Biomedical subjects

H L Fung

Publications and source records attributed to H L Fung.

At least 109 records · Page 6Linked to original sources

PubMed1987

Pharmacokinetics and pharmacodynamics of organic nitrates.

The pharmacokinetic and pharmacodynamic aspects of organic nitrates are discussed, with particular emphasis on the 3 major organic nitrates currently in use, nitroglycerin (NTG), isosorbide dinitrate and isosorbide-5-mononitrate. After intravenous administration, both NTG and isosorbide dinitrate exhibit large systemic clearances and both nitrates appear to be extensively distributed in vascular and other peripheral tissues. Two pharmacokinetic features appear particularly notable for NTG: there is a significant arteriovenous extraction of the drug, and its systemic clearance is related to cardiac output. Both of these features, plus other evidence, suggest that organic nitrates may be substantially removed from the systemic circulation by the vasculature itself. During nitrate tolerance, plasma drug concentrations remain elevated, but vascular activity is diminished. This apparent paradox might be explainable by a unifying hypothesis of reduced nitrate metabolism during vascular tolerance; thus, in the tolerant state, reduced systemic clearance of the intact drug brought about elevated plasma concentrations, whereas reduced cellular metabolism at the smooth muscle brought about a decrease in vascular activity. The complex relations among plasma kinetics, vascular metabolism and pharmacologic action of organic nitrates are still poorly understood.

Animals↗

PubMed1987

Haemodynamic effects of combined oral nifedipine and sublingual nitroglycerin in patients with chronic stable angina.

We examined the pharmacokinetics of nifedipine after acute and sustained oral therapy and the potential haemodynamic interaction between nifedipine and sublingual nitroglycerin in nine patients with chronic stable angina. Nifedipine pharmacokinetics after a single oral dose and sustained dosing (three times daily for five days) were not significantly different. Single dose nifedipine produced a statistically significant decrease in standing and supine systolic and diastolic blood pressures when compared to placebo. A significant decrease in the supine systolic pressure was observed after sustained nifedipine therapy. Except for this change, other hypotensive effects of nifedipine after sustained therapy were not different to those of placebo, in spite of persistent plasma nifedipine concentrations after repeated dosing. There were no observable correlations between nifedipine haemodynamics and pharmacokinetics in these patients, nor were there any significant haemodynamic interactions between sublingual nitroglycerin with either acute or sustained nifedipine treatment. The transient haemodynamic effects of sublingual nitroglycerin were not potentiated by either acute or sustained nifedipine therapy.

Administration, Oral↗

PubMed1987

Hemodynamic evaluation of isosorbide dinitrate in alcoholic cirrhosis. Pharmacokinetic-hemodynamic interactions.

Isosorbide dinitrate, a long-acting organic nitrate, has been shown to decrease portal pressure in the experimental animal and humans. We conducted a double-blind randomized hemodynamic evaluation of the effects of placebo and 10 mg and 20 mg isosorbide dinitrate in stable individuals with alcoholic cirrhosis. Baseline values for all three groups were similar. Isosorbide dinitrate resulted in a peak reduction of the hepatic venous gradient of 24.7% +/- 3.0%, with significantly decreased values 4 h after the administration of the 20-mg dose. A reduction of arterial pressure and cardiac index (peak decrease of 25.7% +/- 1.5%) was well tolerated by 13 of 15 patients. Changes in mean arterial pressure were not predictive of modifications in the hepatic vein wedge pressure. There was no relation between the area under the plasma isosorbide dinitrate concentration curve and hemodynamic changes. Levels of isosorbide-5-mononitrate, a vasoactive metabolite, were detectable for an 8-h period. Isosorbide dinitrate significantly reduced portal pressure in stable cirrhotics, in association with systemic hemodynamic changes. Thus, titration of isosorbide dinitrate is required to maximize hemodynamic benefits in individual patients. As the decrease in portal pressure is more predictable than the effect of previously tested pharmacologic agents, isosorbide dinitrate should be evaluated for its efficacy in the management of portal hypertension.

Blood Pressure↗

PubMed1986

Pharmacokinetics of pentaerythritol tetranitrate following intra-arterial and oral dosing in the rat.

