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H L Fung

Publications and source records attributed to H L Fung.

At least 127 records · Page 7Linked to original sources
PubMed1984

Pharmacokinetics of nitroglycerin after parenteral and oral dosing in the rat.

The pharmacokinetics of nitroglycerin was characterized in detail using venous plasma after different intravenous bolus doses (0.15-2.48 mg/kg), intra-arterial infusion (8.2 micrograms/min over 5 h), and oral doses (7-100 mg/kg). Venous plasma clearance was found to be approximately 650 mL/kg and was independent of the intravenous or intra-arterial dose. This confirmed earlier reports that the venous plasma clearance of nitroglycerin in rats exceeded the value of normal cardiac output. A terminal half-life of approximately 15 min was observed after high intravenous bolus doses of nitroglycerin. This slow disappearance phase was likely rate limited by redistribution of drug back into the plasma. The bioavailability of oral nitroglycerin (F) showed an apparent Michaelis-Menten dependency on dose. F was less than 5% at doses less than 20 mg/kg, but increased to a plateau of approximately 20% from 50-100 mg/kg. First-pass metabolism of nitroglycerin is thus apparently controlled by at least two systems (sites or enzymes). Coadministration of mannitol hexanitrate, a potential competitive inhibitor of first-pass metabolism, did not increase F.

Administration, Oral↗
PubMed1984

Blood vessel uptake and metabolism of organic nitrates in the rat.

Recent reports have suggested that the unusual pharmacokinetics observed for nitroglycerin (NTG) and isosorbide dinitrate (ISDN) may be partially explained by extensive uptake and/or metabolism of these drugs by vascular and other extrahepatic tissues. Using the rat as an animal model, this hypothesis was examined by in vivo intravessel NTG and [14C]ISDN infusion and injection into various vessel segments, viz. the femoral vein, inferior vena cava [IVC: lower, middle and upper) and the aorta. NTG and [14C]ISDN concentrations were determined in these blood vessels and in plasma. Blood vessel segments nearest the input site had the greatest amounts of nitrate, whereas segments further away from the input site had progressively less nitrate, with the exception of aorta, which appeared to take up NTG less extensively, on a per weight of vessel basis, than the IVC. Blood vessel NTG concentrations (nanogram per gram) were generally higher (10-fold) and declined about twice as slowly as NTG plasma concentrations (nanograms per milliliter). [14C]NTG and [14C]ISDN were also incubated with cofactors in IVC, aorta, abdominal muscle, lung and liver. The amounts of nitrate metabolites formed from parent drug were larger in each extrahepatic tissue incubation than in the controls (P less than .05). The results are consistent with the hypothesis that vascular and other extrahepatic tissues can take up and/or metabolize organic nitrates. The data appear to provide a partial explanation for the large systemic clearance seen with nitrates and appear consistent with existing mechanistic hypotheses for the vascular action of these compounds.

Animals↗
PubMed1984

Isosorbide dinitrate disposition in the rat: metabolite pharmacokinetics and interactions.

The pharmacokinetics of isosorbide dinitrate (ISDN) and its isomeric mononitrate metabolites (2- and 5-ISMN) were examined in the rat. At a dose of 2 mg/kg, the oral bioavailability of ISDN was found to be about 40%. This finding corrects a previous belief that organic nitrates, when administered via the oral route, are completely metabolized by hepatic first-pass metabolism. ISDN was metabolized exclusively via its mononitrate metabolites, with the 5-ISMN being the principal product (about 90%). The ratio of 2- to 5-ISMN produced was dependent on the route of administration, being 0.18 +/- 0.03 after i.v. dosing and 0.11 +/- 0.03 after oral dosing (both mean +/- S.D.). 2-ISMN was found to decrease the plasma clearance of ISDN; this metabolite interaction occurred when drug and metabolite were administered either at the same or different intravascular sites. 5-ISMN did not affect ISDN plasma clearance when these compounds were administered at different intravascular sites. However, when 5-ISMN and ISDN were given at the same vascular site, a decrease in plasma ISDN clearance was observed. These results provide an interesting example of divergent pharmacokinetic interactions exhibited by two isomeric metabolites.

