Comparative effects of oxygen supplementation on theophylline and acetaminophen clearance in human cirrhosis.

BACKGROUND & AIMS: Sinusoidal capillarization in cirrhosis may impair the transfer of oxygen into hepatocytes; this may contribute to impaired oxidative drug metabolism. The aim of this study was to test this hypothesis by comparing the effects of oxygen supplementation in cirrhotic patients on the clearance of theophylline, which is dependent on hepatic oxidative metabolism, with its effect on the clearance of acetaminophen, which is reliant on hepatic conjugation reactions. METHODS: Ten cirrhotic patients awaiting liver transplant and 5 control subjects were studied. Oral acetaminophen (1000 mg) and intravenous theophylline (3 mg/kg) were administered simultaneously on two separate occasions, 7 days apart. Subjects were randomized to breathe either room air or oxygen via face mask at 12 L/min for 9 hours of blood sampling. RESULTS: Theophylline and acetaminophen clearances were significantly reduced by a mean of 54% and 50%, respectively, in cirrhotic patients compared with controls. Oxygen supplementation improved plasma theophylline clearance in cirrhotic patients by a mean of 34% (P = 0. 001), whereas acetaminophen clearance remained unchanged. CONCLUSIONS: These findings indicate that, in cirrhosis, impaired hepatocyte oxygenation contributes to reduced oxidative drug metabolism and that oxidative drug metabolism can be improved by oxygen supplementation.

Perindopril chronically inhibits angiotensin-converting enzyme in both the endothelium and adventitia of the internal mammary artery in patients with ischemic heart disease.

BACKGROUND: ACE inhibitors are widely used in treating hypertension and heart failure, but the sites and mechanisms of ACE inhibition in human blood vessels are not understood. The present study was undertaken to assess the sites and extent of in vivo inhibition of ACE by long-term perindopril treatment in different layers of the internal mammary artery in patients with ischemic heart disease. METHODS AND RESULTS: Sixteen patients with ischemic heart disease were treated either with perindopril (4 mg/d PO) for up to 36 days before surgery (n = 9) or without the inhibitor as control subjects (n = 7). The segments of the internal mammary artery were collected for measurement of vascular free and total ACE by quantitative in vitro autoradiography with 125I-351A binding. The patients treated with perindopril had lower plasma ACE (P < .001) and plasma angiotensin (Ang) II-to-Ang I ratio (P < .05). In the internal mammary artery, free ACE was similarly inhibited by perindopril in the endothelium (P < .05) and adventitia (P < .05), and the free ACE-to-total ACE ratio, an index of ACE inhibition, was markedly decreased by perindopril in parallel in the endothelium (P < .001) and adventitia (P < .001). Moreover, plasma ACE correlated highly with vascular ACE in the endothelium (r = .85, P < .001) or adventitia (r = .78, P < .001), and mean arterial pressure correlated significantly with free ACE in the endothelium (r = .52, P < .05) or adventitia (r = .53, P < .05) and with the plasma Ang II-to-Ang I ratio (r = .53, P < .05). Light microscopic autoradiographs of 125I-351A binding revealed a marked inhibition of ACE by perindopril in both layers of the vascular wall. CONCLUSIONS: The present demonstrates that long-term administration of perindopril potently inhibits both endothelial and adventitial ACE to a comparable degree in the human internal mammary artery. These results indicate that perindopril effectively penetrates the vascular wall to inhibit ACE in the adventitia, thus providing evidence that perindopril may be beneficial in inhibiting both circulating Ang II and its local formation in the vascular wall.

Comparative pharmacokinetics of enalapril and lisinopril, alone and with hydralazine.

A single-dose, single-blind, crossover study of vasodilator/angiotensin-converting enzyme (ACE) inhibitor interactions was carried out in 16 volunteers. Enalapril 20 mg and lisinopril 20 mg were administered either alone or in combination with hydralazine 25 mg. Co-administration of hydralazine significantly increased the area under the plasma concentration time curve (AUC) of lisinopril (AUC0-48 h 766.8 +/- 66.3 ng.h/ml (lisinopril) vs 1022.3 +/- 115.3 ng.h/ml (lisinopril + hydralazine)). This did not occur with enalaprilat (AUC 710.1 +/- 51.2 ng.h/ml (enalapril) vs 681.9 +/- 44.9 ng.h/ml (enalapril + hydralazine); mean +/- SEM). Urinary recovery of lisinopril showed a similar trend, but group differences did not achieve statistical significance despite comparable confidence intervals. Although hydralazine had no effect on the bioavailability of enalapril, significantly increased bioavailability was observed with lisinopril. This type of drug interaction is rare. The underlying mechanism is unclear, but may relate to increased absorption of lisinopril.

Absorption and elimination of bismuth from oral doses of tripotassium dicitrato bismuthate.

The pharmacokinetics of bismuth subcitrate were studied in plasma and urine under conditions of single and multiple dosing (28-56 days) using atomic absorption technique. Single dose plasma pharmacokinetics showed peak concentrations of 5.5-57.5 micrograms.l-1 (mean = 24.7 micrograms.l-1), reached between 30 and 60 min post dosing with an apparent biphasic elimination pattern. Multiple dose studies showed a continuing rise in plasma concentration and urine excretion rate reaching apparent steady-state levels over 7-29 days (mean = 18 days). Washout studies in 6 individuals reciprocated accumulation. Maximum equilibrated plasma levels of 7.6-58.3 micrograms.l-1 (mean = 38.3 micrograms.l-1) were well below those associated with encephalopathy. The half-life of bismuth elimination was 20.7 days. Present patterns of intermittent dosing with bismuth are unlikely to be associated with bismuth accumulation despite slow accumulation and elimination.

Improved assay for bismuth in biological samples by atomic absorption spectrophotometry with hydride generation.

This simple, rapid, sensitive, reliable, and economical assay for bismuth in plasma, erythrocytes, and urine is based on atomic absorption spectrophotometry with hydride generation. Acid digestion eliminates the problem of foaming, which hitherto has complicated such assay of bismuth in plasma and erythrocytes. The detection limit of the assay has been improved to 0.1 micrograms/L, as compared with a previously documented limit of 2.5 micrograms/L. Average recovery exceeded 95% in all biological fluids. Economy of use derives from elimination of need for electrodeless discharge lamps and atomic absorption grade borohydride. Determination of basal concentrations of bismuth in clinical samples of body fluids gave reference intervals of 0.1-3.5 micrograms/L for plasma, 0.3-4.6 micrograms/L for urine.