Serum Disopyramide Concentration Research Articles

Bioavailability assessment of disopyramide using pharmacokinetic-pharmacodynamic (PK-PD) modeling in the rat.

The relationship between the serum concentration and the pharmacological effect of disopyramide was investigated quantitatively to estimate the extent of its oral bioavailability (EBA(p.o.) and to evaluate the drug interaction with miconazole, a CYP3A4 inhibitor. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was used to describe the relationship between the serum concentrations and changes in QT interval (pharmacological data) of disopyramide after intra-vascular infusion for 15 min (i.v. short-term infusion) to rats. A two-compartment model was applied to the pharmacokinetics of disopyramide. The pharmacological data after short-term infusion were well explained using a PK-PD link model. To validate the present PK-PD model. disopyramide was administered intra-vascularly in separate experiments, and the doses were predicted only from the pharmacological data. The model predicted doses were identical to the actual doses, regardless of the dosing rates. This result indicates that the PK-PD model used in the present study is appropriate, and that the relationship between the serum concentrations and changes in QT intervals is independent of the dosing (input) rate. When miconazole was co-administered orally 1 h before disopyramide infusion, the serum disopyramide concentrations were significantly higher than that following disopyramide alone. The raised serum concentrations under miconazole co-administration were well explained by nonlinear elimination clearance. The pharmacological effects of disopyramide under miconazole co-administration, were also greater than those following disopyramide alone. The results of the PK-PD analysis indicated that the enhanced pharmacological response under miconazole co-administration was simply caused by a pharmacokinetic change. The EBA(p.o.) values estimated from the pharmacological effects predicted the observed values reasonably well. In conclusion, we demonstrated following: (1) the pharmacological effect after intra-vascular administration of disopyramide is related quantitatively to the serum concentrations using a PK-PD model; (2) miconazole affects only the elimination clearance of disopyramide to enhance the pharmacological effect; (3) the EBA of disopyramide can estimated reasonably only well from the pharmacological data using the PK-PD model; (4) there is no dosing-rate-dependent or dosing-route-dependent pharmacological effect of disopyramide.

服薬指導における症例報告 その２ ピルメノールにより肝障害を引き起こしたと疑われた一症例およびその検討

A 56-year-old woman inpatient that had been administrated warfarin, digoxin, verapamil and disopyramide after undergoing surgery for a mitral and aortic valve replacement associated with artrial fibrillation received a 300mg daily dose of disopyramide therapy before and after the operation. Although the serum disopyramide concentration was within the normal therapeutic range, dry mouth appeared as a side effect. Disopyramide was thus changed to pirmenol. The trough level of pirmenol was 2.1μg/mL at seven days after starting pirmenol therapy at the dose of 300 mg/day, and the dose was there after decreased to 200mg/day. About two weeks after pirmenol therapy was started, liver injury was observed. At approximately 30 days after pirmenol administration was stopped, the liver function returned to a normal level.On the other hand, according to recent reports pirmenol was suggested to show a high level in the liver. The reported levels of pirmenol were also similar to for amiodarone and aprindine, which are both well known to induce side effect in the liver. Therefore, one of the reasons that pimenol induced liver injury may be due to its high levels in the liver.

ジソピラミド服用入院患者における徐放剤と非徐放剤との血中濃度のバラツキの比較

The variation in serum disopyramide concentration at early morning (6: 00) in inpatients administered 300mg per day of sustained-release disopyramide tablet (Rthmodan R, preparation A) or the same dose of non sustained-release disopyramide capsule (Rthmodan, preparation B) was studied. Twenty-one inpatients, whose mean age was 68.4 ±10.2 (SD) yr and mean body weight was 52.0±7.6kg, received preparation A (q 12 hr at 7: 00 & 19: 00). Nineteen inpatients, whose mean age was 68.3±12.9 yr and body weight was 54.0±11.3kg, received preparation B (tid at 7: 00, 12: 00 & 19: 00). No differences were observed in the mean ratio of serum disopyramide concentration at 6: 00 to dose between inpatients receiving preparations A and B, although a signficant difference was observed in its variation. When the intra-individual variability in inpatients monitored more than three times was compared, the CV was 4.93±1.74%(SD) in inpatients receiving preparation A versus 21.8±7.8% in inpatients received preparation B. Therefore, this suggests that the variation in serum disopyramide concentration in inpatients receiving preparation A was significantly decreased over that of preparation B.

A Simple Method for the Simulation of Unbound Serum Disopyramide Concentration in Patients.

