摘要:

Marked species differences in xenobiotics metabolism in the liver seriously limit extrapolations from animals to man. Because access to human liver is limited and periodic, we have set up a human “liver bank” available for metabolic studies. The liver tissue is obtained shortly after circulatory arrest from cadaveric (cerebral infarction) kidney transplant donors. Postmortem changes are minimal. Subcellular liver fractions are prepared immediately and part of this is used directly for assay. Intact pieces and subcellular fractions are stored in different media at −80°. Each liver is characterized by light and electron microscopy. Several enzymes, including cytochromes P‐450 and b5, NADPH‐cytochrome c reductase, demethylation of aminopyrine and amitriptyline, epoxidation of carbamazepine, oxidation of acetaminophen, and benzo[a]pyrene, were tested with freshly prepared fractions so that each liver got a “drug metabolic profile.” This “test battery” was repeated after storing to evaluate the effect of storage. Our preparation technique gave a well‐preserved microsomal fraction with minimal contamination. In freshly prepared microsomes the following activities (levels) were observed: cytochrome P‐450, 0.13 to 0.73 nmole/mg protein; NADPH‐cytochrome c reductase, 70 to 426 nmole/mg protein; demethylation of aminopyrine, 0.9 to 4.1, and of amitriptyline, 0.11 to 0.92 nmole/mg protein; carbamazepine‐10,11 epoxidation, 0.03 to 0.46 nmole/mg protein; oxidation of acetaminophen, 0.48 to 2.11, and of benzo[a]pyrene, 0.04 to 0.11 nmole/mg protein · min. These values are generally higher than in the literature. Our storage conditions were efficient: most of the activities were well preserved during storage for at least 6 mo. When pairs of enzyme activities (levels) were plotted against each other with fresh tissue there was good correlation between some but not all activities.Clinical Pharmacology and Therapeutics(1980)27, 711–

ISSN:0009-9236    

DOI:10.1038/clpt.1980.102

年代:1980

数据来源: WILEY

摘要:

Seven healthy subjects were given oral propranolol (1 mg/kg) alone or in combination with hydralazine 25, 50, or 100 mg on separate occasions. Hydralazine induced variable increases in the peak concentrations (p<0.05) and in the area under the propranolol concentration: time curves (p<0.02) without change in the recovery of14C‐propranolol/metabolites in urine or in the systemic clearance of propranolol; i.e., oral hydralazine enhanced the systemic availability of propranolol by alteration of “first‐pass” (hepatic) clearance. The results indicate the possibility of change in presystemic clearance without reciprocal change in systemic clearance and also suggest that propranolol or any other high‐clearance drug should be administered in fixed relationship to hydralazine and other drugs capable of altering “first‐pass” hepatic extraction (either due to alteration in splanchnic blood flow or competitive inhibition of metabolism) if large variations in plasma concentrations are to be avoided.Clinical Pharmacology and Therapeutics(1980)27, 726–732; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.103

年代:1980

数据来源: WILEY

摘要:

Oxprenolol is an experimental beta adrenergic blocker with intrinsic sympathomimetic activity. To compare the effects of long‐term administration of oxprenolol on hypertension and hemodynamics with the effects of propranolol, 20 patients with essential hypertension were divided in a double‐blind random manner into two 10‐patient groups and given placebo for 2 wk, followed by equipotent doses of oxprenolol or propranolol for 5 wk and by placebo for another 2 wk. Right heart cardiac catheterization was performed at the beginning and at the end of the 5‐wk beta blockade. Heart rates and blood pressures fell markedly with both agents, although standing heart rate was lowered more by propranolol than by oxprenolol. Plasma renin activity was much lower after beta blockade with either drug. There was no correlation between decreases in blood pressure and renin activity. Although during the stress of repeat cardiac catheterization heart rates remained significantly lower than control, the intra‐arterial pressures were not altered significantly by oxprenolol or propranolol, nor was there significant change in pulmonary pressure, vascular resistance, or cardiac output. Thus oxprenolol closely parallels the effects of propranolol in essential hypertension. The negative chronotropic action of both drugs is more marked than their antihypertensive activity.Clinical Pharmacology and Therapeutics(1980)27, 733–743; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1980.104