The pharmacokinetics of pentaerythritol tetranitrate (2,2-bis(hydroxymethyl)-1,3-propanediol tetranitrate, 1) were studied in rats following a single intra-arterial or oral dose (2 mg/kg) of the 14C-labeled drug. Blood levels of the tetranitrate and its metabolites were determined using a thin-layer radiochromatographic procedure. The apparent systemic clearance of 1 was 0.61 +/- 0.16 L/min/kg (mean +/- SD, n = 6) which exceeded the value of normal cardiac output in rats. The steady-state volume of distribution was 4.2 +/- 1.1 L/kg (n = 6), and the elimination half-life was estimated at 5.8 +/- 0.6 min (n = 6). Blood levels of 1 were only detectable (higher than 4.0 ng/mL) in three of the six rats examined after the oral dose. The trinitrate derivative (2,2-bis(hydroxymethyl)-1,3-propanediol trinitrate, 2) the active metabolite of 1, was not detectable following oral dosing with the tetranitrate. The oral bioavailability of 1 was in the range of 0-8%. In spite of the low water solubility of 1 (i.e., 1 microgram/mL), a rather high fraction of the radioactive oral dose [25.7 +/- 10.3% (n = 4) versus 62.4 +/- 14.5% (n = 4) from the intra-arterial dose] was recovered in the urine. A significant portion of the intra-arterial dose (32.7 +/- 11.0%, n = 4) was eliminated in feces, indicating enterohepatic recycling of radioactivity. Analysis of the metabolite pattern in urine indicated extensive metabolism of 1, 2, and the dinitrate derivative 3 (2,2-bis(hydroxymethyl)-1,3-propanediol dinitrate). Less than 0.2% of the dose was recovered as unchanged drug and 2 following either route of administration.

Administration, Oral↗

PubMed1986

Cardiac output is an apparent determinant of nitroglycerin pharmacokinetics in rats.

The steady-state pharmacokinetics of nitroglycerin (NTG) were investigated in 11 rats after sequential infusions of either NTG alone (10 micrograms/kg/min) or NTG plus vasopressin (the latter at 5.5 mU/kg/min). Arterial and venous plasma concentrations of NTG in the femoral bed were obtained at 41 and 45 min during each infusion phase. Cardiac output was estimated twice in each animal using 85Sr and 141Ce microspheres. NTG systemic clearance in arterial plasma was found to be strongly correlated with cardiac output (r = 0.784, n = 22, P less than .001). Because NTG distribution between red blood cells and plasma was independent of concentration (up to 150 ng/ml in plasma) and hematocrit (25-48%), the systemic clearance of NTG in arterial blood could be estimated as about 3/4 of cardiac output. Vasopressin co-infusion decreased both the cardiac output and the arterial NTG plasma clearance, but it also increased the arteriovenous extraction of NTG. Thus, vasopressin had not net effect on the venous plasma clearance, of NTG. In animals with NTG infusions alone, cardiac output also significantly correlated with NTG venous plasma clearance (P less than .01) and arteriovenous extraction (P less than .05). These data indicate that, in the absence of vasopressin, NTG pharmacokinetics are dependent on the cardiac output, thus providing an example wherein the systemic clearance of a drug was shown to be related to systemic blood flow. These results support the concept that the vasculature acts as a clearing organ for organic nitrates, and they also provide a hemodynamic explanation for the high variability in NTG plasma concentrations observed under presumed steady-state conditions.

Animals↗

PubMed1986

Nitrosothiol and nitrate tolerance.

Our studies on Sprague-Dawley rats showed that, in aortic tissues, nitrate tolerance is accompanied by reduced production of the 1,2-glyceryl dinitrate metabolite. This reduced vascular metabolism is consistent with the view that intracellular metabolic processes occur prior to vasodilation. The individual roles of the denitrated metabolites in nitrate tolerance are still unclear. S-nitroso N-acetyl penicillamine retains its vasodilating properties toward blood vessels which have been made tolerant toward nitroglycerin. This finding is consistent with the Ignarro Nitrosothiol Hypothesis for nitrate action. Further studies are being conducted in our laboratory to determine whether nitrosothiols are indeed non-tolerance producing "nitrates" and whether they possess suitable pharmaceutical and toxicological properties for them to become therapeutic agents themselves.