There were remarkable differences in the serum total and unbound concentrations of disopyramide (DP) and mono-N-dealkyldisopyramide (MND), the major metabolite of DP, among patients with arrhythmias. Serum levels of alpha 1-acid glycoprotein (AAG) also varied among the same patients. To predict the unbound DP concentrations, we have obtained the serum concentration-time curves of unbound DP in these patients by means of total DP concentration, DP pharmacokinetic parameters, AAG levels and dissociation constants of DP and MND at specific AAG binding sites. In patients with normal AAG levels, the theoretical values of unbound DP were in good agreement with the measured concentrations. On the other hand, in patients with high AAG levels, the theoretical values could be obtained by correcting the calculated values using both AAG levels of each patient and the equation correlating the unbound DP fraction to AAG concentrations. These findings indicate that patient AAG levels can provide valuable information permitting the rapid estimation of unbound DP concentrations, the pharmacologically active fraction, and the development of effective DP dosage regimens.

Disopyramide induces insulin secretion and plasma glucose diminution: Studies using the in situ canine pancreas

The mechanism of disopyramide-induced hypoglycemia, a life-threatening complication in the antiarrhythmic drug treatment, is still controversial. To elucidate this, we have evaluated plasma insulin (IRI) and glucagon (IRG) responses in the pancreatic vein (PV) of the in situ pancreas as well as responses of plasma IRI, IRG, and glucose in the femoral artery (FA) to disopyramide phosphate administration in anesthetized dogs. First, infusion of disopyramide at a dose of 50 mg for ten minutes directly into the pancreatic artery, but not the vehicle, increased significantly plasma IRI concentration in the PV ( P < .05 or less), where the IRI response started within three minutes and reached a peak of 2.8-fold preinfusion value at 30 minutes after starting the infusion (n = 7). Plasma IRI concentration in the FA also increased slightly but significantly ( P < .05). Plasma IRG concentration in the PV initially decreased significantly ( P < .05 or less) and in the FA at one point ( P < .05) during the infusion, and then increased significantly after cessation of the infusion, showing a peak of 1.9-fold preinfusion value at 60 minutes in the PV and the FA ( P < .05). Plasma glucose concentration in the FA decreased slowly and significantly after the infusion ( P < .05 or less) and fell by 16% of the baseline value at 60 minutes ( P < .05). Second, infusion of disopyramide at a dose of 7 mg/kg body weight (BW) for ten minutes into the femoral vein induced a peak of serum disopyramide concentration of 13.7 ± 2.8 μg/mL at ten minutes, which corresponds to a twofold to threefold concentration of the human therapeutic level (n = 4). The disopyramide infusion, but not vehicle, induced a significant increment of plasma IRI concentration in the PV at ten minutes ( P < .05), accompanying a very slight IRI rise in the FA. Plasma IRG concentration in the PV again increased after the cessation of the infusion ( P < .05). Arterial plasma glucose level decreased significantly by 14% at 60 minutes ( P < .01). The present results indicate that disopyramide provokes a prompt and significant insulin secretion, and also induces a concomitant fall of plasma glucose level in face of an ongoing IRG secretion. The results thus suggest that the disopyramide-induced glucose fall is caused by decreased hepatic glucose output due to the hepatic action of insulin released by the drug rather than by increased peripheral glucose uptake due to the peripheral action of insulin. It may be an additional explanation for the glucose fall that disopyramide blunts the hepatic glucose output, which should be stimulated by the augmented glucagon secretion. Thus, if combination of the present glucose-lowering factors occurs in the elderly and malnourished patients with the impaired hepatic and renal function, who especially have poor hepatic glycogen storage and gluconeogenic activity, the disopyramide-induced hypoglycemia may easily develop.

Clinical pharmacokinetics of controlled-release disopyramide in patients with cardiac arrhythmias.

The pharmacokinetics of the controlled-release preparation of disopyramide phosphate (Norpace CR, Searle Laboratories, Chicago, IL) were studied in ten patients with cardiac arrhythmias. Multiple-serum disopyramide concentrations were obtained after a 300-mg oral dose. Each patient then received chronic oral therapy with the controlled-release preparation (400 to 1000 mg/day) on an every-12-hour schedule. At steady state, disopyramide trough concentrations were obtained. Serum disopyramide concentrations were determined by high performance liquid chromatography. The regimen was well tolerated by all patients. The mean (+/- SD) time to maximum concentration, maximum concentration, and concentrations 11 and 24 hours after the initial dose were 5.5 +/- 1.3 hours and 2.8 +/- 0.8, 2.0 +/- 0.9, and 1.2 +/- 0.5 micrograms/mL, respectively. A low Cmax to trough concentration ratio of 1.35 +/- 0.26 was observed after the initial dose. Linear regression analysis of the serum disopyramide concentrations 11 hours after initial dose (trough) versus trough concentrations at steady state (dose adjusted) showed a strong correlation (r = 0.87, intercept = 0.03, and slope = 1.9). Regression analysis also showed a strong relationship between the area under the curve (AUC) from time 0 to 11 hours after the initial dose and the trough at steady state (r = 0.86). The controlled-release preparation of disopyramide, when administered every 12 hours in patients with cardiac arrhythmias, should produce low peaks to trough fluctuations. Because disopyramide concentrations after the initial dose correlate well with trough concentrations at steady state, these concentrations may provide a simple and convenient method for prospective monitoring of disopyramide therapy in patients receiving the controlled-release preparation.

