Influence of biophase distribution and P‐glycoprotein interaction on pharmacokinetic‐pharmacodynamic modelling of the effects of morphine on the EEG

Abstract

Background and purpose: The aim was to investigate the influence of biophase distribution including P-glycoprotein (Pgp) function on the pharmacokinetic-pharmacodynamic correlations of morphine's actions in rat brain. Experimental approach: Male rats received a 10-min infusion of morphine as 4 mg kg À1 , combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg À1 . EEG signals were recorded continuously and blood samples were collected. Key results: Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment (k 1e ) was 0.038 min À1 , being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment (k eo ) decreased 60% after GF120918. The EEG effect was directly related to concentrations in the effect compartment using the sigmoidal E max model. The values of the pharmacodynamic parameters E 0 , E max , EC 50 and Hill factor were 45.0 mV, 44.5 mV, 451 ng ml À1 and 2.3, respectively. Conclusions and implications: The effects of GF120918 on the distribution kinetics of morphine in the effect compartment were consistent with the distribution in brain extracellular fluid (ECF) as estimated by intracerebral microdialysis. However, the time-course of morphine concentrations at the site of action in the brain, as deduced from the biophase model, is distinctly different from the brain ECF concentrations.

Induction of P‐glycoprotein and Bcrp at the rat blood–brain barrier following a subchronic morphine treatment is mediated through NMDA/COX‐2 activation

“…The pharmacokinetic–pharmacodynamic relationships between the plasma concentration of morphine and its CNS effect EEG were clearly demonstrated by Groenendaal et al . who showed that P‐gp modulates the distribution of morphine within the biophase and so helps delay its CNS effect by (Groenendaal et al . ).…”

Enhanced Analgesic Responses After Preferential Delivery of Morphine and Fentanyl to the Olfactory Epithelium in Rats

“…In this study we used the analgesic effect, as determined by the tail-flick latency test, as a measure of the opioid drug distribution to the CNS. Pharmacokinetic studies have determined the use of effect to be a suitable surrogate for extracellular brain concentrations (17–18). The correlations between plasma pharmacokinetics and effect allow a mechanism to determine any direct nose-to-CNS distribution after olfactory nasal administration.…”

Translational pain research: Evaluating analgesic effect in experimental visceral pain models

“…A neurophysiological objective assessment of pain response and analgesic effect is EEG, which also can support the subjective findings in experimental pain studies. Previous investigations have shown that quantitative (spectral) analysis of the increase in delta frequency band of the resting EEG is a suitable biomarker for the PK-PD correlation of opioids [20,21] . In a study of biophase kinetics within the PK-PD analysis of a wide range of opioids, morphine showed profound hysteresis between the blood pharmacokinetics and EEG effect [22] .…”