Animals↗

PubMed1985

Examination of the in vitro degradation of [14C] pentaerythritol tetranitrate in rat and human blood with an improved thin-layer radiochromatographic procedure.

Improvements were made on a reported thin-layer radiochromatographic assay for the determination of [14C]pentaerythritol tetranitrate (PETN) and its metabolites in whole blood, using methanol instead of dioxane as the extracting solvent. Recovery of total radioactivity for the entire work-up procedure was greater than 90%, and the distribution of PETN and its metabolites in degraded blood samples was found to be reproducible. This modified method appeared simpler and yielded better recovery of radioactivity than the literature method. In vitro metabolism of [14C]PETN in rat and human blood was examined by incubation of the drug with fresh blood at 37 degrees C for 60 min. In rat blood, the half-life of PETN degradation was about 15 min producing the trinitrate, dinitrate and mononitrate metabolites. Human blood was also capable of degrading PETN in vitro, but at a lower rate than rat blood, yielding only the trinitrate metabolite in quantifiable amounts during the incubation period. Equilibrium of PETN between plasma and red blood cells was observed within 1 min after PETN addition to both rat and human blood. The apparent plasma/red blood cells partition ratios of PETN were 1.1 and 1.7 for rat and human blood, respectively. PETN degradation was approximately ten times slower in rat plasma than in rat blood, suggesting that enzymes in erythrocytes are important for PETN metabolism in rat whole blood.

Animals↗

PubMed1985

Effect of infusion administration set on the delivery rate and plasma concentration of nitroglycerin in dogs.

A randomized crossover study with eight dogs was carried out to determine whether the in vitro difference observed in the delivery of nitroglycerin using polyvinyl chloride (PVC) and polyethylene (PE) infusion sets would result in a measurable difference in steady-state plasma concentration. At the same apparent infusion rate of 40 micrograms/min, PVC infusion sets produced steady-state plasma nitroglycerin concentrations that were only 40% of those generated with PE sets (p less than 0.0001). Attainment of steady-state drug levels appeared more rapid with the PE administration sets, but in three out of eight animals, these infusion systems appeared to produce a "bolus" dosing effect. PE sets did not reduce the variability in plasma nitroglycerin concentration observed with PVC sets.

Animals↗

PubMed1985

Pharmacokinetics and pharmacodynamics of isosorbide dinitrate.

It has long been believed that organic nitrates, including isosorbide dinitrate (ISDN), are completely metabolized during their first passage through the liver and that oral therapy with this class of compounds is thus irrational. In the past few years, convincing data have been obtained in patients showing that intact ISDN is significantly bioavailable to the systemic circulation after oral administration; the oral bioavailability is about 20% relative to an intravenous dose and about 45% relative to a sublingual dose, with the balance metabolized to isosorbide mononitrates. These pharmacologically active metabolites have longer biologic half-lives than ISDN and are thus believed to contribute to the sustained duration of action of this drug. After acute dosing, changes in the pharmacologic effects of ISDN mirror those in plasma concentration. However, after long-term therapy, partial nitrate tolerance develops despite elevated plasma ISDN concentrations. Available evidence suggests that during sustained dosing, nitrate metabolism is generally reduced throughout the body; thus reduced hepatic and peripheral tissue metabolism raises plasma ISDN concentrations while reduced vascular tissue metabolism decreases the metabolic activation (perhaps to nitrosothiols?) necessary for vascular relaxation.

Administration, Oral↗

PubMed1985

The effects of dietary calcium on lead absorption, distribution, and elimination kinetics in rats.

A pharmacokinetic analysis of lead absorption, distribution, and elimination was conducted in rats maintained on calcium-deficient, control, and calcium-supplemented diets. Dietary calcium affected lead disposition in a number of ways. Systemic lead clearance after a 10-mg/kg intracardiac lead dose was approximately 25% lower than control in rats administered dietary calcium supplements. Intestinal absorption of 10 mg/kg po lead doses was not affected by the calcium supplements. In rats maintained on a calcium-deficient diet, systemic lead clearance was estimated to be 40% less than control. The apparent volume of lead distribution was increased. The apparent systemic availability of 1-, 10-, and 100-mg/kg oral lead doses was three- to fourfold greater than control in calcium-deficient rats. The percentage absorption was dose-dependent in control and calcium-deficient rats. The observed changes in lead absorption and systemic clearance associated with the calcium-deficient diet represent synergistic effects that could elevate blood lead accumulation and thus potentially influence susceptibility to lead toxicity.

