Distribution of ceftazidime in rat tissues.

The pharmacokinetics and tissue distribution of ceftazidime (CFT), a third generation cephalosporin antibiotic commonly used in clinical practice, were investigated in rats after intravenous administration of the antibiotic. Studies using intravenous bolus administration were carried out at two dose levels (5 and 20 mg) of the antibiotic. Results of these studies showed a linear disposition of CFT, no differences between the arterial and venous plasma compartments, and linear distribution in all of the tissues assayed. Experiments carried out under steady-state conditions after constant infusion of the antibiotic showed that CFT distribution was restricted to the extracellular water of the rat tissues, as deduced from the tissue-to-plasma partition coefficients lower than 1 obtained in these experiments. Concentration of CFT in the extracellular water appears to be equal to that of plasma at the same sampling time.

[Relation between the total plasma IgE concentration and the prevalence of the various RAST (radioallergosorbent) classes of allergy]. / Estudio de la relación entre la concentración plasmática total de IgE y la prevalencia de las distintas clases RAST (Radio-Allergo-Sorbent-Test) de alergia.

The aim of this study was to analyze the prevalence of every RAST (Radio-Allergo-Sorbent-Test) class in terms of total IgE serum level, and to establish the existing relationship between the total IgE level and the probability to obtain a definite specific IgE concentration. The analyzed sample was 352 total IgE values obtained by means of RIA in 611 patients of both sexes and ages from 5 to 15 years [corrected], and the RAST results of every one of them. As mathematical model, Logit was used. It was established a mathematical function [p = 1/(1 + K(-1).IgE-beta)], which allows to calculate the probability to obtain a definite RAST class of allergy for a definite total IgE level. The propounded model establishes that, for a plasmatic IgE level lower or equal to 17.0 kU/l (11.5-23.3), the probability to obtain a specific IgE concentration lower than 0.35 kU/l (absence of allergy) is 0.95. For a total IgE level of 23.32 kU/l (16.43-30.91) there is a probability of 0.95 that RAST result to be negative or slightly positive. Finally, for a total IgE level of 62.6 kU/l (49.20-76.55) specific IgE levels of classes 0 or 1 or 2 would be obtained. The mathematical model allows to predict the most probably RAST class of allergy result once known the total IgE level. It makes easier the allergological diagnostic and facilitates, in some cases, to omit the RAST, with the resulting saving of time and money.

Panhypopituitarism as a consequence of metastase of breast cancer in sella turcica.

A 49-year-old female with breast cancer after mastectomy and chemotherapy was found suffering from diabetes insipidus and panhypopituitarism syndrome. Whole body bone scan showed hyperfixation in sella turcica. This site is extremely rare, especially in breast cancer metastases.

Use of rats chronically cannulated in the jugular vein and the duodenum in pharmacokinetic studies. Effect of ether anesthesia on absorption of amoxicillin.

In order to be able to use unanesthetized rats in pharmacokinetic studies it is necessary to find methods of drug administration and repeated blood sampling that do not stress the animals and therefore avoid possible alterations in the pharmacokinetic parameters caused by stress. Two surgical procedures that permit chronic cannulation of the jugular vein and duodenum of the rat are described in this paper, and the influence of ether (CAS 60-29-7) anesthesia on the intestinal absorption of amoxicillin (CAS 26787-78-0) is evaluated. Amoxicillin (2.2 mg) was administered to the rats by the oral and intraduodenal routes. Intraduodenal administration was performed in conscious rats, whereas oral administration was performed under light and heavy ether anesthesia. In each animal, 10 blood samples were collected through the jugular cannula at fixed times after drug administration and the plasma antibiotic concentration was determined by a microbiological diffusion procedure, with Micrococcus luteus as the test organism. Plasma concentration versus time curves of amoxicillin after intraduodenal and oral administration under light anesthesia were similar, with a slight delay in the tmax value for the oral administration. However, after oral administration of amoxicillin to rats under heavy anesthesia, antibiotic absorption was very irregular, with a decreased Cmax value and an increased tmax value as compared with the other two administration methods. Furthermore, the amount of amoxicillin absorbed in rats given the drug under heavy anesthesia was smaller than in the other two groups. These results suggest that drugs can be administered to rats under light ether anaesthesia without altering their pharmacokinetic features, but heavy anaesthesia can significantly alter their absorption.

Studies on the renal excretion mechanisms of cefadroxil.

