Prediction of the residue levels of drugs in eggs, using physicochemical properties and their influence on passive diffusion processes.

Based on a physiologically based pharmacokinetic model, describing the relationship between the plasma concentration of a drug and its deposition into eggs, general transport constants into yolk and albumen were derived, for a number of compounds, using experimental data from literature. Using only generally accepted concepts in passive diffusion theory, these transport constants were used to derive and calibrate general equations, describing the transport into yolk and albumen, in terms of the physicochemical properties of a drug. It is shown that, in theory, it is possible to calculate/predict the transport constants, using the physicochemical parameters: pKa and plasma protein binding. For a number of sulfonamides, the model was used to predict their distribution between egg yolk and albumen; the outcome was compared to data found in literature. Within this dataset, the lipophilic nature of a drug does not seem to play a major role in explaining the distribution ratio of a drug between albumen and yolk.

Kinetic modelling and residue depletion of drugs in eggs.

1. A physiologically-based pharmacokinetic model was developed for the purpose of describing the relationship between plasma concentration of drugs and their deposition into eggs. 2. By incorporating the physiology of egg formation into the model, the transfer of drugs into the egg albumen and yolk could be described using rate constants. 3. The model was used to describe concentrations in albumen and yolk of sulphanilamide, sulphaquinoxaline and pyrimethamine as a function of time using datasets from the literature. 4. The model could be used as a tool to obtain an insight into those properties of a drug which are responsible for the amount of residue in eggs, and could help in the design of critical studies for determining withdrawal periods for eggs.

Fish intake and cardiovascular risk among middle-aged Japanese in Japan and Brazil.

BACKGROUND: Studies of immigrant populations are useful for analysis of the effects of environmental factors on cardiovascular disease. We have examined the association between dietary habit of fish intake and cardiovascular risk. METHODS: Population-based samples of 433 middle-aged Japanese men and women in Japan (Shimane (group JS) and Okinawa (group JO)) and 269 Japanese immigrants in Brazil (Sâo Paulo (group BS) and Campo Grande (group BC)), who had originally moved to Brazil mainly from Shimane and Okinawa, were recruited to the study. They underwent blood pressure measurement, 24-h urine collection, blood tests and electrocardiographic examination, and completed a dietary questionnaire. RESULTS: There was a significant gradient through the groups, from JS to JO, BS and BC with respect to the prevalence of obesity, hypertension, increased glycohaemoglobin concentrations and ST-T segment change on the electrocardiogram (prevalences for men and women combined: group JS 2.0%, group JO 3.8%, group BS 3.9% and group BC 9.0%; P < 0.025). The prevalence of hypercholesterolaemia was noted more frequently in groups BS and BC. Twenty-four-hour urinary taurine excretion in both sexes and n-3 polyunsaturated fatty acids (n-3 PUFA) in plasma phospholipids in men were significantly higher in groups JS and JO than in groups BS and BC. A striking negative gradient in the frequency of fish intake per week was found from group JS (men/women, 4.7/4.8) to groups JO (3.8/3.6), BS (1.9/1.6) and BC (0.5/0.5). CONCLUSIONS: This study suggests a possible association between fish intake and reduced cardiovascular risk, through the beneficial effects of taurine and n-3 PUFA and a habitual low intake of calories and fat.

Cardiovascular diseases and alimentary comparison study: preliminary analysis from Brazil.

The Cardiovascular Diseases and Alimentary Comparison (CARDIAC) Study (1) was designed to study the relationship of dietary factors to blood pressure (BP) and other major cardiovascular disease (CVD) in widely different populations of both industralized and developing countries. The primary aim of the research was to test specific hypotheses linking the intake of certain dietary constituents, e.g., sodium (Na), potassium (K), calcium (Ca), and protein, to BP (core study). The final aim was to contribute to the scientific information base required to guide the formulation of dietary goals for the primary prevention of CVD. The results of the preliminary analysis of data from Brazil in 57 inhabitants (22 men and 35 women) suggest a nonsignificant statistical correlation of Na intake estimated by urinary Na excretion and diastolic BP (DBP) and systolic BP (SBP) (p greater than 0.05), K intake estimated by urinary K excretion for DBP and SBP (p greater than 0.05), and taurine intake estimated by taurine urinary excretion for DBP and SBP (p greater than 0.05). A positive correlation was found between body mass index (BMI) and BP (p less than 0.01), for both DBP and SBP.