Animals↗

PubMed1985

Dose-related prolongation of the bleeding time by intravenous nitroglycerin.

The effects of intravenous nitroglycerin (NTG) upon the bleeding time, platelet aggregation response, and plasma 6-keto-PGF1 alpha concentration were measured in 17 patients about to undergo coronary bypass grafting. NTG produced a dose-related prolongation of the bleeding time that correlated with the accompanying decrease in systolic blood pressure. Platelet aggregation was not affected and measurements of 6-keto-PGF1 alpha failed to reveal detectable levels (less than 10 pg/ml) either before or after NTG infusion. This suggests that the prolonged bleeding time associated with NTG infusion may be due to vasodilation and increased venous capacitance, rather than altered vascular-platelet interaction.

Adult↗

PubMed1985

Nitrate formulations and drug delivery systems--an overview.

An overview of some of the pharmacokinetic and therapeutic characteristics of nitrate formulations is given here. Significant advances in nitrate formulations and delivery systems have been made in providing better bioavailability and sustained plasma concentrations of these drugs. New dosing modes involving nitrate-free intervals appear to hold promise in avoiding the occurrence of tolerance. These advances may combine to stimulate development of future formulations that will produce the desired therapeutic profile(s) for organic nitrates.

Animals↗

PubMed1984

Transdermal nitroglycerin in angina pectoris.

The hemodynamic and antianginal efficacy of transdermal nitroglycerin (TGTN) patches were assessed in patients with chronic, stable angina pectoris. In 11 patients, acute dosing with 10, 20 and 30 cm2 of TGTN (designed to deliver 5, 10 and 15 mg GTN over 24 hours) improved treadmill walking time 2 and 4 hours after application, but no clinical effects were seen at 24 hours. In a second study in 6 patients with doses of 30, 60 and 90 cm2 of TGTN treadmill walking time was improved at 2 and 4 hours, but no changes were seen at 24 hours except with the 90-cm2 preparation. After daily therapy with 30-cm2 patches of TGTN for 1 to 2 weeks, exercise tolerance was similar to that seen during daily placebo therapy. These results suggest that TGTN patches are of inadequate size to produce 24-hour antianginal protection. During sustained therapy, tolerance develops to the antianginal efficacy of this form of GTN administration.

Administration, Topical↗

PubMed1984

Role of the liver in the disposition of intravenous nitroglycerin in the rat.

Previous studies have indicated that the liver is the main site of nitroglycerin (NTG) elimination when the drug is systematically infused. To examine this hypothesis, we measured the apparent systemic clearance (Cls) of nitroglycerin in anesthesized rats receiving a constant intravenous infusion at a dose of 100 micrograms per kg per min. Animals were divided into shunt and sham groups; the former had undergone a portal vein ligation 10 days prior to the study, while the latter was subjected to a sham operation. On the study day, half of the animals of each group also received probenecid at 200 mg/kg, i.v., a drug previously reported to inhibit organic nitrate ester reductase (ONER) activity in rat liver. Arterial NTG samples were obtained at 41, 43 and 45 min of infusion in all four experimental groups; Cls was 439 +/- 32 ml per kg per min (mean +/- S.E.) in sham, 460 +/- 44 in sham and probenecid, 477 +/- 39 in shunt, and 461 +/- 34 in shunt and probenecid animals. During NTG infusion, hepatic blood flow (measured with a constant infusion of indocyanine green) was decreased markedly in shunted rats as was liver/body weight, indicating hepatic atrophy. The specific activity of hepatic ONER was similar in all four groups. In spite of marked differences in hepatic blood flow and hepatic mass, the Cls was similar in all four groups. The liver does not appear to be a major site for the elimination of systemic nitroglycerin as hitherto assumed.

Animals↗

PubMed1984

Transdermal isosorbide dinitrate in angina pectoris: effect of acute and sustained therapy.