The mechanisms of renal excretion of cefadroxil were investigated in conscious rats. The drug was intravenously infused at several infusion rates (0.27, 1.08, 5.40, 12.00, and 31.35 mg/hr), and the total and renal clearances were determined after the steady-state was reached. Renal clearance accounted for approximately 91% of total clearance. Renal clearance of cefadroxil increased from 2.51 +/- 0.39 to 3.57 +/- 0.43 ml/min as the steady-state cefadroxil plasma concentration increased from 1.7 +/- 0.3 to 24.4 +/- 3.8 micrograms/ml, and this has been attributed to a saturable renal tubular reabsorption of the antibiotic. The ratio of unbound cefadroxil renal clearance to glomerular filtration rate was larger than unity, which indicates that the antibiotic also undergoes active renal tubular secretion. When cefadroxil was administered together with cephalexin, an increase in the renal clearance of cefadroxil was observed, which has been attributed to a competitive inhibition of the tubular reabsorption of cefadroxil by cephalexin. A pharmacokinetic model for the renal excretion of cefadroxil was developed, and mathematical expressions showing the relationship between renal clearance and steady-state plasma concentration were deduced.

Low bioavailability of amoxicillin in rats as a consequence of presystemic degradation in the intestine.

Several studies have been carried out to elucidate the causes of the low oral bioavailability of amoxicillin in rats. The hepatic first-pass effect of the antibiotic was estimated by comparing the area under the plasma drug concentration-versus-time curve from time zero to infinity (AUC0-infinity) obtained after injecting the drug into a mesenteric vein with the AUC0-infinity value obtained after injecting the drug into the jugular vein of conscious rats. No hepatic first-pass effect was detected. The bioavailability of amoxicillin after intraduodenal administration was only 51%, and the fraction of the dose remaining in the intestine at the end of the experiment was 4.5%. This was far less than the fraction that did not reach systemic circulation, which indicates a presystemic loss of drug, probably at the intestine. In vitro studies corroborated the fact that amoxicillin is subjected to presystemic degradation by intestinal juices and intestinal tissues. The greatest loss of drug occurred in the complete intestine (45% of the initial amount), and it was mainly due to the action of intestinal tissues (28% of the initial amount) but was also due to the action of intestinal juices (15% of the initial amount). The absorption of amoxicillin in three parts of the intestine (upper, middle, and lower) was also evaluated. The largest AUC0-infinity value and the highest plasma drug levels were obtained when amoxicillin absorption took place in the middle intestine. The smallest AUC0-infinity value and the lowest plasma drug levels corresponded to absorption from the upper intestine.

Nonlinear pharmacokinetics of cefadroxil in the rat.

The pharmacokinetics and bioavailability of cefadroxil in the rat were examined after intravenous and oral administration at three doses (2.5, 10, and 15 mg). Cefadroxil disposition kinetics was clearly nonlinear, with an increase in plasma clearance as the dose increased (2.65 +/- 0.55, 3.17 +/- 0.48, and 3.82 +/- 0.39 ml/min for the three doses assayed). This phenomenon was attributed to a saturable renal tubular reabsorption of the antibiotic. After oral administration, the normalized Cmax was lower for the largest dose (4.6 +/- 0.7 micrograms/ml) than for the other two doses (5.5 +/- 0.5 and 5.4 +/- 0.7 micrograms/ml). Renal excretion of cefadroxil in the rat after intravenous and oral administration was investigated at two level doses (2.5 and 15 mg). No significant differences were found between doses or administration routes, and the mean percentage of dose recovered in the urine for the intravenous and oral routes was 80.7 +/- 6.1% and 76.4 +/- 3.7%, respectively. Cefadroxil bioavailability estimated from plasma levels or from the amounts of drug excreted in the urine was high and ranged from 90% to 100%.

Influence of permanent cannulation of the jugular vein on pharmacokinetics of amoxycillin and antipyrine in the rat.

The effect of chronic cannulation of the rat jugular vein on the pharmacokinetics of amoxycillin and antipyrine administered by the i.v. and oral routes has been evaluated. Animals that received the i.v. dose of amoxycillin on the eighth day after jugular vein cannulation showed decreased clearance (4.0 +/- 0.3 ml/min) and steady-state volume of distribution (105 +/- 8 ml) compared to animals that received the i.v. dose on the fourth day (5.5 +/- 1.1 ml/min and 155 +/- 17 ml, respectively). Rats first dosed by the i.v. route showed an oral bioavailability of 54 +/- 12%, whereas for those first dosed by the oral route the calculated bioavailability was 31 +/- 6%. Antipyrine was administered to rats by the i.v. and oral routes on the first and fourth days after jugular vein cannulation. Animals intravenously dosed on the fourth day showed a decreased clearance (1.9 +/- 0.3 ml/min) compared to rats intravenously dosed on the 1st day (2.7 +/- 0.6 ml/min). Antipyrine bioavailability was larger in animals first dosed by the i.v. route than in animals first dosed by the oral route (173 +/- 43 and 74 +/- 15%, respectively). These results argue against the use of crossover studies in rats with permanently implanted cannulas since kinetic changes induced by cannulation can be larger than previously proposed.