We studied the influence of posterior pituitary extract, vasopressin, and somatostatin on hepatic elimination function. Hepatic clearance and its two biological determinants, hepatic blood flow and metabolic activity (clearance Vmax/Km), were determined from hepatic indocyanine green elimination at steady-state in cirrhotic patients. Intravenous infusion of posterior pituitary extract (oxytocin, 59%; vasopressin, 41%) at the constant rate of 0.3 unit per kg per hr decreased hepatic clearance (p less than 0.05) and Vmax/Km (p less than 0.05) but did not change hepatic blood flow. Intravenous infusion of vasopressin (0.3 unit per kg per hr) decreased hepatic clearance (p less than 0.05), Vmax/Km (p less than 0.05) and hepatic blood flow (p less than 0.05). Intravenous infusion of somatostatin (250 micrograms per hr following a bolus i.v. injection of 250 micrograms) decreased hepatic clearance (p less than 0.05), Vmax/Km (p less than 0.05), and hepatic blood flow (p less than 0.05). This study shows that the vasoactive agents used in the management of upper digestive bleeding in cirrhotic patients may have deleterious effects on the metabolic activity of the liver in addition to their effects on hemodynamics. The results suggest that the vasoactive substances either increased the fraction of total hepatic blood which bypassed intact hepatocytes or directly impaired metabolic activity of hepatocytes. Reduction in the metabolic activity of the liver produced by vasoactive agents may have important implications in therapy of portal hypertension.

Female↗

PubMedDate not supplied

Pharmacokinetics of hydroxy-3(S)-dihydroquinidine in healthy volunteers after intravenous and oral administration.

The pharmacokinetics of hydroxy-3(S)-dihydroquinidine (HDHQ) were studied in 6 healthy volunteers following a 15 min intravenous infusion of a 300 or 400 mg dose, a 300 mg oral dose in solution and a 300 mg tablet administration on three separate occasions (random order) with at least one week intervals. Using a specific HPLC assay for HDHQ, the post-infusion and post-absorption plasma HDHQ concentrations declined bi-exponentially. Both oral forms of HDHQ were absorbed rapidly (tmax 1 h-1.2 h) with an absolute bioavailability of the oral solution (F = 0.54 to 0.93) which was not significantly different from that of the tablet (F = 0.66 to 0.90). HDHQ was rapidly and extensively distributed to the tissues with a high steady-state volume of distribution (6.82 +/- 1.85 l X kg-1). Mean elimination half-life was 6.7 +/- 1.4 h after IV infusion, 8.4 +/- 1.7 h after the oral solution and 11.3 +/- 4.4 h after the tablet administration. HDHQ was partially eliminated from the body in the unchanged non-conjugated form by the urine and renal clearance represented approximately 50% of the total body clearance. These results show that HDHQ is rapidly and almost completely absorbed and has potential for a twice daily administration regimen for the treatment of cardiac arrhythmias.

Administration, Oral↗

PubMedDate not supplied

Amiodarone pharmacokinetics in coronary patients: differences between acute and one-month chronic dosing.

The pharmacokinetics of amiodarone (A) and its desethylamiodarone metabolite (DEA) were compared in the same coronary patients after a first 1000 mg dose and one-month chronic oral dosing. Terminal half-life (t1/2 el) of amiodarone increased from a mean (SD) 24.1 +/- 19.5 h after the first dose to 20.4 +/- 4.8 days after the last dose. Desethylamiodarone slowly appeared in the plasma after the first oral dose and its apparent t el was 61.6 +/- 26.6 h. After one-month dosing apparent t1/2 el of desethylamiodarone increased to 29.5 +/- 9.7 days. Mean maximal plasma amiodarone/desethylamiodarone concentration ratio decreased from 9.2 +/- 5.0 to 2.0 +/- 0.6 after chronic dosing. This change was mainly related to an increase in the plasma concentration of desethylamiodarone. These data suggest that after long-term treatment with amiodarone, the complete elimination of the drug and its metabolite may need 3-4 months in some patients. The results of this study were presented in part at the meeting of the Societe Francaise de Therapeutique et de Pharmacologie Clinique, Paris, December 1985.

Administration, Oral↗

PubMedDate not supplied

A study of dromotropic effects of intracoronary arterial injections of various contrast materials in anesthetized dogs.

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Animals↗

PubMedDate not supplied

Cardiac electrophysiologic effects of quinidine and propranolol isomers in anesthetized dogs: concentration-response relationships.

Electrophysiological properties of quinidine and the two isomers of propranolol were compared in pentobarbital-anesthetized dogs using His bundle recordings and programmed stimulation in order to differentiate the effects resulting from beta-blockade from those related to nonspecific membrane-stabilizing effects. Quinidine in the plasma concentration range of 2.7-20 microM/liter resulted in concentration-dependent increases in atrionodal and His-Purkinje system conduction times and in the atrial effective refractory period. Quinidine did not produce any significant concentration-dependent change in atrioventricular (AV) nodal and ventricular refractory periods, sinus node automaticity, or QTc interval duration. Propranolol isomers in concentration range of 0.03-0.85 microM/liter produced a concentration-dependent increase in atrionodal conduction time but exerted no significant effect on His-Purkinje conduction time, QTc duration, or ventricular refractory period. Both isomers increased the atrial effective refractory period, but with slopes of concentration-response regression lines which were significantly different from those of quinidine. Only l-propranolol produced concentration-dependent increases in AV nodal refractory period, Wenckebach cycle length, and sinus node recovery time. These results suggest that the electrophysiological effects of propranolol isomers are related to beta-blockade and are significantly different from those resulting from the membrane-stabilizing effect of quinidine.

Anesthesia↗