Yin-Gail Yee

Verapamil protein binding in patients and in normal subjects

Verapamil plasma protein binding was studied in four groups of 12 subjects each: (1) normal subjects; (2) patients with moderate renal insufficiency and patients requiring dialysis; (3) patients 1 to 4 days after coronary artery surgery; and (4) patients undergoing cardiac catheterization. In normal subjects, plasma protein binding of verapamil was 89.6 ± 0.17% and was concentration independent over a range of 35 to 1,557 ng/ml, which includes the usual clinical plasma range. In normal subjects, plasma protein binding of verapamil was not affected by addition of its major metabolite, norverapamil, in ratios of 1.2 to 26.3 (norverapamil/verapamil) or by the addition of 10 µg of warfarin. The plasma protein binding of verapamil was not altered in the postsurgical state or in the dialysis patients. Verapamil protein binding was initially lower in the cardiac catheterization patients (x̄ = 86.34 ± 2.13%, p < 0.001) than in normal subjects and was still lower (x̄ = 83.29 ± 3.04%, p < 0.02) after heparinization. There was also a small increase in binding in the patients with renal insufficiency (p < 0.05). Plasma protein binding of verapamil in mongrel dogs (x̄ = 90.7%) was of the same order. We found verapamil to be approximately 90% bound in man and dogs and not markedly changed by any of the conditions studied.

Atenolol determination by high-performance liquid chromatography and fluorescence detection.

A high-performance liquid chromatographic procedure using a fluorescence detector for the analysis of atenolol in plasma and whole blood is described. It employs a simple and rapid method of preparation. Atenolol and metoprolol as the internal standard are chromatographed as ion pairs with heptanesulfonic acid. The method is sensitive and reproducible with accurate detection at concentrations as low as 2 ng/ml in whole blood and plasma, and a coefficient of variation of 4.7% over the range 2 ng/ml to 1000 ng/ml.

Interaction between warfarin and propafenone in healthy volunteer subjects

The effect of propafenone on the pharmacokinetics and pharmacologic effects of warfarin was studied in healthy normal male volunteer subjects. Each drug was administered alone for 1 week followed by a combined administration for 1 additional week. Blood samples were analyzed for propafenone and warfarin concentrations and the effect of each treatment on the prothrombin time was assessed. The concurrent administration of warfarin did not produce any changes in the absorption or disposition kinetics of propafenone. Concurrent propafenone administration did lead to a reduction in the clearance of warfarin, resulting in an average increase of 38% in the mean steady‐state plasma warfarin concentration. During the combined therapy phase, the prothrombin time increased significantly (P < 0.01) from the “warfarin alone” phase. We conclude from this study that the concomitant administration of propafenone and warfarin may lead to an enhanced anticoagulant effect that may require a reduction in the warfarin dose.

High-pressure liquid chromatographic analysis of drugs in biological fluids. V. Analysis of acebutolol and its major metabolite.

A high-pressure liquid chromatographic analysis for acebutolol and its major metabolite in blood, plasma and urine is reported. The analysis, in which the above mentioned compounds are chromatographed as ion pairs with dodecyl sulfonic acid, uses a simple and rapid method of sample preparation. The technique is more sensitive and rapid than those previously reported and it has equivalent or better reproducibility. The method is applied to the measurement in blood of acebutolol and its acetyl metabolite after a single oral dose.

Binding of antiarrhythmic drugs to purified human α1-acid glycoprotein☆

Abstract The binding of lidocaine, verapamil, propafenone and propranolol to isolated, purified human α 1 -acid glycoprotein was studied using equilibrium dialysis. Lidocaine and verapamil bound to a single class of binding sites which was characterized by high affinity ( k d 1 for lidocaine was 5.79 × 10 −6 M −1 and for verapamil 3.43 × 10 −6 M −1 ) and low capacity (n = 0.40 for lidocaine and 0.62 for verapamil). The binding of propafenone revealed two classes of binding sites, both with high affinity ( k d 1 was 7.62 × 10 −6 M −1 and kd 2 was 6.00 × 10 −8 M −1 ) and low capacity (n 1 = 0.79 and n 2 = 0.20). Propranolol bound to at least two classes of binding sites ( k d 1 was 2.56 × 10 −6 M −1 ; n 1 = 0.58). Complete characterization of the binding parameters of the second site was not possible due to failure to achieve saturation.

Influence of congestive heart failure on prazosin kinetics.

The kinetics of oral prazosin was studied in 10 healthy normal subjects (NS) and in 9 patients with congestive heart failure (CHF). NS received a single 5‐mg dose, and blood concentrations of prazosin (CB) were measured, using a specific HPLC assay, during an 8‐hr period. CHF patients received a 2‐mg dose after which CB was measured for 10 hr. These patients then received 2 to 5 mg prazosin every 8 hr for 48 hr. After the last dose of prazosin, CB was measured for 24 hr. After the initial dose, time to peak CB did not differ significantly between that of the NS (123 ± 19 SEM min) and of patients with CHF (132 ± 31.3 min). AUC/mg prazosin was greater (p < 0.001) in patients with CHF (3,385 ± 380 ng < min/ml) than in NS (1,603 ± 208 ng × min/ml). Elimination of prazosin from blood was slower in CHF patients (t½ = 374 ± 33.4 min) than in NS (t½ = 144.5 ± 4.3 min) (p < 0.001). These data suggest that in patients with CHF the elimination of prazosin is substantially slower than in NS and therefore higher steady‐state prazosin concentrations can be expected in CHF patients than in NS.

Dose-dependent acebutolol disposition after oral administration

The relationship between dose and area under the blood concentration‐time curve has been studied in 6 healthy subjects following both oral and intravenous doses of acebutolol. There is a more than proportional increase in area with increasing oral doses, and the area over a dosing interval following multiple oral doses is greater than the total area after a single dose of the same size. The role of an acetyl metabolite in producing these effects is discussed, as is the relevance of these observations to the clinical use of acebutolol.

Prazosin First-Pass Metabolism and Hepatic Extraction in the Dog

The short half-life, low plasma concentrations, and extensive bio-transformation of prazosin suggest that it might be subject to extensive first-pass metabolism. Bioavailability, disposition, and hepatic extraction were studied in the dog. In conscious dogs whole blood prazosin concentrations were measured after oral and intravenous administration of the drug. Anesthetized dogs were used to measure prazosin concentrations in arterial and hepatic venous blood samples drawn simultaneously. The bioavailability of prazosin was 0.38

Effect of albumin on the electrophysiologic stability of isolated perfused rabbit hearts.

pM 0.11. In anesthetized dogs the hepatic extraction of prazosin was 0.47

Influence of hepatic dysfunction on the pharmacokinetics of propafenone.

pM 0.08 for a predicted availability of 0.53