Showing papers on "Bioavailability published in 1978"
TL;DR: Food and its components and contaminants may have both short and long term effects on both the absorptive and biotransformation processes influencing systemic availability of drugs.
Abstract: Food intake exerts a complex influence on the bioavailability of drugs. It may interfere not only with tablet disintegration, drug dissolution and drug transit through the gastrointestinal tract, but may also affect the metabolic transformation of drugs in the gastrointestinal wall and in the liver. Different food components can have different effects, and food may interact in opposite ways, even with drugs that are chemically related. Therefore, the net effect of food on drug bioavailability can be predicted only by direct clinical studies of the drug in question. As judged mainly from single meal, single dose studies, food intake enhances the bioavailability of several different drugs, such as propranolol, metoprolol, hydrallazine, hydrochlorothiazide, canrenone (from spironolactone), nitrofurantoin, erythromycin (stearate), dicoumarol, phenytoin and carbamazepine, but reduces that of drugs such as isoniazid, rifampicin, tetracycline, penicillin and ampicillin, while having no consistent effect on the bioavailability of metronidazole, oxazepam, melperone, propylthiouracil, sulphasomidine and sulphonylureas. For some drugs such as digoxin and paracetamol, the rate but not the extent of absorption is reduced. Food may enhance bioavailability even though, or rather because, the rate of gastric emptying is reduced; this is apparently the case with hydrochlorothiazide and nitrofurantoin. The food induced enhancement of bioavailability of propranolol, metoprolol and hydrallazine is probably due to reduced first pass metabolism of these drugs, while food induced improvement of drug dissolution may explain the enhanced bioavailability of carbamazepine, canrenone, dicoumarol and phenytoin. An increased gastrointestinal pH may be in part the cause of the food induced reduction of the bioavailability of drugs such as isoniazid and tetracycline. In addition to single meal effects, repeated intake of protein-rich meals enhance, while carbohydrate-rich meals reduce, the rate of oxidation of antipyrine and theophylline. Moreover, intake of charcoal broiled meat markedly accelerates the oxidation of phenacetin and variably accelerates elimination of theophylline. Thus, food and its components and contaminants may have both short and long term effects on both the absorptive and biotransformation processes influencing systemic availability of drugs.
296 citations
TL;DR: Ionizable iron at pH 7.5 determined as described in this study can be used as a reliable measure of bioavailability of nonheme iron in foods.
239 citations
TL;DR: The results indicated that the intramuscular and intravenous routes are virtually interchangeable for parenteral cimetidine, and that the oral liquid, although exhibiting a reduced area under the blood level curve as compared with the parenTERal doses, nevertheless demonstrated equivalence with respect to the time the blood levels remained above 0.5 μg per ml.
164 citations
TL;DR: The bioavailability of sodium fluoride tablets is approximately 100% and there was a great intra‐ and intersubject variation, as well as poor agreement between the two methods of calculations.
Abstract: Fluoride (3 mg) was administered as a continous intravenous infusion during 30 min to 6 healthy subjects. Plasma concentrations and urinary excretion of fluoride in these experiments were compared with those obtained following oral administration of 2.82 mg, 4.50 mg, 5.64 mg, and 9.40 mg in the form of tablets and capsules. There were large day-to-day variations in the renal clearance of fluoride. This was shown to be due to differences in the urinary flow, an increase in flow causing an increase in renal clearance. The mean value of renal clearance from all experiments was 66.2 +/- 27.8 (SD; n = 16) ml/min. The extrarenal clearance, suggested to represent mainly the clearance to the bone pool, showed less interindividual variation: mean 110.3 +/- 32.3 (SD; n = 6) ml/min; the fraction remaining in the bone pool was highly consistent: 0.579 +/- 0.049 (SD; n = 6). When apparrent bioavailability was calculated from plasma and from urinary data, there was a great intra- and intersubject variation, as well as poor agreement between the two methods of calculations. This was found to be due to the day-to-day variation in renal clearance, which, in turn, varied with urinary flow. By use of equations that corrected for these variations, it was found that the bioavailability of sodium fluoride tablets is approximately 100%.
120 citations
TL;DR: It is suggested that the rate of degradation of fluorouracil by the liver is quite variable and may become saturated with increasing dose, and monitoring of plasma levels of the drug in individual patients may be useful.