Animals↗
PubMed1984

Oral ethanol ingestion altered nifedipine pharmacokinetics in the rat: a preliminary study.

We examined the pharmacokinetics of intravenously administered nifedipine in the presence or absence of concomitant alcohol ingestion in the rat. In the presence of alcohol, the area under the nifedipine plasma concentration vs. time curve and half-life of drug elimination were increased, and the rate constant of elimination was significantly decreased (p less than 0.05), while the apparent volume of distribution was apparently unaffected. Clearance, normalized to control, was significantly decreased (p less than 0.01). Since nifedipine and ethanol both undergo dehydrogenation in their metabolism, it is possible that this observed drug-drug interaction may be due to a metabolic interference. It is not known at this time whether such an interaction exists in man.

Animals↗
PubMed1983

Pharmacokinetics of nitroglycerin and long-acting nitrate esters.

The current literature on the human pharmacokinetics of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrates is briefly reviewed and evaluated. The pharmacokinetics of nitroglycerin are unusual in that its systemic clearance is extremely large and that there is a distinct arterial-venous gradient in plasma concentration. These features had created substantial difficulties in the documentation and interpretation of nitroglycerin plasma concentrations and pharmacokinetics. Studies with isosorbide dinitrate showed that this nitrate is absorbed as intact drug at about 20 percent of a comparable intravenous dose, firmly disproving a previous belief that orally administered nitrate is completely degraded by presystemic metabolism. The current data suggest that plasma nitrate concentration may relate to some of its pharmacologic effects after short-term dosing, but the concentration-response relationship is complex after long-term dosing. Studies of nitrate pharmacokinetics in their presumed sites of action, namely, the vasculature, appear to be useful for the further understanding of the mechanism of action for these vasodilators.

Absorption↗
PubMed1983

Inhibition of oral lead absorption in rats by phosphate-containing products.

Recent studies indicate that elevated blood lead levels in children are largely a result of exposure to this metal via the oral route. A logical approach to decrease or prevent lead intoxication would be to reduce its absorption as soon as lead ingestion is known or suspected. Presently, however, there are no readily available products recommended to accomplish this goal. It was found that a phosphate-buffered, saline laxative reduced lead absorption over 50% in rats administered a single oral lead acetate dose, presumably by promoting the formation of less soluble lead salts. A popular phosphate-containing carbonated beverage also decreased lead absorption approximately 30% after oral lead acetate or lead-based paint doses, possibly by decreasing solubility, dissolution rate and/or GI motility. It is possible that these household products, and those with similar ingredients, may be safely used to reduce lead absorption in humans.

Administration, Oral↗
PubMed1983

Isosorbide dinitrate kinetics and dynamics after intravenous, sublingual, and percutaneous dosing in angina.

Isosorbide dinitrate (ISDN) kinetics and dynamics were examined after various routes of administration for angina. Given intravenously, ISDN kinetics were apparently linear over the range of infusion rate (0.083 and 0.133 mg/min) and duration (15 min and 1 and 2 hr) studied. Mean +/- SD systemic clearance of ISDN was 3.4 +/- 1.4 l/min and volume of distribution (VdSS or Vdarea) about 100 l. These data are consistent with the presence of extensive extrahepatic metabolism. In six patients, sublingual ISDN (5 mg) was also given and mean bioavailability of 59% (19% to 93%) for this route was determined. For this group, sublingual absorption of intact ISDN was incomplete and variable. The presence of a longer disappearance t 1/2 after sublingual dosing suggested that the input process may be rate limiting. After percutaneous application of a topical formulation (100 mg over an area of 400 cm2), steady-state plasma concentrations at about 7 ng/ml were maintained from 6 to 24 hr. The bioavailability of the topical application was estimated at 30%. At the doses given, intravenous ISDN had no apparent effect on heart rate but induced significant reduction in standing systolic blood pressure. The effect vs the ISDN concentration profile was described by a hysteresis loop, indicating that changes in blood pressure response lag behind changes in plasma ISDN concentration. After intravenous dosing, peak plasma ISDN concentration and peak effect (maximum change in standing systolic blood pressure). At the doses used, both sublingual and percutaneous ISDN induced less distinct circulatory changes than the intravenous infusion.