Systemic arterial hypertension: results of the change from pharmacological to nonpharmacological treatment.

The effect of nonpharmacological measures--diet (restriction to salt), weight reduction, stress avoidance, stopping smoking, and exercise--are analyzed after being applied to 145 hypertensive individuals (average age 60.3 years) using antihypertensive drugs for 6 months without nonpharmacological therapy. The initial systolic arterial pressure was 177 mm Hg; at the end of 4 weeks of treatment, it was 151.3 mm Hg. The initial diastolic arterial pressure was 98.5 mm Hg; at the end of 4 weeks it was 89.8 mm Hg (p less than 0.001). The proposal for treating hypertension with nonpharmacological measures represents a challenge and opens a new horizon to scientific research.

The absorption of a new sustained release furazolidone formulation from the digestive tract of piglets and calves.

Chyme concentrations and total recoveries of furazolidone (5 mg/kg body-weight) were determined by a HPLC-method, after oral administration of two different furazolidone formulations to piglets (n = 6) and pre-ruminant calves (n = 8), provided with an ileal re-entrant canula. Additional blood samples were taken from the calves to measure the time dependent plasma levels of furazolidone. In the case of the normal crystalline preparation, the results indicate an almost complete absorption of the drug from the upper parts of the digestive tract. In both species, 96-99% of the dose had been absorbed by the time it reached the end of the ileum. The mean ileal recovery of the newly developed furazolidone formulation in calves and piglets was 14% and 38%, respectively. In calves the observed maximum plasma concentrations of furazolidone after oral application of the sustained release formulation were 14 times lower than with the normal crystalline preparation.

The elimination of furazolidone and its open-chain cyano-derivative from adult swine.

1. A sensitive method for the determination of 3-(4-cyano-2-oxobutylidene amino)-2-oxazolidone, the open-chain cyano-derivative of the veterinary drug furazolidone, in swine plasma and tissues is described. 2. After dosing adult swine orally with furazolidone (690 mg/animal per day) for 10 days no furazolidone was detected in liver, kidney and muscle (less than 2 ng/g). The half life of furazolidone as measured from the terminal phase of the plasma curves was 45 minutes. In urine, small amounts (less than 0.3% of total dose) of furazolidone were detected. 3. In contrast to other animals, 3-(4-cyano-2-oxobutylidene amino)-2-oxazolidone is a minor metabolite in swine with a plasma half life of 4 h. No cyano-derivative was detected in liver and kidney (less than 5 ng/g) 2 h after the last administration of furazolidone; 24 h after the last administration, the concentration in plasma was less than 2 ng/ml and in muscle less than 5/g. 4. The cyano-derivative was not mutagenic in the Salmonella/microsome test, with or without metabolic activation.

Quantitative urine collection in renal clearance studies in the dog.

A double-walled urinary catheter is described which allows rapid and quantitative urine collection at short time intervals. The catheter consists of a polyurethane outer cannula in which a small Teflon cannula is inserted. The essential of the catheter is that at the end of a collection period, residual urine in the bladder can be collected completely via the outer cannula by flushing the bladder with physiological salt through the inner cannula. In this manner urine can be collected in a very reproducible way at intervals down to 5 min. The use of the catheter was illustrated in a study on the renal clearance of hippuric acid in the dog. Plasma concentration and renal excretion rate were followed after i.v. injection of 0.9 g sodium hippurate. In accordance with previous studies, it was found that the renal excretion of hippuric acid consisted of glomerular filtration and active tubular secretion. A large variability was observed in the tubular transport maximum (3,800-11,600 micrograms/min) and the Michaelis-Menten constant (22-190 micrograms/ml), which were used to characterize the secretory system. The interpretation and value of these transport parameters is discussed briefly.

Simultaneous kinetic modelling of plasma levels and urinary excretion of salicyluric acid, and the influence of probenecid.