Abstract: The pharmacokinetics of fluorouracil after oral, intravenous and rectal administration were compared in 12 patients with colorectal cancers. Oral administration of 10 to 15mg/kg gave variable plasma levels (0 to 10.5μg/ml) and bioavailability (0 to 74%; mean 28%). Bioavailability increased markedly with increases in dose, suggesting saturation of the ‘frst pass’ hepatic metabolism of the drug. Differences in bioavailability could not be related to standard liver function tests or the presence of metastatic deposits i the liver. Plasma levels were not detectable after rectal administration in the 4 patients studied and were very low (0 to 8μg/ml) during high dose (20 to 30mg/kg/24h) slow intravenous infusion in 6 patients. These findings indicate that different dose schedules and routes of administration produce markedly different plasma levels. They suggest that the rate of degradation of fluorouracil by the liver is quite variable and may become saturated with increasing dose. For these reasons monitoring of plasma levels of the drug in individual patients may be useful.
112 citations
TL;DR: In this paper, Spironolactone: Disposition, Metabolism, Pharmacodynamics, and Bioavailability is discussed and a review of drug metabolism reviews is given, with a focus on drug metabolism.
Abstract: (1978). Spironolactone: Disposition, Metabolism, Pharmacodynamics, and Bioavailability. Drug Metabolism Reviews: Vol. 8, No. 1, pp. 151-188.
99 citations
Journal Article•
TL;DR: Comparison of bioavailability and absorption characteristics suggest usefulness of some oral sustained-release theophylline preparations for the purpose of maintaining safe and effective blood levels with twice-a-day dosing.
Abstract: Plasma theophylline concentrations were measured in 20 adults after single doses of 8 mg/kg of each of six oral sustained-release theophylline preparations. Twelve subjects were studied in a multiple-dose trial. Comparison of bioavailability and absorption characteristics suggest usefulness of some of these products for the purpose of maintaining safe and effective blood levels with twice-a-day dosing.
97 citations
TL;DR: Computer simulation based on the measured pharmacokinetic parameters demonstrated that a loading dose after dialysis should result in therapeutic plasma concentrations for susceptible organisms and avoid toxic levels.
Abstract: Kinetics and bioavailability of flucytosine were studied in 5 subjects with normal renalfunction. Kinetic parameters and absorption were compared after a 500-mg dose administered in the following manner: intravenously, aqueous solution, and capsules while fasting; capsules after meals; and capsules with antacid. Encapsulation, food, and antacid decreased the absorption rate constant but the total amount absorbed orally did not differ significantly. Bioavailability assessed by the urinary recovery or comparison of the AUCo to AUCiv on the average showed 76% to 89% oral absorption. In 3 patients on hemodialysis, the serum concentrations in the β-phase following oral flucytosine in capsules during fasting were in the same range as those after a comparable intravenous dose. The mean steady-state distribution volume (Vdss) was 0.679 L/kg in normal subjects and ranged between 0.413 and 0.706 L/kg in 9 patients with renal failure. The mean t½β was 4.2 hr in normal subjects and the renal clearance was comparable to creatinine clearance. In renal failure, a linear regression analysis showed the t½β (hr) to be numerically about 5 times the steady-state serum creatinine concentration (mg/dl). Under the conditions of the study, hemodialyzer clearance of flucytosine was rapid and similar to creatinine hemodialyzer clearance. Computer simulation based on the measured pharmacokinetic parameters demonstrated that a loading dose (20 mg/kg) after dialysis should result in therapeutic plasma concentrations for susceptible organisms and avoid toxic levels.
89 citations
TL;DR: On the basis of urinary nitrofurantoin excretion determined after oral and intravenous drug administration, orally administered nitro furantoin in a suitable dosage form is well absorbed and has a short elimination half-life in whole blood or plasma.
Abstract: Nitrofurantoin is a urinary tract antibacterial agent whose clinical effectiveness depends on the high urinary drug levels encountered during therapeutic drug dosage. Under these conditions, only low blood drug concentrations are usually found. On the basis of urinary nitrofurantoin excretion determined after oral and intravenous drug administration, orally administered nitrofurantoin in a suitable dosage form is well absorbed. In vitro testing does not accurately reflect nitrofurantoin bioavailability, which is affected by formulation differences, drug particle size, and dosage form. Nitrofurantoin is readily absorbed and quickly distributed into most body fluids. It is rapidly excreted in large amounts in bile and urine. With the exception of the active drug secretion in the kidney tubule and biliary drug transport, nitrofurantoin transfer across body membranes occurs by diffusion. Nitrofurantoin has a short elimination half-life in whole blood or plasma. In conjunction with its rapid excretion by the primary routes, there is little evidence for any prolonged binding of nitrofurantoin to either plasma proteins or tissues. The first-order kinetics involved in nitrofurantoin absorption and elimination is most appropriately described by a one-compartment open model. Biliary and urinary excretion of unchanged nitrofurantoin and enzymatic degradation are the primary means of elimination.