Twelve patients with chronic, stable angina pectoris underwent hemodynamic investigations and treadmill exercise testing before and during a 24-hour period after the application of 100 mg of transdermal isosorbide dinitrate (ISDN) and matching placebo. Compared with placebo, there were no changes in systolic blood pressure or heart rate at rest or during exercise; but treadmill walking time to the onset of angina and to the development of moderate angina was significantly prolonged at 2, 4 and 8 hours, but not at 24 hours, after drug application. Patients subsequently received these same treatment regimens for 7 to 10 days and underwent repeat exercise testing. During this sustained phase of the investigation, treadmill walking time to the onset of angina and to the development of moderate angina was similar 4, 8 and 24 hours after application of ISDN and placebo. Thus, transdermal ISDN in a dose of 100 mg is effective for 8 hours during acute therapy, but during sustained therapy tolerance developed and no antianginal effects of ISDN persisted.

Administration, Topical↗

PubMed1984

Pharmacokinetic determinants of nitrate action.

An update on some of the recent studies relating to organic nitrate pharmacokinetics and pharmacodynamics is presented. The systemic clearance of nitroglycerin was found to be unaffected by portacaval shunting in animals. Thus, the liver only plays a minor role in the metabolism of systemic nitroglycerin. Organic nitrates are extensively taken up by blood vessels in which metabolic activation can occur to produce vascular activity. During sustained therapy, nitrate metabolites may decrease the systemic and hepatic clearance of the parent drug, thus increasing its plasma concentration. Metabolites could also decrease the extent of metabolism in vascular tissues, thus contributing to vascular nitrate tolerance. Therefore, during long-term angina therapy when metabolites are present, the same plasma nitrate concentration may produce less effects compared with that obtained after acute dosing. Nitrate action was shown to be possibly dependent on the rate of drug input. An alternate dosing mode is proposed that speculatively may provide an improvement in producing and maintaining nitrate action in long-term angina therapy.

Angina Pectoris↗

PubMed1984

Determination of the partitioning, stability, and metabolite formation of isosorbide dinitrate in human and rat blood using an improved gas-liquid chromatographic assay.

A simple and highly sensitive gas-liquid chromatographic method using electron-capture detection has been developed for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites in rat and human plasma. This method has a limit of quantitation of about 5 ng/ml for the mononitrates and of 1 ng/ml for ISDN using 0.1 ml of plasma, and is thus useful for pharmacokinetic studies of these compounds in small animals, and in humans when the available volume of blood is limited. Using this method, we found the apparent in vitro partitioning ratio of ISDN between erythrocyte and plasma in rat and human blood at 37 degrees C to be 0.22 and 0.13, respectively. In spite of this poor affinity for red blood cells, ISDN degradation in whole blood was mediated primarily via this blood fraction. Loss of ISDN in blood appeared to proceed exclusively through its mononitrate metabolites, resulting in a 6:1 product ratio of the 5-mononitrate to its 2-isomer. These data suggest that although blood degradation of ISDN and erythrocyte partitioning occur per se, these phenomena do not contribute significantly to the very rapid in vivo clearance of ISDN observed in man and in the rat.

Animals↗

PubMed1984

Statistical prediction of drug stability based on nonlinear parameter estimation.

The classical approach in Arrhenius prediction of drug stability uses two sequential steps of linear regression involving (a) a function of drug content versus time to obtain the rate constants (k) at several elevated temperatures and (b) the relationship of logarithm of mean k versus reciprocal temperature to predict the room temperature rate constant and hence the shelf-life of the drug. Uncertainties in drug content determinations are often neglected in the second regression. The classical approach also provides a wide and unsymmetrical 95% confidence interval for the predicted shelf-life. We have developed equations which allow for direct statistical prediction of shelf-life using observed values of drug content, time, and temperature. Nonlinear regression analysis was employed to provide parameter estimates of drug shelf-life and the energy of activation. The developed approach was shown to provide good estimates of shelf-life with meaningful statistics of reactions over a wide range of stability and energetics, with various kinetic orders, with different levels of noise in the data, and with different types of data structure. Comparison between the nonlinear approach and the classical approach showed that the nonlinear approach provided better mean estimates of shelf-life with much smaller and more symmetrical 95% confidence intervals than the classical approach. The method appears sufficiently robust and wide-ranging as to be potentially applicable for the prediction of the drug stability of pharmaceutical products.

Chemistry, Pharmaceutical↗