In a fundamental study on the effect of probenecid on the plasma kinetics and the renal handling of some organic anions known to be transported by the tubular secretion mechanism in the mammalian kidney, we measured plasma levels and urinary excretion rates of salicyluric acid in male Beagle dogs, after intravenous application of salicyluric acid, with and without co-administration of probenecid. The animals were anaesthetized with sodium pentobarbital (30 mg/kg) and provisions were made for blood and urine sampling. In order to obtain a sufficiently high and constant urine flow, an infusion of a solution containing 5% inulin (2 ml/min) was given throughout an experiment. Inulin was added for measurement of the glomerular filtration rate. Linear plots of the urinary excretion rate against the average plasma concentration of each urine collection period were drawn as an illustrative way to depict the relation between plasma concentration and urinary excretion rate. In order to quantify the effect of probenecid on the plasma kinetics and the renal handling of salicyluric acid, we conceived a dynamic model, able to describe changes in plasma kinetics as well as in urinary excretion. The effect of probenecid on the pharmacokinetics of salicyluric acid can be adequately described in terms of a non-competitive inhibition of the tubular secretory mechanism for salicyluric acid. Parameters for the description of this interaction were estimated by a simulation procedure with the aid of the computer program CSMP III.

Comparative plasma ampicillin levels and bioavailability of five parenteral ampicillin formulations in ruminant calves.

Plasma ampicillin concentrations were determined in an eight-ways crossover trial involving six ruminant calves, which were treated intravenously (i.v.) with sodium ampicillin at 15.5 mg/kg and intramuscularly (i.m.) with five different ampicillin trihydrate or ampicillin anhydrate formulations at 7.7 mg/kg. The mean plasma concentration-time curve (Cp) after intravenous ampicillin sodium administration was described biexponentially, as: Cp = 38.8 e -0.0268t + 0.45 e -0.0058t. Intramuscular injection, into the lateral neck, of Ampikel-20 and Polyflex resulted in 100 per cent bioavailabilities within 12 h post injection (p.i.), but the biological half-lives (t1/2) were different, being 2.1 and 3.8 h, respectively. Ampikel-20 produced the highest peak plasma drug concentrations (mean C max :4.8 microgram ampicillin/ml). After intramuscular injection of Penbritin the mean bioavailability for the first 12 h p.i. was 63 per cent, the mean t1/2 was 5.9 h, and the mean Cmax was 1.8 microgram/ml. Treatment with Albipen and Duphacillin resulted in low plasma ampicillin levels, which were maintained for 3 to 6 days p.i., limited bioavailability during the first 12 h p.i., and a mean t1/2 of 22.2 and 11.9 h, respectively. Plasma concentrations of ampicillin from four hours onwards after i.m. and s.c. administration of Ampikel-20 at a dose level of 15.5 mg/kg were similar. The duration of potentially therapeutic plasma ampicillin concentrations after administration of each formulation is presented. Pre-slaughter withdrawal times for diseased calves are suggested for the different formulations studied.

Kinetic modeling of the renal excretion of iodopyracet in the dog.

In a fundamental study on the kinetics of the urinary excretion of a number of agents secreted by the renal tubules of the mammalian kidney, we measured plasma levels of iodopyracet after intravenous application to male beagle dogs. The animals were anesthetized throughout the experiments with sodium pentobarbital, and provisions were made for the collection of blood and urine samples. In order to obtain a sufficiently high urine flow throughout the experiments, the dogs received a constant infusion of a solution containing 5% mannitol and 0.5% inulin. Inulin was added for measurement of the glomerular filtration rate. Linear plots of the urinary excretion rate against the average plasma concentration of each urine collection period were drawn as an illustrative way to depict the relation between plasma concentration period were excretion rate. For the mathematical description of these so-called tubular titration curves, a dynamic model was conceived to characterize the various renal transport mechanisms. Parameters for the description of the renal handling of iodopyracet were estimated by a simulation procedure with the aid of the computer program CSMP III.

Effect of Tomanol on the pharmacokinetics and tissue distribution of penicillin G in dairy cows.

Following concomitant intravenous administration of Tomanol and sodium penicillin G to six Dutch Friesian dairy cows a significant decrease in total body clearance of penicillin (34.7%) and a prolongation of the elimination half-life of penicillin (17.2%) was observed. Tomanol did not affect other pharmacokinetic parameters such as rate constants of drug transfer (k12/k21, alpha en beta), distribution volume of the central compartment (V1), and extrapolated serum drug levels. Intravenous or intramuscular administration of Tomanol had no effect on the tissue distribution of penicillin G, because neither a change in the ratios of muscle to serum and of kidney cortex to serum nor a change in an induced steady state level of low penicilline G serum concentrations was observed. From the data obtained it is concluded that concomitant Tomanol administration with penicillin induces an elevation of the serum penicillin concentration and prolongs the persistence of penicillin residues in carcass meat and organs.