82 citations
TL;DR: The bioavailability of labetalol was increased in liver disease due to reduced first-pass metabolism, and fell in supine heart rate and blood pressure which tended to be greater after oral administration in the patients with liver disease, suggesting an exaggerated response related to the increased bioavailability.
Abstract: The effect of chronic liver disease on the rate of elimination and extent of "first-pass" metabolism of labetalol was studied. Pharmacokinetic measurements were made after both oral and intravenous administration to seven healthy subjects and to 10 patients with chronic liver disease. Plasma half life was similar in the two groups. Plasma concentrations were considerably higher in the patients than in the healthy subjects after oral administration but similar after intravenous injection. Thus the bioavailability of labetalol was increased in liver disease due to reduced first-pass metabolism. Bioavailability in the group of patients correlated negatively with serum albumin concentration. There were falls in supine heart rate and blood pressure which tended to be greater after oral administration in the patients with liver disease, suggesting an exaggerated response related to the increased bioavailability. Oral dosage requirements of labetalol and possibly other drugs susceptible to first-pass metabolism are reduced in the presence of liver disease.
71 citations
TL;DR: The vasoconstrictor assay for topical steroids has been modified and extended so that it may be used to screen for activity and to determine bioavailability and exceeds the FDA Bioequivalence Requirements and In Vivo Bioavailability Procedures.
Abstract: Summary
The vasoconstrictor assay for topical steroids has been modified and extended so that it may be used to screen for activity and to determine bioavailability. The precision, sensitivity and reproducibility were good for a bioassay. Hydro-philic preparations containing steroid in solution exhibited rank-order relationships between applied concentration and vasoconstriction (Cartesian, semilog, log-probability and log-logistic coordinates). Similar response curves obtained using applied concentration in vivo or amount of steroid released in vitro suggested that vasoconstriction data reflected the amount of steroid penetrating to the capillaries. Pharmacokinetics were non-linear. The assay as developed exceeds the FDA Bioequivalence Requirements and In Vivo Bioavailability Procedures.
Journal Article•
TL;DR: S-R theophylline therapy, with the use of formulations of acceptable bioavailability, provides excellent control of chronic childhood asthma, offers the advantage of extended dosing intervals, and encourages improved patient cooperation in drug compliance.
Abstract: The efficacy of continuous, around-the-clock sustained-release (S-R) theophylline therapy, adjusted to approximate serum or plasma steady state theophylline concentrations (Tc) of 15 microgram/ml three hours following the last dose, was assessed in 18 children suffering from moderately severe chronic asthma. Two of the three formulations studied, Slo-Phyllin Gyrocaps and Theo-Dur, had excellent bioavailability and produced stable therapeutic Tc throughout an eight-hour dosing interval, using average doses of 8.7 +/- 0.5 and 8.4 +/- 0.6 (SE) mg/kg/dose, respectively. Pulmonary function responses paralleled Tc and were also stable throughout the dosing interval. Aerolate provided comparatively less stability, and higher doses (11.3 +/- 0.7 mg/kg) were necessary to produce therapeutic Tc. Toxicity was not evident when dosage was adjusted to avoid Tc exceeding 20 microgram/ml. S-R theophylline therapy, with the use of formulations of acceptable bioavailability, provides excellent control of chronic childhood asthma, offers the advantage of extended dosing intervals, and encourages improved patient cooperation in drug compliance.
TL;DR: The results of the single dose and steady-state experiments demonstrate that cholestyramine's reduction of digoxin oral bioavailability is related to the dose of cholencyramine and the proximity of the time of administration of the two drugs.
Abstract: SUMMARY This study tested the hypothesis that hypocholesterolemic interventions interfere with the bioavailability of orally administered digoxin. Using single dose studies of bioavailability, cumulative six-day urinary digoxin excretion (expressed as a percentage of each individual's control value) was 103% with a normal fiber diet, 82% with a high fiber diet, 83% with 4 g of cholestyramine, 69% with 8 g of cholestyramine, 80% with 8 g cholestyramine administered eight hours before digoxin, 92% with 8 g of cholestyramine administered eight hours after digoxin and 80% after completion of two weeks of treatment with para-aminosalicylic acid.Analysis of the urinary excretion data and associated serum levels revealed significant interference with the absorption of digoxin in all instances except for administration of digoxin either with a normal fiber diet or administration eight hours before cholestyramine. The cholestyramine-digoxin interaction was further studied using steady-state investigation of bioavailability. Serum levels and daily urinary digoxin excretions (expressed as a percentage of each individual's control value) were: 75% and 80% for digoxin administered simultaneously with 4 g of cholestyramine daily; 69% and 86% for digoxin administered simultaneously with the first daily dose of cholestyramine given as 4 g, four times a day, and 96% and 93% with cholestyramine 8 g twice a day, eight hours before and eight hours after digoxin ingestion. Serum levels and urinary excretions for all three cholestyramine interventions were significantly less than control.The results of the single dose and steady-state experiments demonstrate that cholestyramine's reduction of digoxin oral bioavailability is related to the dose of cholestyramine and the proximity of the time of administration of the two drugs.
