ABSTRACT
Recent pharmacokinetic studies indicate that both flow and permeability contribute to intercompartmental clearance. A previous analysis of flow and permeability components of transcapillary exchange has been adapted to a three-compartment model of PA and NAPA pharmacokinetics. Data from a study that simultaneously determined the pharmacokinetic parameters of these two compounds made it possible to estimate permeability coefficients for the fast equilibrating compartment averaging 3.32 liters/min for PA and 1.35 liters/min for NAPA, and for the slow equilibrating compartment averaging 2.05 liters/min for PA and 0.78 liters/min for NAPA. These results were then used to estimated flow-intercompartmental clearance relationships for PA and NAPA and to predict the extent of hemodynamic changes causing the slow intercompartmental clearance of NAPA to decrease by 77% during hemodialysis without an apparent alteration in fast intercompartmental clearance.
Subject(s)
Capillary Permeability , Pharmaceutical Preparations/metabolism , Regional Blood Flow , Erythrocytes/metabolism , Humans , Kinetics , Models, Biological , Molecular WeightABSTRACT
We describe a method for routinely measuring plasma concentrations of procainamide (PA), N-acetylprocainamide (NAPA) and desethyl N-acetylprocainamide (NAPADE) by high-performance liquid chromatography (HPLC). The method has been used together with mass spectrometry of the appropriate chromatographic fraction to demonstrate that NAPADE is a metabolite of NAPA. In addition, comparison of NAPADE concentrations in the plasma of patients receiving PA and NAPA indicates that NAPA is not an intermediate for most of the NAPADE formed from PA. We propose that the principal route of NAPADE formation from PA occurs by initial dealkylation to form rho-amino-N-[2-(ethylamino)ethyl]benzamide (PADE), a hypothetical PA metabolite that has yet to be identified.U
Subject(s)
Acecainide/analogs & derivatives , Acecainide/metabolism , Procainamide/analogs & derivatives , Procainamide/metabolism , Acecainide/blood , Chromatography, High Pressure Liquid , Humans , Mass SpectrometryABSTRACT
The kinetics of N-acetylprocainamide (NAPA) deacetylation to procainamide (PA) were determined in a normal subject using NAPA-13C, labeled in the acetyl group. The deacetylation clearance of NAPA (ClD) was found to be 6.5 ml/min whereas total NAPA elimination clearance was 231 ml/min, so that 2.8% of the administered NAPA-13C was metabolized by deacetylation. This estimated of ClD was shown to be representative of the rate of NAPA deacetylation in four patients on long-term NAPA therapy. Steady-state [PA]/[NAPA] ratios averaged 0.024, but would be expected to rise to 0.057 if functionally anephric patients were treated with NAPA. Despite reports that patients with the PA-induced systemic lupus erythematosus-like reaction have had symptomatic and immunologic remission when switched to NAPA, the demonstration that NAPA is deacetylated to PA indicates that the apparently greater immunologic safety of NAPA may be relative rather than absolute.
Subject(s)
Acecainide/metabolism , Procainamide/analogs & derivatives , Adult , Humans , Kinetics , Male , Metabolic Clearance Rate , Procainamide/urineABSTRACT
Investigation of three nursIng women given theophylline intravenously defined the kinetics of theophylline transfer into breast milk. In each subject, R was constant, with no significant delay between the attainment of peak plasma and peak milk concentrations. The amount of theophylline eliminated into milk was equal to the product of R, milk volume, and the simultaneous maternal plasma concentration. The data indicate that theophylline cumulation to toxic concentrations should not occur in most breast-fed infants of asthmatic women treated with appropriate doses of theophylline.
Subject(s)
Milk, Human/metabolism , Theophylline/metabolism , Adult , Aminophylline/metabolism , Asthma/metabolism , Female , Humans , Kinetics , Models, Biological , Theophylline/bloodSubject(s)
Acecainide/pharmacology , Hemodynamics/drug effects , Procainamide/analogs & derivatives , Acecainide/blood , Animals , Blood Pressure/drug effects , Cardiac Output/drug effects , Depression, Chemical , Dogs , Heart Rate/drug effects , Heart Ventricles , Myocardial Contraction/drug effects , Stimulation, Chemical , Stroke Volume/drug effects , Vasodilation/drug effectsABSTRACT
Monitoring plasma concentrations of therapeutic drugs presents special problems when these drugs are metabolized to compounds that have pharmacologic activity. This presentation reviews several methods for evaluating the pharmacologic activity of drug metabolites and describes the impact of active drug metabolites on the pharmacokinetic design of dose regimens and on the formulation of guidelines for plasma level interpretation. Lidocaine and monoethylglycinexylidide illustrate the considerations that pertain when both a drug and its active metabolite have similar therapeutic and toxic actions. Procainamide and N-acetylprocainamide exemplify the much more complex situation that arises when a drug and its active metabolite have different pharmacologic activity.
Subject(s)
Drug Therapy , Pharmaceutical Preparations/metabolism , Animals , Humans , Kinetics , Lidocaine/blood , Lidocaine/metabolism , Lidocaine/pharmacology , Procainamide/blood , Procainamide/metabolism , Procainamide/pharmacologyABSTRACT
NAPA pharmacokinetics were studied in 6 functionally anephric patients. Distribution and nonrenal elimination of this drug were found to be the same as in individuals with normal renal function but renal clearance was reduced, resulting in a mean elimination t 1/2 of 41.9 hr (6.2 hr in normal subjects). Renal clearance of NAPA correlated well with ClCr. Dialysis removed NAPA from both red blood cells and plasma and increased ClT approximately fourfold. Dialysis itself resulted in a 77% reduction in ClS that limited the total amount of NAPA removed by this procedure. This reduction in ClS was sustained for at least 3 hr after dialysis and attenuated rebound in plasma NAPA concentrations.
