Microdialysis study of imipenem distribution in the peritoneal fluid of rats with experimental acute pancreatitis.

Imipenem distribution was characterized by microdialysis in the peritoneal fluid of rats with experimental pancreatitis. The ratios of peritoneal fluid to blood area under unbound concentration-versus-time curves were close to unity, suggesting that imipenem was not degraded in peritoneal fluid.

Microdialysis study of imipenem distribution in skeletal muscle and lung extracellular fluids of Acinetobacter baumannii-infected rats.

The aim of this study was to investigate imipenem distribution in muscle and lung interstitial fluids of rats with Acinetobacter baumannii pulmonary infection. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.

Investigation of oral bioavailability and brain distribution of the Ind(8)-Val conjugate of indinavir in rodents.

Protease inhibitors are successfully used for the treatment of acquired immune deficiency syndrome (AIDS) although their biopharmaceutical characteristics are not optimal. Prodrugs have therefore been synthesized to increase protease inhibitor bioavailability and brain distribution. Among several compounds tested, a valine derivative of indinavir (Ind(8)-Val) showed promising characteristics using an in-vitro Caco-2 cell model. The objective of this study was to further investigate this compound using in-situ and in-vivo approaches. The pharmacokinetics of indinavir (Ind) and Ind(8)-Val were investigated in rats after intravenous and oral administration. Free indinavir resulting from in-vivo hydrolysis of Ind(8)-Val could not be detected in the plasma of rats receiving Ind(8)-Val. Furthermore Ind(8)-Val bioavailability was only 32% on average compared with 76% for indinavir, and effective permeability coefficients determined with a single-pass intestinal perfusion method were close to 25x10(6)cms(-1) for the two compounds. Brain-to-plasma concentration ratios in the post equilibrium phase after intravenous administration to mice were 9.7+/-8.1% for indinavir and 2.5+/-2.7% for Ind(8)-Val. In conclusion, the promising biopharmaceutical characteristics of Ind(8)-Val suggested from previous in-vitro experiments with the Caco-2 cell model were not confirmed by in-situ and in-vivo experiments.

Simultaneous central nervous system distribution and pharmacokinetic-pharmacodynamic modelling of the electroencephalogram effect of norfloxacin administered at a convulsant dose in rats.

The objective of this study was to investigate the contribution of norfloxacin blood-brain barrier (BBB) transport to its delayed electroencephalogram (EEG) effect in rats. Norfloxacin was injected as a bolus dose of 150 mg kg(-1). Blood samples were collected for total norfloxacin plasma concentration measurements. The corresponding unbound levels were determined in brain extracellular fluid (ECF) using microdialysis. Quantitative EEG recording was conducted during 9 h post-dose. Brain ECF norfloxacin concentrations were much lower than plasma levels (AUC ratio=9.7+/-2.8%) but peaked very early, and concentration versus time profiles were parallel in both biological fluids. The best pharmacokinetic (PK) modelling was obtained by considering that ECF concentrations were part of the central compartment, with a proportionality factor. The peak of EEG effect was delayed and the effect versus plasma concentration curves exhibited a dramatic hysteresis. A PK-pharmacodynamic (PD) effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site successfully described the data. Comparisons of PK-PD parameters estimated from plasma and ECF concentrations show that most of the delayed norfloxacin EEG effect is not due to BBB transport, but also that PD parameters derived from plasma data must be carefully interpreted when drug distribution at the effect site is restricted, as may often be the case for centrally acting drugs.

Dose ranging pharmacokinetics and brain distribution of norfloxacin using microdialysis in rats.

The purpose of this study was to investigate the effect of dose on norfloxacin pharmacokinetics and distribution into the brain extracellular fluid (ECF), in freely moving rats. Unbound concentrations of norfloxacin in hippocampus were determined by microdialysis after an i.v. bolus dose of 12.5, 25, 50, 100, or 150 mg/kg in rats. In vivo recovery of norfloxacin was determined by retrodialysis by calibrator. Among three fluoroquinolones (enoxacin, pefloxacin, and ciprofloxacin) selected as potential calibrators, ciprofloxacin was selected as the best one. Maximum ECF brain norfloxacin concentrations are rapidly obtained but the ECFbrain/plasma areas under curves (AUC) ratios are low and independent of dose with a mean value of 8.2 +/- 5.8%. By contrast, norfloxacin systemic pharmacokinetics was nonlinear, with total plasma clearance decreasing significantly from 23.0 +/- 3.4 to 14.4 +/- 3.8 mL/min/kg when dose increased from 12.5 to 150 mg/kg.

Ignoring pharmacokinetics may lead to isoboles misinterpretation: illustration with the norfloxacin-theophylline convulsant interaction in rats.

PURPOSE: To investigate the norfloxacin-theophylline convulsant interaction in vivo, with an experimental approach distinguishing between pharmacodynamics and pharmacokinetics contributions to the observed effect. METHODS: Male Sprague Dawley rats (n = 38) were infused each compound separately or in different combination ratios. Infusion was maintained until the onset of maximal seizures. Cerebrospinal fluid and plasma samples were collected for high performance liquid chromatography drug determination. The nature and intensity of the pharmacodynamics interaction between drugs was quantified with an isobolographic approach. RESULTS: Isobolograms suggested a relatively marked antagonism between norfloxacin and theophylline at the cerebrospinal fluid (previously shown to be part of the biophase) and dose levels, but not at the plasma (free and total concentrations) levels. These apparent discrepancies could be explained by nonlinear distribution or/and distribution desequilibrium phenomenon. CONCLUSIONS: These findings showed that the quantitative isobolographic approach is appropriate to assess the nature and intensity of the pharmacodynamic interaction between two drugs when data are collected within the biophase, but that data interpretation outside the biophase can be risky due to further pharmacokinetic complexities, in particular slow or/and nonlinear diffusion into the biophase.