The Impact of Inflammation on Brain Delivery of Oxycodone

Academic Background

Oxycodone is a widely used opioid analgesic with a unique property of being actively transported from the blood to the brain across the blood-brain barrier (BBB). This process is believed to be associated with the proton-coupled organic cation (H+/OC) antiporter system. However, inflammatory conditions may affect drug delivery to the brain, particularly by altering the function of the BBB. Previous studies have shown that lipopolysaccharide (LPS)-induced systemic inflammation can significantly change the permeability of the BBB, thereby affecting the distribution of drugs in the brain. However, research on the mechanisms of oxycodone brain delivery under inflammatory conditions and its sex-specific differences remains limited.

This study aims to explore the impact of LPS-induced inflammation on oxycodone brain delivery using a rat model, particularly focusing on its transport mechanisms across the BBB and the blood-cerebrospinal fluid barrier (BCSFB). The study also examines the influence of sex differences on the pharmacokinetics of oxycodone, providing new insights into drug delivery under inflammatory conditions.

Source of the Paper

The paper was co-authored by Frida Bällgren, Margareta Hammarlund-Udenaes, and Irena Loryan from the Department of Pharmacy at Uppsala University, Sweden. It was published in 2024 in the journal Fluids and Barriers of the CNS, titled “Reduced oxycodone brain delivery in rats due to lipopolysaccharide-induced inflammation: microdialysis insights into brain disposition and sex-specific pharmacokinetics.”

Research Process and Results

1. Experimental Design and Animal Model

The study used 26 Sprague-Dawley rats, divided into healthy and LPS-treated groups. The LPS-treated rats received three LPS injections (3 mg/kg each) within 28 hours after microdialysis surgery to induce systemic inflammation. Using brain microdialysis, the researchers dynamically monitored the unbound concentrations of oxycodone in blood, striatum, lateral ventricle, and cisterna magna.

2. Microdialysis Experiment

The microdialysis experiment was divided into four phases: stabilization, constant-rate infusion, post-infusion washout, and steady-state. During each phase, dialysate samples were collected via microdialysis probes, and the concentrations of oxycodone were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Oxycodone-d3 was used as a calibrator to correct for probe recovery.

3. Assessment of BBB Integrity

To evaluate the impact of LPS on BBB integrity, the study used 4 kDa fluorescent dextran (Tritc-dextran) as a marker. The results showed that LPS treatment significantly increased BBB permeability, particularly in the right striatal area where the probe was implanted, with a 5.8-fold increase in permeability.

4. Brain Delivery of Oxycodone

The results indicated that LPS treatment significantly reduced the active uptake of oxycodone across the BBB, but its uptake across the BCSFB remained unaffected. Specifically, the unbound brain-to-plasma concentration ratio (Kp,uu) of oxycodone in the striatum of LPS-treated rats was 2.72, significantly lower than the 4.4 observed in healthy rats. However, the brain exposure in LPS-treated rats was similar to that in healthy rats, primarily due to increased systemic exposure induced by LPS.

5. Sex Differences

The study also found that LPS treatment had sex-specific effects on the systemic pharmacokinetics of oxycodone. LPS-treated female rats exhibited significantly lower clearance of oxycodone compared to healthy females, leading to increased plasma exposure. However, sex differences did not significantly affect the transport of oxycodone across the BBB and BCSFB.

Conclusions and Significance

This study demonstrates that LPS-induced inflammation significantly reduces the active uptake of oxycodone across the BBB but does not completely abolish it. This finding suggests that, although inflammatory conditions may affect drug delivery to the brain, oxycodone can still achieve sufficient therapeutic concentrations in the brain. Additionally, the study highlights the sex-specific effects of LPS on the systemic pharmacokinetics of oxycodone, emphasizing the importance of considering sex differences in inflammatory conditions.

Research Highlights

1. Impact of Inflammation on the BBB: LPS treatment significantly increased BBB permeability, but the active uptake mechanism of oxycodone remained intact.
2. Sex Differences: LPS treatment had sex-specific effects on the systemic pharmacokinetics of oxycodone, with significantly reduced clearance in female rats.
3. CSF as a Surrogate for Brain Exposure: Under LPS-induced inflammation, the concentration of oxycodone in cerebrospinal fluid (CSF) was similar to that in brain interstitial fluid, suggesting that CSF can serve as a surrogate for brain exposure.

Research Value

This study provides new insights into the mechanisms of drug delivery to the brain under inflammatory conditions, particularly for drugs that rely on active uptake mechanisms. The findings suggest that drug delivery to the brain may be affected by changes in BBB function during inflammation, but therapeutic effects can still be achieved by adjusting dosage or administration strategies. Furthermore, the study underscores the importance of considering sex differences in drug development, especially in the context of inflammation and infectious diseases.

By revealing the impact of LPS-induced inflammation on oxycodone brain delivery, this study offers important scientific evidence for optimizing drug delivery strategies under inflammatory conditions.