Absorption↗
PubMed1983

Hepatic extraction of isosorbide dinitrate in cardiac patients.

Hepatic extraction of organic nitrates, including that of isosorbide dinitrate (ISDN), has been thought to be nearly complete in man but has never been directly measured. We examined the time course of plasma ISDN and metabolite concentrations in arterial and hepatic venous blood in four cardiac patients receiving an intravenous ISDN infusion. Apparent hepatic extraction of ISDN was high (90%) at the beginning of infusion but fell to about 44% 1 hr after termination of infusion. The decrease in ISDN concentration gradient across the liver correlates with an increase in plasma isosorbide-5-mononitrate concentration, but a cause-and-effect relationship resulting from metabolite inhibition cannot be established. The time-averaged hepatic extraction of ISDN, at about 70%, agreed with its oral bioavailability in patients.

Biological Availability↗
PubMed1983

Prolonged plasma half-life after oral isosorbide dinitrate in patients with angina pectoris.

The plasma concentration of isosorbide dinitrate (ISDN) was monitored up to 24 h after a chronic oral dose of 60 mg in six patients with coronary artery disease. A terminal half-life of 7.7 +/- 2.6 h (mean +/- s.d.) was observed. The presence of this prolonged disappearance phase provided at least a partial explanation for the observed accumulation of ISDN in plasma after chronic dosing on a six hourly regimen.

Angina Pectoris↗
PubMed1983

Intravenous nitroglycerin in the treatment of spontaneous angina pectoris: a prospective, randomized trial.

A prospective, randomized study of i.v. nitroglycerin (TNG) in the management of repetitive spontaneous angina pectoris was undertaken in 40 consecutive patients. The clinical effectiveness of i.v. TNG (group A) was compared with that of oral isosorbide dinitrate (ISDN) and topical 2% nitroglycerin ointment (NO) in combination (group B) during a 72-hour treatment period. The doses of both nitrate regimens were adjusted so that the mean arterial pressure in the two groups was reduced by 15 +/- 3% of control values to the same level (77 mm Hg). The i.v. TNG dose of 10-200 micrograms/min yielded arterial plasma TNG levels of 1.2-65.3 ng/ml and estimated plasma (arterial) clearance of 106 +/- 55 ml/min/kg of body weight (mean +/- SD). In group B, the doses were 20-60 mg (oral ISDN) and 1/2-2 inches (NO) every 6 hours. Intravenous TNG reduced the number of spontaneous ischemic episodes from 3.3 +/- 0.8 per 24 hours during the control period to 1.0 +/- 0.3 per 24 hours during the treatment period (p less than 0.01), while the ISDN/NO combination reduced the number of episodes from 3.1 +/- 0.4 to 1.4 +/- 0.3 (p less than 0.01). Overall, the magnitude of the therapeutic effect of i.v. TNG was statistically indistinguishable from that of ISDN/NO, although i.v. TNG did have somewhat greater clinical benefit on day 2 of the 3-day treatment period. Furthermore, the data suggested more consistent control of ischemic episodes with i.v. TNG during the first 24 hours of the trial. Although both regimens markedly reduced the frequency of spontaneous ischemic episodes, only 36% of patients in group A and 17% in group B experienced no ischemic episodes during the study period (NS). Forty-three percent of patients in group A and 61% in group B (NS) required early coronary artery bypass surgery to control recurrent ischemic episodes refractory to medical therapy. We conclude that i.v. TNG and ISDN/NO, when administered in doses adjusted to produce similar effects on systemic arterial pressure, have nearly equivalent clinical effects in the management of patients with frequent episodes of spontaneous angina pectoris. Intravenous TNG offers the advantage of more consistent control of ischemic episodes during the first 24 hours of treatment. Nevertheless, the recurrence rate of spontaneous ischemic episodes during medical therapy is high with both regimens, and early coronary artery bypass surgery may be required for long-term management.

