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.

Furosemide disposition in cirrhotic patients.

Furosemide disposition in 7 cirrhotic subjects and 4 age-matched healthy controls was studied to determine the contribution of differences in pharmacokinetics to the decreased responsiveness observed in cirrhotics. Subjects were given 80 mg of furosemide orally and intravenously on separate occasions, and plasma and urine samples were collected and analyzed for furosemide by high performance liquid chromatography. The half-life of furosemide was 74% greater in the cirrhotic subjects, the result of a smaller increase in volume of distribution (30%) and a decrease in total plasma clearance (15%). The change in plasma clearance was due entirely to a change in nonrenal clearance, since renal clearance was very similar in both groups. The fraction of furosemide not bound to plasma proteins increased by 48%. Furosemide bioavailability was the same in cirrhotic subjects and controls. Consistent with other reports, there was considerable intersubject variability in all of the measured and computed parameters. The results show that differences in disposition play little, if any, role in the decreased renal responsiveness to furosemide.

The stereoselective disposition of disopyramide in the dog.

The disposition of d-, 1-, and d,1-disopyramide was studied in 5 conscious dogs after intravenous administration (15 mg/kg) of each compound using a balanced crossover design. The clearance of d-disopyramide (15.4 +/- 5.10 ml/min/kg) was significantly greater than that of the l-isomer (9.45 +/- 2.52 ml/min/kg) (p < 0.001). The clearance of the d,1-mixture was intermediate between that obtained for the d- and l-isomers. The steady-state volume of distribution of the three compounds was similar (approximately 1.4 liters/kg). The elimination half-life reflected differences in clearance, being 76.4 +/- 7.30 min for d-disopyramide, 112 +/- 23.4 min for 1-disopyramide, and 97.2 +/- 15.1 min for d,1-disopyramide. The effect of general anesthesia with urethane and chloralose on the disposition of the compounds was also examined. General anesthesia decreased the clearance and increased the half-life of all three compounds. No consistent differences in the volume of distribution were observed with anesthesia as compared to control. Thus, there is stereoselective elimination of the optical isomers of disopyramide in the dog, and general anesthesia decreases the clearance of d-, 1-, and d,1-disopyramide.

Effects of clofibrate and warfarin alone and in combination on the disposition of vitamin K1.

Clofibrate may interact with warfarin by potentiating its effects on vitamin K disposition. To examine this possibility, specifically labeled [3H]vitamin K was given intravenously to four healthy volunteers under conditions of no drug administration, administration of warfarin or clofibrate alone, or co-administration of both drugs. Clofibrate alone did not affect the disposition of tritiated vitamin K. Warfarin alone produced an accumulation in plasma of substantial amounts of vitamin K epoxide, a metabolite of vitamin K which is reconverted to vitamin K by a specific reductase. Although reconversion is apparently blocked to a large extent by warfarin, the plasma disappearance of tritiated vitamin K in the presence of warfarin is almost superimpossible to that observed in the absence of drugs. Clofibrate coadministration did not result in greater accumulation of vitamin K epoxide in plasma. These results indicate that clofibrate does not enhance the inhibition of the reductase enzyme. Analysis of the tritiated vitamin K plasma disappearance data indicates that the pool size of vitamin K in the body is small, and is turned over almost 10 times daily. The vitamin K epoxide data suggest that, in the absence of drugs, a relatively small proportion of the epoxide is reconverted to the vitamin.

Quantitation of radio-labelled vitamin K1 and vitamin K1 epoxide in plasma by high pressure liquid chromatography.

A convenient, accurate and reproducible high pressure liquid chromatographic method for the quantitation of radio-labelled vitamin K1 and vitamin K1 epoxide in plasma is described. The method involves the determination of total ether extractable radioactivity, and a chromatographic separation to determin the relative quantities of radio-labelled vitamin K1 and vitamin K1 epoxide. The method is useful over a wide range of ratios of the two compounds, and has a coeffcient of variation of approximately 5%.

The consequences of habitual knuckle cracking.

Habitual knuckle cracking in children has been considered a cause of arthritis. A survey of a geriatric patient population with a history of knuckle cracking failed to show a correlation between knuckle cracking and degenerative changes of the metacarpal phalangeal joints.