Disopyramide in acute myocardial infarction: problems with changing pharmacokinetics.

In the acute phase of myocardial infarction it is recognized that serum disopyramide concentrations may be lower than expected. This has generally been attributed to reduced oral bioavailability. This report describes data obtained routinely from 6 patients with acute myocardial infarction and cardiac dysrhythmias treated initially with intravenous disopyramide. Serum disopyramide concentrations were consistently lower than expected, on average by 2.6 micrograms/ml. This was interpreted as being due to relatively high drug clearance, calculated as 6.7 +/- 1.5 l/h, compared to expected values of 3-4 l/h. Dosage schedules determined on the basis of the acute phase pharmacokinetics subsequently produced higher than predicted concentrations at later times on average by 2.8 micrograms/ml. Clearance at this time was calculated to be 3.1 +/- 0.6 l/h. Thus even with intravenous disopyramide therapy there are problems with changing pharmacokinetic parameters after myocardial infarction.

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.

Serum disopyramide concentrations and suppression of ventricular premature contractions.

Serum disopyramide determinations and 24-hour Holter monitoring were performed in 20 cardiac subjects with ventricular premature contractions (VPCs) after the first, seventeenth, and thirty-seventh doses of disopyramide, 100 mg (10 subjects; low-dose group) or 200 mg (10 subjects; high-dose group) every 6 hr for 10 days to assess the ability of single- or first-dose data to predict serum disopyramide concentrations at steady state and the relationship between steady-state serum disopyramide concentrations and VPC suppression. Control Holter recordings were made for 48 hr in each subject. There were strong correlations in both groups between data for the AUC over 0 to 6 hr for the first dose (AUC60) and average (C ss) and trough (C min) steady-rate serum disopyramide concentrations after the seventeenth and thirty-seventh doses and the two combined. C ss and C min were related to AUC60 by the following expressions for both dosage groups: C ss = 0.22 AUC60 + 0.90 and C min = 0.20 AUC60 + 0.70. There were good correlations between 6-hr serum disopyramide concentration after the first dose and C ss and C min. There was strong correlation between overall average steady-state serum disopyramide concentration and suppression of VPC frequency. The relationship between VPC suppression and overall average trough serum disopyramide concentration at steady state, on the other hand, was weak.

Serum drug concentrations and adverse effects in cardiac patients after administration of a new controlled-release disopyramide preparation.

Despite widespread marketing of a controlled-released preparation of disopyramide phosphate (Norpace-CR, G. D. Searle), literature demonstrating its efficacy in maintaining uniform serum drug levels over a 12-h dosing interval is derived from only normal healthy volunteers. Twenty patients with cardiac arrhythmias (ages 37-80 years) were administered 400-800 mg/24 h (5.1-10.5 mg/kg/day) of controlled-release disopyramide in two equally divided doses on a q. 12 h. schedule. After achievement of steady-state equilibrium drug concentration, disopyramide levels were determined by high-pressure liquid chromatography on sera obtained from blood samples drawn 2, 7, and 11 h after an oral dose. Mean maximal and minimal disopyramide serum concentrations were 3.2 +/- 1.0 and 2.5 +/- 0.9 microgram/ml, respectively. Adverse drug effects occurred in nine (45%) subjects, necessitating discontinuation of the preparation in five patients (25%). These data demonstrate that in a population of patients with cardiac arrhythmias q. 12 h. dosing with a controlled-release disopyramide phosphate preparation is associated with an acceptable variation between maximal and minimal serum disopyramide concentrations, and is tolerated by the majority of subjects. The preparation should, therefore, offer greater patient convenience and compliance without sacrificing antiarrhythmic efficacy.

Evaluation of Assay Methods for Serum Disopyramide Levels

We evaluated two assay methods to determine serum disopyramide concentrations in application to the practice of medicine. The methods are high-performance liquid chromatography (HPLC) and enzyme immunoassay (EMIT).In HPLC method disopyramide was separated on a reverse phase. The degrees of precision in HPLC method and EMIT method were less than 5.2% and 5.7% in C. V., respectively. Both methods gave excellent reproducibiliy with C. V.: less than 5.7% in HPLC method and 5.5% in EMIT method. The recovery ratio ranged from 98.0 to 100.7% in HPLC method and from 102.1 to 103.8% in EMIT method. Disopyramide concentrations in sera of healthy subjects and those of patients measured by HPLC method correlated well with those by EMIT method. We conclude both HPLC and EMIT methods are suitable in the routine practice of medicine for measurement of serum disopyramide concentrations.