Pharmacokinetics and pharmacodynamics of irbesartan in patients with hepatic cirrhosis.

The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single- and multiple-dose (7 consecutive days) administration to normotensive subjects in an open-label, multiple-dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half-life (t1/2), area under the plasma concentration-time curve (AUC), apparent oral clearance (Cl(t)/F), renal clearance (Cl(r)), and accumulation index (AI). Steady-state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild-to-moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

The effect of nefazodone on the single-dose pharmacokinetics of phenytoin in healthy male subjects.

The effect of nefazodone on the pharmacokinetics of a single dose of phenytoin was evaluated in 18 healthy male subjects. The subjects received a single oral dose of phenytoin, 300 mg, on day 1 of the study and the pharmacokinetic profile of the drug was determined. After a washout period followed by oral administration of nefazodone, 200 mg twice daily for 7 days, subjects received a single dose of phenytoin, 300 mg concomitantly with the morning dose of nefazodone on day 12, and the pharmacokinetic profile of phenytoin was determined again. Minimum plasma concentrations of nefazodone and its main metabolites indicated that steady state had been achieved for nefazodone when phenytoin and nefazodone were administered concomitantly. No significant differences were demonstrated between mean single-dose pharmacokinetic parameters of phenytoin when administered alone on day 1 and concomitantly with nefazodone on day 12. Assessment of adverse events, clinical laboratory parameters, electrocardiograms, vital signs, and physical examinations indicated that concomitant administration of nefazodone and phenytoin was safe and well tolerated. These data demonstrate that nefazodone does not affect the single-dose pharmacokinetics of phenytoin, but do not preclude the possibility of such an interaction when phenytoin is administered on a long-term basis. A clinically significant interaction between nefazodone and phenytoin through a pharmacokinetic mechanism is unlikely.

Systemic hemodynamics, renal function and hormonal levels during inhibition of neutral endopeptidase 3.4.24.11 and angiotensin-converting enzyme in conscious dogs with pacing-induced heart failure.

The systemic hemodynamic, renal and hormonal responses to SQ 28,603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-beta-alanine) the selective inhibitor of neutral endopeptidase 3.4.24.11, the angiotensin-converting enzyme inhibitor captopril and their combination were determined in conscious dogs after 1 or 3 weeks of rapid ventricular pacing. Coadministration of captopril (100 or 10 mumol/kg i.v.) and SQ 28,603 (10 mumol/kg i.v.) significantly reduced mean arterial pressure, systemic vascular resistance and renal vascular resistance and increased cardiac output, stroke volume and renal blood flow in the conscious dogs paced for 1 week. This pattern of hemodynamic improvement was not predicted by the activity of the individual inhibitors. The combination of inhibitors did not significantly increase sodium excretion because of the variability introduced by the depressor activity; however, the pressure-natriuresis curve was steeper and shifted leftward, indicating that sodium excretion was maintained at lower renal perfusion pressures. The increases in urinary and plasma levels of cyclic GMP and atrial natriuretic peptide stimulated by SQ 28,603 were not affected by captopril. The data indicated that the hemodynamic and renal responses produced by SQ 28,603, presumably by elevating atrial natriuretic peptide levels, were enhanced by suppression of angiotensin II or that the combination of inhibitors protected other vasodilator/natriuretic peptides from degradation. Qualitatively similar responses to SQ 28,603, captopril and the combination of inhibitors were obtained in dogs paced for 3 weeks. In summary, the combined angiotensin-converting enzyme and neutral endopeptidase 3.4.24.11 inhibitors improved systemic hemodynamics and maintained renal function in conscious dogs with pacing-induced heart failure.