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Eight healthy volunteers received a single 500 mg intravenous dose of procainamide hydrochloride by 30-min infusion on three occasions in random sequence. The three modes of administration were (a) control, without concurrent drugs; (b) during coadministration of propranolol, 80 mg three times daily; and (c) during coadministration of metoprolol, 100 mg two times daily. Procainamide kinetics were determined from multiple serum concentrations measured by enzyme-multiplied immunoassay (EMIT) during 10 h after each dose. A metaproterenol infusion study verified a high degree of beta-blockade during trials 2 and 3. Mean procainamide half-life during the three trials (1.9, 2.2, and 2.3 h, respectively) tended to show prolongation during beta-blocker treatment, but the overall difference was of borderline significance (0.05 less than p less than 0.1). Total procainamide clearance (16.2, 14.1, and 13.7 ml/min/kg) did not differ significantly between the three trials, nor was there a significant change in area under the serum concentration curve for N-acetylprocainamide, the major metabolite. Thus the kinetics of procainamide in healthy persons are not importantly altered by typical therapeutic doses of two beta-adrenergic blockers.

Acetaminophen is a widely prescribed analgesic/antipyretic metabolized by hepatic glucuronide and sulfate conjugation. Twelve patients, 30-66 years of age, with stable Class III or IV congestive heart failure (CHF) and 12 healthy controls matched for age, sex, and weight received single 650-mg intravenous doses of acetaminophen. Pharmacokinetic variables were determined from multiple plasma acetaminophen concentrations measured by liquid chromatography during 12 h after the dose. Compared with controls, mean total clearance of acetaminophen was reduced in CHF patients (3.56 vs. 4.59 ml/min/kg, p less than 0.025), indicating reduced biotransformation capacity in this disease. Volume of distribution was also significantly reduced in CHF patients (0.85 vs. 1.02 L/kg, p less than 0.05). Since elimination half-life depends on both volume of distribution and clearance (both of which were reduced), the half-life was similar between groups (2.87 vs. 2.34 h, NS). Thus, hepatic conjugation of acetaminophen is impaired in CHF. The finding may also apply to other drugs biotransformed by conjugation.

The influence of the serotonin antagonist ketanserin on the kinetics of digoxin and digitoxin were evaluated in healthy volunteers. Subjects received a single intravenous dose of digoxin (1.25 mg) or of digitoxin (1.0 mg) on two occasions: once in the control state, and again during treatment with ketanserin, 40 mg twice daily. Ketanserin caused a prolongation of digoxin elimination half-life (50 versus 40 h) and reduction in clearance (2.4 versus 3.7 ml/min/kg), but differences were not significant. For digitoxin, ketanserin caused a small but significant (p less than 0.005) increase in volume of distribution (0.89 versus 0.78 L/kg), but no significant effect on half-life (7.0 versus 6.8 days), or clearance (0.063 versus 0.059 ml/min/kg). Thus, ketanserin coadministration is not likely to alter steady-state concentrations of digoxin or digitoxin during clinical use of these two digitalis glycosides.