年代:1980

数据来源: WILEY

摘要:

The relationship between plasma levels of 4 propranolol metabolites—naphthoxylactic acid (NLA), 4‐hydroxypropranolol (4‐OH), naphthoxy acetic acid (NAA), and propranolol glycol (PG)—and propranolol plasma levels was determined in healthy, adult male subjects after increasing single oral doses of propranolol. NLA was present at plasma levels 6 to 25 times that of propranolol. More than 90% of circulating NLA was in the plasma fraction, where it was 95% protein bound. The ratio of plasma concentrations of the pharmacologically active metabolite 4‐OH to propranolol approached unity 0.5 hr after propranolol, 160 mg or 320 mg orally, but fell rapidly. Plasma levels of NAA were in the same range as propranolol, especially as time progressed. PG circulated at plasma levels less than 12% of propranolol. As oral doses of propranolol were increased from 20 to 320 mg, there was a decrease in intrinsic plasma clearance (Cli) from 425 to 200 l/hr. Half‐life rose from 3 to 5 hr. Urinary recovery of 4‐OH fell as Clirose. Urinary recovery of propranolol conjugates, NLA, andN‐desisopropylpropranolol (NDIPP) rose as Clifell. Our results suggest that naphthalene ring oxidation of propranolol represents a high‐affinity low‐capacity enzymatic pathway(s) that plays an important role in the extensive hepatic extraction of propranolol after small doses orally. Plasma NLA and plasma NAA were determined before and after hemodialysis in 14 uremic patients receiving long‐term propranolol therapy. Mean plasma NLA was 4,372 ng/ml, and mean plasma NAA level was 238 ng/ml when mean plasma propranolol level was 15 ng/ml.Clinical Pharmacology and Therapeutics(1980)27, 744–755; d

ISSN:0009-9236    

DOI:10.1038/clpt.1980.105

年代:1980

数据来源: WILEY

摘要:

The kinetics and dose‐response characteristics of metoprolol were examined in a series of hypertensive patients. In 14 the elimination half‐life of metoprolol after single 100‐mg doses (4.1 ± 0.6 hr) was prolonged (p<0.05) after 6 to 12 wk of therapy (5.6 ± 0.7 hr). In 5 patients receiving 100 mg twice daily evidence of nonlinear metoprolol kinetics emerged, because the area under the concentration‐time curve at steady state was 86.8% more (p<0.02) than predicted from a single dose. Kinetic data from single doses of metoprolol appear to be a poor predictor of steady‐state kinetics. Single metoprolol dosage also induced a fall (p<0.01) in blood pressure with pretreatment levels (163/108), reaching a minimum at 5 hr (133/89). During long‐term therapy incremental doses of metoprolol between 100 and 600 mg/day in 34 hypertensive patients resulted in a relatively horizontal dose‐response curve at doses above 200 mg/day.Clinical Pharmacology and Therapeutics(1980)27, 756–762; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.106

年代:1980

数据来源: WILEY

摘要:

To determine whether beta blockers prevent the more rapid onset of effort angina during the postprandial state, metoprolol 100 mg was given before and after an 800‐calorie meal in 12 male patients with stable angina and coronary artery disease. Three graded treadmill exercise tests were done daily on 2 days. After an overnight fast the first test on each day was done after a placebo to detect day‐to‐day variations. The second test was done 90 min after metoprolol or placebo given orally in a double‐blind randomized fashion. Immediately thereafter the patients ate their meal and did their third test 30 min later. There was no significant difference between the first test on each day. After placebo the postprandial state was associated with an earlier onset of effort angina (310 and 370 sec, p<0.01) and with greater heart rate and systolic blood pressure rises for any work load. After metoprolol, however, there was no significant difference between the pre‐ and postprandial findings. During the postprandial state metoprolol delayed the onset of angina more than placebo (385 and 310 sec) and positive electrocardiogram (310 and 228 sec) and induced lowering of maximal heart rate (120 and 144 bpm) and systolic blood pressure (157 and 187 mm Hg) (p<0.01). Metoprolol slowed the rapid onset of effort agina during the postprandial state.Clinical Pharmacology and Therapeutics(1980)27, 763–768; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1980.107

年代:1980

数据来源: WILEY

摘要:

