Magnetic characterisation of rat muscle tissues after subcutaneous iron dextran injection.

Ex vivo freeze-dried rat muscle tissues, collected at different times t after a single dose of subcutaneously injected iron dextran, have been magnetically characterised. The AC susceptibility of the tissues shows an overall superparamagnetic behaviour and the dependence on t of, especially, the out-of-phase component is remarkably systematic despite the fact that each tissue originates in a different rat individual. The experiments show that the akaganéite (beta-FeOOH) nanoparticles contained in the injected drug are progressively degraded in the living tissue and, at times of the order of 1 month and for all the analysed rat individuals, converge to a magnetically well-defined species with much narrower magnetic activation energy distribution than iron dextran. Thorough transmission electron microscopy experiments of the same tissues indicate the presence of oxyhydroxide particles, whose size decreases for increasing t in agreement with the interpretation of the magnetic susceptibility. The conclusions drawn from the magnetic study do well correspond to the properties of the whole tissue since no biochemical extraction work has been done. The AC susceptibility appears to be a valuable and complementary tool in pharmacological studies of iron-containing drugs.

Limited capacity of neonatal rabbits to eliminate enrofloxacin and ciprofloxacin.

The pharmacokinetics of enrofloxacin (ENR) and ciprofloxacin (CIP) in newborn and young rabbits were studied. Rabbits of different ages (1-, 8-, 16-, and 30-day-old) were administered, by the intraperitoneal route (i.p.), a dose of 7.5 mg of either drug/kg. In 1-, 8-, and 16-day-old rabbits, blood samples were drawn by cardiac puncture, under light ether anaesthesia, at predetermined times after drug administration. In 30-day-old rabbits, serial blood samples were drawn through an arterial catheter. Plasma was immediately obtained and analysed using an HPLC method. ENR and CIP plasma protein binding was also determined. The plasma pharmacokinetic profiles of ENR and CIP obtained for 30-day-old rabbits agreed with those reported in the literature for healthy adult rabbits. Nevertheless, significant differences were observed for the body clearance, the slope of the terminal phase, the volume of distribution, and the area under the curve when compared with those for younger animals (1-, 8-, and 16-day-old rabbits), indicating a limited capacity of neonatal rabbits to eliminate ENR and CIP. No differences were found when we compared the calculated values for ENR or CIP plasma protein binding as a function of the postnatal age, indicating that development does not seem to alter the free fraction of these drugs in the rabbit. Taking into account that extensive placental and milk transfer has been reported for these drugs after administration to pregnant or nursing rabbits, a cautious, attitude regarding their use in these animals must be adopted.

Deacetylation of diltiazem by several rabbit tissues.

PURPOSE: Diltiazem (DTZ) undergoes extensive metabolism yielding several metabolites, some of which retain a certain degree of pharmacological activity. N-demethylating activity has been detected mainly in the liver. Nevertheless, the organs involved in the formation of the deacetylated metabolite of DTZ (M1) have not been fully elucidated. In order to address this issue, we have carried out in vitro studies using the blood, lung, brain, small intestine, and liver as enzyme sources. METHODS: DTZ (1,000 ng/ml) was incubated in 10,000 x g supernatant homogenates of selected tissues or in whole blood for 240 minutes at 37 degrees C. Multiple samples were withdrawn, and DTZ and its metabolite M1 were assayed by HPLC. RESULTS: The apparent degradation rate constant of DTZ was in the rank order blood > lung > brain > liver > small intestine. This trend can also be observed for the AUC and for the percentage of DTZ metabolized. In all the tissue homogenates examined there was a net production of the deacetylated metabolite. The M1 metabolite was also detected in the blood (500 ng/ml after 240 minutes of incubation). CONCLUSIONS: The widespread distribution of the DTZ deacetylase activity described in this study suggests that extrahepatic metabolism of DTZ to M1 may play a relevant role in the overall pharmacokinetics of DTZ.

Pharmacokinetics of ciprofloxacin in sheep after single intravenous or intramuscular administration.

The disposition and urinary excretion of ciprofloxacin (CIP) following intravenous (IV) or intramuscular (IM) administration of 7.5 mg/kg body weight in sheep (n = 5) was studied. The intravenous plasma concentration curve was best described pharmacokinetically by a two-compartment open model, while the intramuscular administration data fitted better to a one-compartment open model. Mean elimination half-lives after IV and IM administration were 72 and 184 minutes, respectively. The absorption of intramuscularly administered CIP in sheep was fast: maximal plasma concentration (Cmax) was reached quickly (tmax 31.93 min) and attained values of 0.69 +/- 0.27 mg/l. The bioavailability was 49%. The urinary data showed a significant decrease in the elimination rate constant of CIP when CIP was administered intramuscularly. The other parameters calculated did not display differences between the two routes of administration. The results obtained suggest that when CIP was administered by the IM route in the assayed dose, it was able to maintain serum concentrations above the MIC of most common pathogens over an 8-hour period.

Penetration of enrofloxacin and ciprofloxacin into breast milk, and pharmacokinetics of the drugs in lactating rabbits and neonatal offspring.

