European Journal of Clinical Pharmacology © by Springer-Verlag 1978
Europ. J. clin. Pharmacol. 14, 261-265 (1978)
The Pharmacokinetics of Slow-Release Procainamide W. J. Tilstone, D. H. Lawson, W. Campbell, I. Hutton, and T. D. V. Lawrie Forensic ScienceUnit, Schoolof PharmaceuticalSciences, Universityof Strathclyde,Glasgow,G1 1XW, Scotland, and ClinicalPharmacologyService and Departmentof MedicalCardiology,RoyalInfirmary,Glasgow,Scotland
Summary. Procainamide was given to 20 patients with normal renal function as an i. v. bolus of 500 mg followed by 1.0 or 1.5 g eight-hourly by mouth in the form of a slow release preparation (Durules). 97.6 + 27.1 (SD)% of the oral procainamide was absorbed, the absorption half life being 1.54 h. The elimination half life following the oral formulation was 6.0 _-4_0.8 h, compared to a mean of 3.4 _+ 0.4 h following i.v. administration. Elimination half life following i.v. administration was slightly related to acetylator status, being 2.75 _+ 0.9 h in fast acetylators, and 4.4 _+ 2.4 h in slow acetylators. This dependence on acetylator status was not seen in half life following oral administration. Total body clearance, steady state plasma procainamide and N-acetylprocainamide were not significantly dependent on acetylator status, although a few patients who are slow acetylators had unexpectedly low clearance and high steady state procainamide concentrations when given the higher dose. Key words: Procainamide, slow release formulations, bioavailability.
There has been renewed interest in the use of procainamide for the prevention of cardiac dysrhythmias. Recent studies confirm its value for this purpose despite a narrow therapeutic index and a wide range of plasma concentrations following administration of a standard dose to different subjects (KochWeser and Klein, 1971). Several attempts have been made to reduce these variations in plasma concentrations by acquiring a better understanding of the effect of factors such as renal function and inherited differences in procainamide clearance by acetylation in the
cell sap enzymes of the liver (Giardina et al., 1976). An alternative method of avoiding toxicity while maintaining effective plasma concentrations of procainamide would be to reduce the within-dose variations by modification of the dosage formulation (Graffner et al., 1975). The present paper reports the pharmacokinetics of one of the modified dosage formulations - p r o cainamide Durules (Astra Chemicals, Watford, England) - in a series of patients recovering from acute myocardial infarction.
Patients and Methods A total of 20 patients was studied, although complete results are not available for every patient. All had had a recent myocardial infarction diagnosed on the basis of a typical history together with the presence of pathological Q waves, sequential ST-T wave changes and/or elevated cardiac enzyme levels in the serum. All had normal liver function as measured by routine liver function tests and plasma creatinine concentrations were measured at the end of the period of study. Procainamide was given for the prevenhon of ventricular dysrhythmias in a dose of 3 g daily to 10 patients and 4.5 g daily to the remaining 10. All patients were given 500 mg i. v. procainamide eight hours before the oral dosage was commenced and, in all, the daily oral dosage was given as procainamide Durules in divided doses at eight-hourly intervals. After the initial i. v. bolus, serial blood samples were taken at 0, 0.5, 1, 1.5, 2, 4, 6 and 8 h. Similar samples were taken at 0 and 2 h after the first morning dose on days 7 and 8 of the regimen, representing the minimum and maximum plasma concentrations. The study was terminated on day 8, but procainamide 0031-6970/78/0014/0261/$01.00
262
W.J. Tilstone et al.: Slow-Release Procainamide
Europ. J. clin. Pharmacol. 14, 261-265 (1978)
The Pharmacokinetics of Slow-Release Procainamide W. J. Tilstone, D. H. Lawson, W. Campbell, I. Hutton, and T. D. V. Lawrie Forensic ScienceUnit, Schoolof PharmaceuticalSciences, Universityof Strathclyde,Glasgow,G1 1XW, Scotland, and ClinicalPharmacologyService and Departmentof MedicalCardiology,RoyalInfirmary,Glasgow,Scotland
Summary. Procainamide was given to 20 patients with normal renal function as an i. v. bolus of 500 mg followed by 1.0 or 1.5 g eight-hourly by mouth in the form of a slow release preparation (Durules). 97.6 + 27.1 (SD)% of the oral procainamide was absorbed, the absorption half life being 1.54 h. The elimination half life following the oral formulation was 6.0 _-4_0.8 h, compared to a mean of 3.4 _+ 0.4 h following i.v. administration. Elimination half life following i.v. administration was slightly related to acetylator status, being 2.75 _+ 0.9 h in fast acetylators, and 4.4 _+ 2.4 h in slow acetylators. This dependence on acetylator status was not seen in half life following oral administration. Total body clearance, steady state plasma procainamide and N-acetylprocainamide were not significantly dependent on acetylator status, although a few patients who are slow acetylators had unexpectedly low clearance and high steady state procainamide concentrations when given the higher dose. Key words: Procainamide, slow release formulations, bioavailability.
There has been renewed interest in the use of procainamide for the prevention of cardiac dysrhythmias. Recent studies confirm its value for this purpose despite a narrow therapeutic index and a wide range of plasma concentrations following administration of a standard dose to different subjects (KochWeser and Klein, 1971). Several attempts have been made to reduce these variations in plasma concentrations by acquiring a better understanding of the effect of factors such as renal function and inherited differences in procainamide clearance by acetylation in the
cell sap enzymes of the liver (Giardina et al., 1976). An alternative method of avoiding toxicity while maintaining effective plasma concentrations of procainamide would be to reduce the within-dose variations by modification of the dosage formulation (Graffner et al., 1975). The present paper reports the pharmacokinetics of one of the modified dosage formulations - p r o cainamide Durules (Astra Chemicals, Watford, England) - in a series of patients recovering from acute myocardial infarction.
Patients and Methods A total of 20 patients was studied, although complete results are not available for every patient. All had had a recent myocardial infarction diagnosed on the basis of a typical history together with the presence of pathological Q waves, sequential ST-T wave changes and/or elevated cardiac enzyme levels in the serum. All had normal liver function as measured by routine liver function tests and plasma creatinine concentrations were measured at the end of the period of study. Procainamide was given for the prevenhon of ventricular dysrhythmias in a dose of 3 g daily to 10 patients and 4.5 g daily to the remaining 10. All patients were given 500 mg i. v. procainamide eight hours before the oral dosage was commenced and, in all, the daily oral dosage was given as procainamide Durules in divided doses at eight-hourly intervals. After the initial i. v. bolus, serial blood samples were taken at 0, 0.5, 1, 1.5, 2, 4, 6 and 8 h. Similar samples were taken at 0 and 2 h after the first morning dose on days 7 and 8 of the regimen, representing the minimum and maximum plasma concentrations. The study was terminated on day 8, but procainamide 0031-6970/78/0014/0261/$01.00
262
W.J. Tilstone et al.: Slow-Release Procainamide