Beta adrenoceptor–mediated responsiveness to isoproterenol was compared in young and old subjects using the production of cyclic adenosine monophosphate (cyclic AMP) by lymphocytes as an index. The mean log dose‐response curve for the elderly group was displaced to the right and the mean maximum response was less than that for the young subjects. The results corroborate evidence of a decreased response to isoproterenol‐induced increases in heart rate in the elderly and raise the possibility of a generalized decrease in beta adrenoceptor–mediated functions in old age.Clinical Pharmacology and Therapeutics(1980)27, 769–772; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1980.108

年代:1980

数据来源: WILEY

摘要:

Oxdralazine, a pyridazine shown to induce prolonged arteriolar dilation in animals, was given orally in doses of 15 to 30 mg to 7 subjects with hypertension. Arterial pressure fell in 2 hr (average mean of 16 mm Hg), peaking in 3 to 4 hr, and was sustained for more than 6 hr. Cardiac output and heart rate rose in 2 hr (2.1l/min and 17 bpm) and were elevated at 6 hr (3.1l/min and 22 bpm). Pulmonary arterial pressure and pulmonary arteriolar resistance did not change. In 6 subjects receiving oxdralazine with hydralazine 50 to 75 mg at 1‐wk intervals, hydralazine induced earlier, less sustained decreases in arterial pressure and systemic vascular resistance and less of a rise in heart rate than oxdralazine alone. Circulating norepinephrine levels (radioenzymatic method) 3 hr after oxdralazine rose from a mean of 159 to 294 pg/ml, a greater (p<0.05) effect than after hydralazine. At the doses tested, oxdralazine is a potent systemic arteriolar dilator with longer‐sustained action and more prominent reflex sympathetic stimulation than hydralazine.Clinical Pharmacology and Therapeutics(1980)27, 773–778; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1980.109

年代:1980

数据来源: WILEY

摘要:

Single and repeated doses of prazosin were given to 17 hypertensive patients, 5 with normal renal function and 12 with impaired renal function. Blood for prazosin assay was drawn after a 1‐mg single dose and after patients reached steady‐state levels with their long‐term maintenance dose. As blood was drawn blood pressure was recorded. Prazosin absorption was not altered in patients with impaired renal function, and there is no cumulation of the drug when given repeatedly to patients with impaired renal function. Elimination kinetics were virtually identical regardless of degree of renal function. Effect on blood pressure was significantly better at the dosage range of 3 to 8 mg/day than at higher doses of 9 to 20 mg/day. There does not appear to be a direct relationship between the peak plasma prazosin level and the nadir of antihypertensive response. This would seem to indicate that the drug leaves the plasma and goes to the vascular smooth muscle receptor site of action. There appears to be no impairment in prazosin elimination in patients with impaired renal function, and its effectiveness (with diuretic or dialysis) is optimum at 3 to 8 mg/day.Clinical Pharmacology and Therapeutics(1980)27, 779–783; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1980.110

年代:1980

数据来源: WILEY

摘要:

Continuous intravenous infusion of furosemide (8 mg/hr) to 6 healthy subjects induced an average diuresis at steady state of 667 ± 144 ml/30 min (±SD) with a mean plasma concentration of furosemide of 623 ± 209 ng/ml. The urinary output of Cl−was 50.4 ± 7.5, of Na+47.7 ± 8.7, and of K+5.4 ± 0.6 mmole/30 min. Intravenous injection of probenecid (1 gm) raised the plasma furosemide level to a maximum of 1,584 ± 151 ng/ml. Despite this, the urinary excretion of water, Cl−, Na+, and K+decreased to 52%, 39%, 39%, and 52%, respectively, of control values. Probenecid greatly reduced the urinary excretion and renal clearance of furosemide. There was no or negative correlation between the plasma levels of furosemide and its diuretic and saluretic effects. The urinary excretion and renal clearance of the diuretic correlated positively with these effects. No effect of probenecid on protein binding of furosemide was detected. The findings show that the diuretic effects of furosemide depend on active tubular secretion of the drug and thus on its tubular fluid concentration.Clinical Pharmacology and Therapeutics(1980)27, 784–790; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1980.111

年代:1980

数据来源: WILEY