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.

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%.

General treatment of the enterohepatic recirculation of drugs and its influence on the area under the plasma level curves, bioavailability, and clearance.

A general treatment of enterohepatic recirculation of drugs has been developed based on the fraction of drug in systemic circulation that is excreted in the bile and the fraction of drug reabsorbed from the gut that reaches systemic circulation in each enterohepatic cycle. The deduced equations make it possible to establish mathematical relationships between the areas under the blood level curves (AUC) of a drug when administered to normal and bile duct-cannulated animals and to predict the effect of enterohepatic recycling on bioavailability and clearance. The results were compared with those obtained by other authors using different approaches to enterohepatic recirculation, and some discrepancies were found in the equations describing the effect of enterohepatic recycling on AUC and bioavailability of drugs. The cause of such discrepancies and the problems associated with the prediction of hepatic extraction ratio from in vitro studies are discussed.

Nonlinearities in amoxycillin pharmacokinetics. I. Disposition studies in the rat.

Several features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady-state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3.5 to 7.0 mg kg-1 for intravenous bolus, and from 4.6 to 20.0 micrograms min-1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intravenous dose is substantially increased (28.0 mg kg-1 bolus), plasma clearance tends to stabilize, probably because saturation of the active tubular secretion of amoxycillin takes place at these doses. Extrarenal clearance seems to remain linear throughout the entire dose range. On the basis of these observations and a review of selected bibliography, an interpretation of the kinetic disposition behaviour of amoxycillin in man is attempted.

Nonlinearities in amoxycillin pharmacokinetics. II. Absorption studies in the rat.

Most factors influencing amoxycillin oral absorption are, even today, unknown. Since many dosage schedules have been shown to lead to incomplete absorption, it would be desirable to find a suitable animal model where these factors could be studied in depth. In this paper, it is shown that, in the rat, plasma level curves obtained after oral doses of 7 and 28 mg kg-1 are poorly fitted using first-order absorption kinetics and that the best fit is obtained through the use of an input equation combining zero and first-order kinetics. In contrast, plasma level curves found after intraduodenal administration of amoxycillin solutions (7 mg kg-1) are well fitted by first-order input kinetics. It would seem that precipitation of some dose fraction of the orally administered antibiotic may occur in proximal gastrointestinal areas; this plays an important role in absorption profiles and prevents any possible saturation phenomena associated with active intestinal transport of the antibiotic. A comparative study of available human oral data revealed close similarities with those found in rats. As a result, the plasma level curve fitting was greatly improved by the use of the input function described here for the rat. Although oral bioavailability (as assessed from urinary excretion data) is lower in this latter species, the use of suitable correction factors led to superimposable plasma level curves in the two species, as occurred in previously reported disposition studies.

Pharmacokinetics and bioavailability of diclofenac in the rat.

Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac bioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.

Evidence of a specialized transport mechanism for the intestinal absorption of baclofen.

Absorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis-Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis-Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12.0 mg h-1 and 8.0 mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but comparable absorption rates were found in the proximal and distal segments of the small intestine, whereas in colon, drug absorption was negligible. Baclofen transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. If these results were extrapolated to humans, they would explain the excellent bioavailability profiles reported for baclofen at normal doses in spite of its physicochemical properties, which do not favour passive diffusion. Based on the same principle, the administration of usual doses at shorter time intervals could be recommended, instead of high, when higher plasma levels at steady-state are needed. On the other hand, more than 8-h sustained-release preparations of baclofen should, probably, be avoided.