Aged↗
PubMed1983

Tolerance to isosorbide dinitrate: rate of development and reversal.

The circulatory response and plasma concentrations of isosorbide dinitrate (ISDN) were determined in 10 patients with chronic, stable angina after administration of 5 mg of sublingual ISDN during the control stage, after 48 hr of therapy with 15 mg of ISDN orally every 6 hr, and subsequently after a 48 hr period when ISDN was substituted by placebo four times daily. Initially, sublingual ISDN induced major reductions in both supine and standing systolic and diastolic blood pressure, but after 45 hr of therapy with oral ISDN, there was a significantly diminished vasodepressor response in both positions. Subsequently, when placebo was substituted for ISDN, the circulatory response initially seen was restored within 21 hr. Plasma ISDN concentrations after the test sublingual dose were slightly higher after 48 hr of oral ISDN dosing (i.e., the tolerant state) than at the start of the study. This suggests that tolerance is unlikely to be caused by reduced bioavailability or accelerated elimination of ISDN. It is possible that tolerance is related to accumulation of ISDN metabolites. The attenuation of the circulatory response to ISDN may be related to the altered antianginal efficacy commonly seen during sustained therapy with ISDN.

Administration, Oral↗
PubMed1983

Effects of disease, route of administration, cigarette smoking, food intake on the pharmacokinetics and circulatory effects of isosorbide dinitrate.

The major goal of this study was to examine the clinical pharmacology of isosorbide dinitrate (ISDN) under various conditions of clinical use. Orally administered ISDN is subjected to extensive metabolism during its first passage through the liver. It is not known, however, whether the systemic availability and the circulatory effects of oral ISDN might be affected in clinical conditions under which hepatic blood flow and/or metabolic activity might have been altered. Sublingual (5 mg) and oral (30 mg) ISDN were given under fasting conditions on two separate occasions to (a) patients with angina pectoris (AP), n = 8; (b) patients with chronic congestive heart failure (CHF), n = 9; (c) smoking AP patients, n = 7; and (d) nonsmoking AP patients, n = 9. Patients in group (a) were also given oral ISDN after a standard breakfast. Circulatory effects, i.e., heart rate, systolic and diastolic pressures were measured over 3 h after sublingual dosing and 6 h after oral dosing in both the supine and standing positions. Plasma ISDN concentrations were measured by gas chromatography over the same periods. The systemic availability of oral ISDN was found to be about half that of sublingual ISDN, but the intersubject variability was large. Thus some individuals absorbed oral ISDN as well as they did sublingual ISDN, while others only absorbed oral ISDN minimally. The extent of oral ISDN absorption was not statistically different between patients with AP and CHF, between smokers and nonsmokers, or between the fasting and postprandial conditions, although there was a trend for higher plasma ISDN concentrations in smokers. Food reduced the apparent absorption rate of oral ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1982

Oral isosorbide dinitrate in angina pectoris: comparison of duration of action an dose-response relation during acute and sustained therapy.

The effects of different oral doses of isosorbide dinitrate administered acutely and four times daily during sustained therapy were studied in 12 patients with angina pectoris. After administration of 30, 60 and 120 mg of isosorbide dinitrate, the average plasma concentrations were higher and the area under the plasma concentration time curve was greater during sustained than during acute therapy (p less than 0.01). Reduction in standing systolic blood pressure was greater during acute than during sustained therapy (p less than 0.001). This reduction in systolic blood pressure was dose-related and persisted for 8 hours during acute therapy, but was not dose-related and was demonstrable for only 4 hours during sustained therapy. Compared with placebo therapy, exercise duration to the onset of angina and to the development of moderate angina increased significantly after each dose of isosorbide dinitrate for 8 hours during acute therapy but for only 2 hours during sustained therapy. During acute therapy, administration of a single dose of 15 or 30 mg of isosorbide dinitrate produced similar improvement in exercise tolerance as did a dose of 60 or 120 mg. During sustained therapy (15 mg four times daily), exercise tolerance increased to the same magnitude as with doses of 30, 60 or 120 mg four times daily. In most patients, near maximal improvement in exercise tolerance occurred after a dose of 15 or 30 mg four times daily. It is concluded that during sustained therapy with isosorbide dinitrate, partial tolerance to the antianginal and circulatory effects develops rapidly.