OBJECTIVE: To determine the pharmacokinetics and milk penetration of enrofloxacin (ENR) and ciprofloxacin (CIP) in lactating rabbits and their disposition in suckling rabbits. DESIGN: Prospective cross-over study. ANIMALS: 6 lactating New Zeland White rabbits and their offspring (16 days after parturition). PROCEDURE: Serial plasma and milk samples were assayed by use of a high-performance liquid chromatography technique. In vitro protein binding in plasma and skim milk was measured by ultrafiltration. Skim-to-whole milk ratio also was determined. The time course of ENR and CIP was fitted by nonlinear least squares regression analysis, and the pharmacokinetic variables were compared. RESULTS: The time courses of ENR and CIP in plasma were similar in lactating adult rabbits (mean body clearances, 23.9 and 27.2 ml/min/kg of body weight, for ENR and CIP, respectively). Observed milk-to-plasma ratios (M/P) were determined, using the area under the milk and plasma concentration versus time profiles (ENR, 2.59; CIP, 3.61). Predicted M/P (ENR, 6.35; CIP, 3.04) were calculated from in vitro measurements. Body clearance calculated for ENR and CIP in suckling rabbit pups involved a decrease of 80 and 74%, respectively, over that found in lactating animals. CONCLUSIONS: Observed CIP M/P were correlated to predicted values, which strengthens the argument that CIP passes into the milk by nonionic diffusion. The lack of correlation between observed and predicted ENR M/P pointed out that ENR undergoes faster elimination from milk than that predicted by the diffusional model. Diminished elimination capacity observed in suckling rabbits would result in greater exposure than that predicted from concentrations alone.

Ciprofloxacin pharmacokinetics in dogs following oral administration.

This paper reports the variation of the pharmacokinetic parameters of ciprofloxacin (CIP) following oral administration of three single doses (10, 20 and 40 mg/kg body weight (b.w.)) to dogs. Plasma and urine samples were assayed by HPLC. The plasma vs. time data were submitted to classical compartmental kinetic analysis (one-compartment open model with a lag time) and to non-compartmental data analysis. The maximal plasma concentrations attained after administration of 10 and 20 mg/kg were 1.55 and 3.08 mg/l, respectively, and agree with results reported in the literature for this species. The absorption was slower and showed a longer and more variable lag time when the dose increased. The elimination rate was significantly smaller after administration of the 40 mg/kg (0.0014/min) than 10 and 20 mg/kg doses (near 0.0024/min). AUC/D also showed significant differences. The non-linearity of CIP pharmacokinetics after oral administration was demonstrated by fitting the data AUC vs. dose to a quadratic equation.

Disposition of ciprofloxacin in the isolated perfused rat liver.

Ciprofloxacin (CIP), a quinolone with a wide spectrum of antibacterial activity, was studied in the isolated perfused rat liver. Three concentrations (1, 5, and 25 mg/liter) were used in the perfusion medium to check whether hepatic transformation and/or biliary elimination of this drug was dose-dependent. Pharmacokinetic parameters of CIP in the perfusion medium were similar when normalized for the dose at all three concentrations. Some dose-dependent changes were observed in biliary excretion of CIP. CIP biliary clearance and the percentage of excreted drug differed at 25 mg/liter and the lower concentrations. In addition, the chromatograms of the bile samples at the highest dose showed a peak that never appeared at the lower concentrations. This evidence, together with the zwitterion characteristics of CIP, reaching a bile/medium area under the concentration-time curve ratio > 10, suggests that an active transport mechanism is involved in the drug's biliary excretion, as has been demonstrated for its renal elimination.

Disposition of ciprofloxacin following intravenous administration in dogs.

The pharmacokinetics of ciprofloxacin (CIP) following intravenous administration in dogs have been investigated. The drug was administered at three doses (2.5, 5 and 10 mg/kg body weight) and was assayed in biological fluid samples (plasma and urine) by an HPLC method. The plasma concentration-time curves were best described by a two-compartment open pharmacokinetic model. The drug was widely distributed (Vd(area) almost 3 l/kg), being distributed in the dog more rapidly than in other species (t1/2(lambda 1) 3 min approximately). The elimination half-life (t1/2 lambda 2) was 129-180 min which is similar to values obtained in other species. The unchanged drug eliminated in urine was less than 37% of the administered dose, which is less than the values obtained in humans, calves and pigs. The glomerular filtration rate and the renal clearance of CIP in the dog suggest that renal elimination probably occurs mainly by glomerular filtration. The results showed that the pharmacokinetics of CIP, as in other species, was linear in dogs in the dose range studied.

Placental transfer of enrofloxacin and ciprofloxacin in rabbits.

Placental transfer of enrofloxacin and ciprofloxacin was evaluated, using a rabbit in situ perfusion model. A two-step infusion program was carried out to obtain steady-state maternal plasma concentrations of these drugs. For each compound, the placenta in 5 rabbits was perfused for 200 minutes with Earle's enriched bicarbonate buffer at flow rate of 1.5 ml/min. To assess reliability of the model, most of the determinants of placental transfer (maternal and fetal pH, gas balance, heart status, rectal temperature, and protein binding) were controlled. In addition, the infusion program included administration of antipyrine, a commonly used indicator of placental exchange. Drug concentrations were measured in maternal plasma and perfusate by use of a high-performance liquid chromatographic assay. Plasma protein-binding estimation indicated no differences between the drugs. Placental clearance of the drugs was significantly (P < 0.01) different (0.88 +/- 0.13 ml/min for enrofloxacin and 0.06 +/- 0.02 ml/min for ciprofloxacin). These values accounted for 81 and 5%, respectively, of the placental clearance found for antipyrine. These results indicate that caution must be taken when enrofloxacin is to be used during pregnancy, and suggest the need to extend this type of experiment to species that can be exposed to these drugs used for therapeutic or prophylactic purposes.