TL;DR: Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration and oral administration of the two commercially available preparations, Rythmodan and Norpace.
Abstract: 1 Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half-life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half-lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. 5 The absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P less than 0.005), the 5--15% difference between the two formulations should not normally be of any clinical significance.
TL;DR: The relative availability of the orally administered hydrophobic antimalarial alpha-(dibutylaminomethyl)-6,8-dichloro-2-(3',4'-dich chlorophenyl)-4-quinolinemethanol from two dosage forms was determined in beagle dogs.
TL;DR: Considerable intra-individual differences in peak level times between the two preparations were observed, whereas the extent of bioavailability was rather similar, compared to pharmacokinetic and bioavailability studies of nitrazepam in humans.
TL;DR: Plasma salicylate levels were not influenced markedly by the various treatments, although levels were higher in fasted than in nonfasted subjects during the 1st hr after dosing, and fat pretreatment tended to produce higher levels than other treatments.
TL;DR: Higher and more uniform serum eryhromycin levels are obtained when erythromycin stearate tablets are given on an empty stomach together with an adequate water volume, probably due to rapid degradation of solubilized, unabsorbed drug in the GI tract.
TL;DR: A gas liquid chromatographic assay was developed to measure in plasma and urine concentrations of the new antiarrhythmic drug lorcainide, its dealkylated metabolite and an added internal standard of similar structure as mentioned in this paper.
Abstract: A gas liquid chromatographic assay was developed to measure in plasma and urine concentrations of the new antiarrhythmic drug lorcainide, its dealkylated metabolite and an added internal standard of similar structure. The limit of sensitivity was 10ng/ml plasma. In 5 healthy volunteers and in 6 patients with ventricular premature beats (VPB) the pharmacokinetics were determined after a single intravenous dose of 100mg. In 4 of the patients with VPB, the disposition was also evaluated under steady-state conditions following oral administration of 100mg twice daily. In 4 of the healthy volunteers, the bioavailability of a single 100mg (n = 2) and 150mg (n = 2) oral dose was determined. In an additional crossover experiment, bioavailability of a single oral dose of 100 and 200mg was also measured in 2 patients with VPB.
TL;DR: The mean oral bioavailability was determined to be 1.6%, firmly supporting the contention that nitroglycerin is extensively metabolized during first passage through the liver.
TL;DR: Of the several powders, carbonyl iron demonstrated the highest bioavailability and was used as a standard, highly bioavailable control in iron-deficient rats.
TL;DR: Iron added to the diets containing isolated soybean protein had bioavailabilities similar to that of iron present in the soybean which supports the common dietary iron pool hypothesis.
Abstract: Evaluations were conducted to assess the biological availability of iron in three food grade isolated soybean proteins and to evanuate the influence of these proteins on iron added to the diet from a source of known high biological availability. Ferrous sulfate was used as the standard iron source in all experiments. The biological availability was measured by a 14-day hemoglobin repletion after a 4 week depletion period using multiple dose response and comparing the test samples and standard iron source by the slope ratio assay procedure. The relative iron bioavailability for three isolated soybean proteins was A = 60%; B = 64% and C = 59% with a mean value of 61%. Autoclaving isolated soybean protein B at 108.4 degrees improved iron bioavailability over the unheated samples while isolated soybean protein A was unaffected by this treatment. Iron added to the diets containing isolated soybean protein had bioavailabilities similar to that of iron present in the soybean which supports the common dietary iron pool hypothesis. The high iron content (0.18 mg/g protein) coupled with the bioavailability data make the isolated soybean proteins a good dietary iron source.
TL;DR: Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule, and half-life was not influenced by urine pH probably as a result of the narrow range of urine pHs observed in the subjects.