Administration, Oral↗
PubMed1982

Rectal absorption of nitroglycerin in the rat: avoidance of first-pass metabolism as a function of rectal length exposure.

Nitroglycerin administered orally undergoes substantial presystemic elimination. It was shown recently that first-pass hepatic metabolism of high clearance drugs can be substantially avoided via rectal administration. In applying this concept to nitroglycerin in rats, it was found that unrestricted rectal instillation of nitroglycerin (at 3.5-mg/kg dose) gave a mean +/-SD bioavailability of 26.7 +/- 7.0% (n=6) compared to 1.8 +/- 0.9% (n=5) from oral dosing. This mode of dosing did not lead to complete avoidance of first-pass metabolism of nitroglycerin in rats. When the rectal exposure length to nitroglycerin was restricted to 3.5 cm from the anus, the mean +/-SD bioavailability increased to 83.5 +/- 74.5% (n=14). However, the variability in bioavailability was extremely large. When the rectal exposure length was restricted to 2.0 cm from the anus (at 1.75-mg/kg dose), nitroglycerin bioavailability was estimated at 91.2 +/- 30.4% (n=6). The plasma nitroglycerin concentrations (greater than 5 min) obtained after this mode of administration were similar to those achieved after intravenous dosing. The data showed that substantial avoidance of presystemic nitroglycerin metabolism can be achieved via rectal administration. This avoidance can be nearly complete if nitroglycerin is limited in exposure to only the lower rat rectum. It was also demonstrated that sustained (at least 24 hr) nitroglycerin delivery via the rat rectal route was feasible with an experimental osmotic minipump. This delivery system also produced nearly complete bioavailability for nitroglycerin in the rat.

Animals↗
PubMed1982

Effects of a nonabsorbable chelating resin on lead absorption, elimination, and accumulation in the rat. Resin effects on lead disposition.

In rats, oral administration of lead-chelating resin (Chelex-100) reduced the absorption of an oral lead dose (10 mg/kg) when both doses were given at approximately the same time. The same oral resin did not reduce blood lead concentrations when administered after the lead dose had been absorbed or after systemic lead administration (1 mg/kg, intracardiac), indicating that the resin did not influence lead elimination. As a dietary supplement the resin was also ineffective in reducing blood and kidney lead concentrations in rats exposed to lead in drinking water. Thus, the possible therapeutic uses of this lead-chelating resin may be limited.

Animals↗
PubMed1981

Nitroglycerin pharmacokinetics after intravenous infusion in normal subjects.

The purpose of this investigation was to examine the pharmacokinetics of nitroglycerin in normal volunteers after intravenous drug administration. Eight subjects (including one subject on two occasions) received a dose of approximately 0.6 mg iv of nitroglycerin at a rate of 18 micrograms/min. Plasma concentrations of intact drug during and after the infusion were determined using a GLC method. Intra- and intersubject variability in nitroglycerin plasma kinetics was substantial. Generally, however, plasma nitroglycerin disposition was characterized by: (a) a large apparent plasma clearance (0.3-1 liter/min/kg), (b) a large volume of distribution (approximately 3 liters/kg), and (c) a rapid plasma half-life (approximately 3 min). From the apparent volume of distribution obtained, plasma drug can be estimated to account for only approximately 1.3% of total drug in the body. Minor fluctuations in tissue distribution, which can be produced by a myriad of external and internal stimuli, could cause dramatic fluctuation in plasma nitroglycerin concentrations and, hence, in the calculated pharmacokinetic parameters. For example, in two subjects studied, plasma nitroglycerin concentrations oscillated to such an extent that pharmacokinetic analysis could not be performed. In some subjects, steady-state concentrations were not observed in spite of the apparent short plasma half-life, and rebound in plasma concentrations during the postinfusion phase were evident. These phenomena were also observed in other kinetic studies involving organic nitrates.

Administration, Sublingual↗