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

Abstract

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.

Figure 1

Model for plasma, peripheral and brain compartments, where k₁₂ and k₂₁ are the transfer microconstants between the central and the peripheral compartments, k₁₀ is the elimination microconstant from the body, k_1b and k_b1 are the transfer microconstants between the central and the brain compartments, k_b0 is the elimination microconstant from the brain, k′_b0 is the sum of elimination and redistribution microconstants from the brain and D is the injected dose of norfloxacin. V₁, V₂ and V_b are the volumes of the compartments: central (V₁), peripheral (V₂) and cerebral (V_b), respectively.

Figure 2

Individual unbound norfloxacin concentrations in brain ECF (dashed lines) and total norfloxacin concentrations in arterial blood (solid lines) upon administration of 150 mg kg of body weight⁻¹.

Figure 3

Total concentrations of norfloxacin in plasma, unbound concentrations of norfloxacin in brain and EEG effect versus time for a representative rat. The broken line represents the best PK fit to the measured concentrations of norfloxacin in plasma, with the following values for PK parameters: A=272 μM (96.7 mg l⁻¹), B=109 μM (38.7 mg l⁻¹), α=0.119 min⁻¹ and β=0.00351 min⁻¹. The solid line represents the best fit to the measured total power of the EEG signal effect, according to the effect compartment model, with the following values for PD parameters: P₀=0.25 mV², B=0.0158 mV² μM⁻¹, n=17.7, k_e0=0.008 min⁻¹.

Figure 4

Simulation of brain concentrations (solid lines) using the model M1a (Figure 1) with different values of CL_out,b from 8.3 × 10⁻⁶ (1) (CSF bulk flow value=2.5 μl min⁻¹) to 8.3.10⁻³ (2) l min⁻¹ kg⁻¹ of body weight and using the previously estimated parameter values of a representative rat: V₁=1.192 l kg⁻¹, V₂=2.264 l kg⁻¹, V_b=0.00195 l kg⁻¹, R=0.094, k₁₂=0.074 min⁻¹, k₂₁=0.0364 min⁻¹, k₁₀=0.0093 min⁻¹, for a dose equal to 150 mg kg⁻¹. The observed ECF brain concentrations are represented by round (0) for the same representative rat.