Francisca Torres-Molina

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 hioavailability 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.

Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats.

The time-dependent elimination kinetics of all-transretinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of timedependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg−1 and 0.40 mg kg−1), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg−1), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h−1 kg−1 of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg−1) was ∼8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.

Non‐linear Intestinal Absorption Kinetics of Cefadroxil in the Rat

Abstract— Absorption of Cefadroxil in a selective intestinal absorption area (the proximal third of the small intestine) of the anaesthetized rat, at seven initial perfusion concentrations, ranging from 0·01 to 10·0 mg mL−1, is shown to be a non‐linear transport mechanism. With the aid of computer‐fitting procedures based on differential and integrated forms of Michaelis‐Menten equation, Vm and Km values of 36·7–37·3 mg h−1 and 12·0–13·0 mg, respectively, were found. The statistical parameters were better than those obtained both for first‐order and for combined Michaelis‐Menten and first‐order kinetics. There is no evidence for substantial passive diffusion processes. The results reported here, together with allometric considerations and literature data analysis, may help to explain some particular non‐linear features of plasma level curves associated with the administration of fairly high oral doses of Cefadroxil to humans.

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.

Determination of busulfan in human plasma using high-performance liquid chromatography with pre-column derivatization and fluorescence detection

A rapid, sensitive and reproducible high-performance liquid chromatographic assay for busulfan in human plasma was developed. After extraction of plasma samples with acetonitrile and methylene chloride, busulfan and the internal standard [1,5-bis(methanesulfonyloxy)pentane] were derivatized with 8-mercaptoquinoline to yield fluorescent compounds which were detected with a fluorescence detector equipped with filters of 360 nm (excitation) and 425 nm (emission). Calibration graphs showed a linear correlation (r>0.9990) over the concentration range of 20-2000 ng/ml. The recovery of busulfan from plasma standards was 70+/-5%. The detection and quantification limits for busulfan in plasma samples were established at 9 ng/ml and 20 ng/ml, respectively. The intra- and inter-assay variations were lower than 8% and 10%, respectively. The applicability of the method was verified by analyzing the plasma concentrations of busulfan in a patient to whom it was administered orally on two different days.

Zinc Uptake in Five Sectors of the Rat Gastrointestinal Tract: Kinetic Study in the Whole Colon

AbstractPurpose. The uptake of zinc as acexamic acid salt in the rat gastrointestinal tract, using an in situ static technique, was studied. Our aim was to investigate an absorption window for zinc and the uptake kinetics in the colon. Methods. To detect selectivity phenomena in zinc absorption, buffered saline solutions of zinc (50 µg/ ml) were perfused in stomach, whole colon and three 33-cm fractions of the small intestine (proximal, middle and distal segments). To characterize zinc uptake kinetics in whole colon, five different zinc concentrations (5, 25, 50, 150 y 250 µg/ml) were assayed. Zinc secreted into the gastrointestinal tract during the experiments was deducted from the uptake. Results. Zinc secretion was characterized as an apparent zero-order process for all the studied segments (mean secretion rate = 0.10 ± 0.03 µg/(ml × min)). The stomach exhibited little ability to absorb zinc (apparent first order rate constant = 0.17 ± 0.07 h−1), whereas the highest transport rates were found in the last two thirds of the small intestine and colon (first order constants: 0.66 ± 0.13 h−1, 1.00 ± 0.06 h−1,0.97 ± 0.14 h−1, 0.96 ± 0.19h−l for proximal, middle, distal and colon segments, respectively). Zinc uptake in the colon was characterized by means of a Michaelis-Menten and first-order combined kinetics, with the following parameters: Vm = 0.36 ± 0.02 µg/(ml × min), Km = 18.01 ± 0.40 µg/ ml and Ka = 0.40 ± 0.01 h−l. Conclusions. Zinc is preferably absorbed in the middle and distal parts of the rat gastrointestinal tract. In the colon a saturable mechanism may be involved in apparent absorption.

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.

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 bio-availability 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.

Physiological pharmacokinetic model for ceftazidime disposition in the rat and its application to prediction of plasma concentrations in humans

Abstract A physiological pharmacokinetic model for the disposition of ceftazidime in the rat was developed. The model is composed of 10 compartments which represent most of the organs and tissues of the body. Ceftazidime concentration-time profiles in the organs and tissues represented in the model were simulated and compared with the observed concentration-time data after i.v. administration of 5 and 20 mg of antibiotic. The model gave an acceptable description of the observed data. The steady-state volume of distribution and total clearance of ceftazidime in healthy humans predicted from data obtained in the rat (0.21 l/kg and 113 ml/min, respectively) were similar to the values reported for these parameters by several authors. The model was scaled to humans by using the tissue volumes and plasma flow rates corresponding to a standard man, the tissue-to-plasma partition coefficients determined in rats, and the total plasma clearance of ceftazidime observed in humans. Good predictions of plasma concentrations of ceftazidime in normal subjects and patients with various degrees of impaired renal function were obtained.

KINETICS OF THE INTESTINAL UPTAKE OF ZINC ACEXAMATE IN NORMAL AND ZINC-DEPLETED RATS

Abstract— The uptake of zinc as acexamic acid salt in the small intestine of the anaesthetized rat was shown to be a two‐phase process in normal animals. The first phase is rapid mucosal binding which satisfies the Freundlich isotherm equation and which involves about 30 per cent of the initially perfused zinc. The second phase was characterized as an apparent absorption step which obeys Michaelis‐Menten and first‐order combined kinetics, with the following parameters: Vm = 6.51 mg h−1; Km = 2.96 mg; ka = 0.306 h−1. In largely non‐saturated conditions, an apparent global rate constant of about 2.50 h−1 was calculated. No significant interference due to endogenous zinc excretion into the small intestine was observed during the absorption period. In zinc‐deficient animals, the two phases were not so well characterized. Binding was non‐linear and apparent absorption efficiency was much greater at high zinc concentrations, so no evidence of saturable kinetics was found, thus confirming the hypothesis of a homeostatic zinc regulation mechanism.