Abstract: Dose tolerance and pharmacokinetic studies of pseudoephedrine sustained action capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg capsules every twelve hours for seven consecutive days in a double-blind parallel design study. Although only one subject in the 150 mg group was discontinued prematurely from this study, a large number of side effects typical of CNS stimulation were seen. A placebo effect might account for a portion of these complaints, however symtoms evaluated as being due to drug were significantly more severe and persistent in the 150 mg group. Pulse rates showed a persistent and significant increase while systolic and diastolic blood pressure fell from the baseline values in both groups. A pharmacokinetic analysis of the pseudoephedrine plasma concentration-time data provided estimates of half-life and the volume of distribution/availability ratio. The values obtained were in good agreement with values reported by others. Half-life was not influenced by urine pH probably as a result of the narrow range of urine pHs observed in the subjects. Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule.
TL;DR: Admixture of cholesterol trimethyl acetate to progesterone in proportions that formed solid solutions resulted in significant increase of oral bio-availability in humans and studies in rats have indicated that increased effectiveness was achieved by increasing lymph absorption.
TL;DR: The concepts of drug bioavailability and bioequivalency are placed in a broader perspective and emphasize the now Food and Drug Administration accepted, although less familiar, approach of using pharmacological data for bioavailability analyses.
Abstract: Pharmacokinetics is that branch of pharmaceutical science which provides the mathematical relationships betwee� the dynamic (time-dependent) manner in which a drug is released to enter the body and the time course of the pharmacological effects that ensue. In this context, pharmacokinetics may be described as quantita tive pharmacology (I). Once a drug has entered into the body, Le. when it becomes bioavailable, there is little that can be done, outside of antidotal procedures, to further affect the time course of its effects on the organism. Therefore, bioavailability is of cardinal importance in clinical pharmacology in that it is the control of drug bioavailability which provides the only practical means by which a drug's therapeu tic and toxic effects can be controlled in a necessarily routine manner. Despite the many excellent treatments of the topic of bioavailability found in the literature (2-7), confusion still exists as to the precise meaning of the term as well as the relationship of bioavailability to bioequivalency; the introduction of in vitro bioequivalency into the federal regulation ·of drug products has also added to the confusion (2, 8). The majority of the published reports on bioavailability are principally oriented to drug product bioavailabilitylbioequivalency testing and procedures that employ chemical and radiological assay techniques to monitor parent drug and/or metabo lite levels in blood and/or urine. The biological, formulation, and manufacturing factors that also affect bioavailability have also been well discussed (9). Therefore. this report seeks to place the concepts of drug bioavailability and bioequivalency in a broader perspective and emphasize the now Food and Drug Administration accepted, although less familiar. approach of using pharmacological.data for per forming drug bioavailability_ analyses. The relative attributes of using direct assay and pharmacological data are compared.
TL;DR: The effect of a kaolin--pectin suspension on the bioavailability of orally administered digoxin was evaluated when both drugs were given concomitantly and when their time of administration was separated by 2 hr.
TL;DR: The single dose bioavailability study was predictive of the steady state findings and the bioavailability of digoxin capsules is equivalent to that of a solution and significantly greater than that of the reference tablet formulation.
Abstract: The bioavailability of single doses of digoxin capsules (0.4 mg), digoxin solution (0.4 mg) and reference tablets (0.5 mg) was compared with that of single intravenous doses (0.4 mg) of digoxin using measurement of 24 hour urinary excretion and area under the plasma concentration curve. The absolute systemic availability of all three oral preparations was significantly less than 100 percent. The bioavailability of capsules and solution was nearly identical (79 percent and 76 percent, respectively, as assessed with values for area under the concentration curve and 65 percent and 62 percent as assessed with urinary excretion values); both forms had greater systemic availability than the tablet, which had bioavailability values of 50 percent using area under the curve and 41 percent using urinary excretion. Capsules and solution also were similar in peak plasma digoxin levels achieved (3.7 and 3.1 ng/ml), time of peak concentration (0.8 and 0.6 hour after dosage) and apparent first order absorption half-life (11.3 and 10.2 minutes); both capsules and solution differed significantly from tablets (peak level 1.6 ng/ml, time of peak concentration 1.2 hours and absorption half-life 27.1 minutes). Single dose findings were substantiated when steady state plasma levels and 24 hour urinary excretion values were measured from days 11 through 16 of the period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and urinary excretion values (45.1 percent of dose) for capsules were nearly identical to those for solution (0.69 ng/ml and 42.5 percent of the dose), and values for both capsules and solution were significantly greater than those for tablets. Within- and between-subject variation in bioavailability was similar for the three oral preparations. Thus the single dose bioavailability study was predictive of the steady state findings. The bioavailability of digoxin capsules is equivalent to that of a solution and significantly greater than that of a reference tablet formulation.