml leur tip syringes, which provide the pressure gradient for filtration. Compared to equilibrium dialysis this technique is far quicker and permits protein binding to be measured at the drug concentration in the original plasma. Ultrafiltration through dialysis membranes was found to be more tedious and time-consuming than it was through Ultrafree filters. Adsorption of disopyramide from the plasma sample and protein leakage were also problems with this method. Leakage of protein did not occur with either Ultrafree filters or equilibrium dialysis. With the Ultrafree method, recovery of 14C-labeled disopyramide in buffer at 1.1 μg ml and 8.4 μg ml was 87% and 89% respectively. In carefully controlled experiments, a comparison of the Ultrafree method with equilibrium dialysis and ultrafiltration gave comparable values for the free fraction of the drug for total concentrations from 0.3–8 μg ml disopyramide.

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.

PROCEEDINGS OF THE AUSTRALASIAN SOCIETY OF CLINICAL AND EXPERIMENTAL PHARMACOLOGISTS

PROCEEDINGS OF THE AUSTRALASIAN SOCIETY OF CLINICAL AND EXPERIMENTAL PHARMACOLOGISTS

Acute oral antiarrhythmic testing with disopyramide.

Acute antiarrhythmic drug testing with disopyramide was accomplished in 25 patients with frequent ventricular premature depolarization (VPD). Systolic time intervals (STI) were used to assess left ventricular performance. Eighteen patients responded after a loading oral dose of 300 mg disopyramide with 80% or greater reduction in VPD and abolition of advanced grades. Mean onset of drug action was 93 min and the mean plasma level at 2 h was 3.4 microgram /ml. During maintenance therapy 2 of the 18 patients had a relapse, In 2 others, initially protected, VPD recurred during both exercise and psychological stress testing. STI showed increments in pre-ejection period (PEP) and in PEP/ejection time ratio at peak concentrations of plasma disopyramide. Acute tests repeated with placebo in a single-blind fashion in responding patients failed to significantly reduce VPD frequency or grade. Side effects consisted of anticholinergic actions of disopyramide. In 3 patients aggravation of heart failure compelled discontinuation of disopyramide which then remitted.

Gas chromatography and enzyme immunoassay compared for analysis of disopyramide in plasma.

Journal Article Gas chromatography and enzyme immunoassay compared for analysis of disopyramide in plasma. Get access A Johnston, A Johnston Search for other works by this author on: Oxford Academic Google Scholar J Hamer J Hamer Search for other works by this author on: Oxford Academic Google Scholar Clinical Chemistry, Volume 27, Issue 2, 1 February 1981, Page 353, https://doi.org/10.1093/clinchem/27.2.353 Published: 01 February 1981

Electrophysiologic effects of disopyramide phosphate on reentrant ventricular arrhythmia in conscious dogs after myocardial infarction

The electrophysiologic actions of disopyramide phosphate on reentrant ventricular tachycardia induced by premature ventricular stimuli were evaluated in conscious dogs 2 to 4 days after myocardial infarction. Disopyramide was administered as a series of intravenous infusions to obtain successive steady state plasma disopyramide concentrations of 1.02 ± 0.02, 2.05 ± 0.08, 3.94 ± 0.09 and 7.69 ± 0.18 μg/ ml (mean values ± standard error of the mean). Disopyramide plasma concentrations of 1.02 ± 0.02 μg/ ml produced an increase in the rate and duration of ventricular tachycardia as well as in the interval during which premature ventricular stimuli produced ventricular tachycardia. The effective refractory period of normal myocardium was decreased and conduction (activation time) was improved in ischemic myocardium. Increasing steady state plasma disopyramide concentrations slowed the rate of ventricular tachycardia without decreasing its duration. Slowing of the rate of tachycardia occurred simultaneously with a depression of conduction in normal and ischemic myocardium and an increase in ventricular refractoriness. Induction of ventricular tachycardia was prevented only at steady state plasma disopyramide concentrations of 7.69 ± 0.18 μg/ ml. The results of this study suggest that subtherapeutic plasma concentrations of disopyramide may facilitate the development of reentrant ventricular arrhythmia in the electrically unstable heart. Ventricular tachycardia or fibrillation, or both, may be prevented only by plasma disopyramide concentrations that are in excess of the normal therapeutic range of 2 to 4 μg/ml.

Disopyramide-Induced Ventricular Tachycardia

A patient with ischemic cardiomyopathy and congestive heart failure was treated with disopyramide phosphate for ventricular arrhythmias. The development of ventricular tachycardia was associated with elevated plasma disopyramide levels and prolongation of the QRS and QT intervals, suggesting a disopyramide-induced depression of ventricular conduction and a prolongation of recovery. Thus, in patients with congestive heart failure, as well as in patients with renal and/or hepatic dysfunction, special care must be exercised with respect to the use of disopyramide.

Simplified method for the measurement of disopyramide in plasma

Simplified method for the measurement of disopyramide in plasma