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Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG). The prevalence of CIPN in patients receiving paclitaxel formulated i) in polyethylated castor oil with ethanol (CreEL-PTX), ii) as albumin-bound (nab-PTX), and iii) in XR17 micelles (micellar-PTX), is unexpectedly varying. We hypothesize that the discrepancy in CIPN prevalence could be governed by differences in the extent of paclitaxel distribution across blood-to-tissue barriers at the CIPN-sites, caused by the specific formulation. Methods: The recently developed Combinatory Mapping Approach for CIPN was used to determine the unbound tissue-to-plasma concentration ratio Kp,uu,tissue, after a 4-h infusion of 4 mg/kg CreEL-PTX, 4 mg/kg nab-PTX or 1 mg/kg micellar-PTX in male and female Sprague Dawley rats. Kp,uu,tissue was determined in conventional (DRG, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN-sites. Results: Based on our data, the Cremophor-free paclitaxel formulations were associated with a higher distribution of paclitaxel to CIPN-sites than CreEL-PTX, e.g., Kp,uu,DRG of 0.70 and 0.60 for nab-PTX and micellar-PTX, respectively, in comparison to 0.27 for CreEL-PTX (p < 0.01). In addition, the fraction of unbound paclitaxel in plasma was on average 1.6-fold higher in nab- and micellar PTX arms and equal to 0.061 and 0.065, respectively, compared to 0.039 for the CreEL-PTX treatment arm (p < 0.0001). Discussion: In the case of similar unbound paclitaxel concentration in the plasma of patients and assumed species-independent extent of paclitaxel transport across the barriers, nab- and micellar-PTX formulations can lead to higher paclitaxel exposure at CIPN-sites in comparison to CreEL-PTX. [ABSTRACT FROM AUTHOR]

The pyrilamine-sensitive proton-coupled organic cation (H+/OC) antiporter system facilitates the active net uptake of several marketed organic cationic drugs across the blood-brain barrier (BBB). This rare phenomenon has garnered interest in the H+/OC antiporter system as a potential target for CNS drug delivery. However, analysis of pharmacovigilance data has uncovered a significant association between substrates of the H+/OC antiporter and neurotoxicity, particularly drug-induced seizures (DIS) and mood- and cognitive-related adverse events (MCAEs). This preclinical study aimed to elucidate the CNS regional disposition of H+/OC antiporter substrates at therapeutically relevant plasma concentrations to uncover potential pharmacokinetic mechanisms underlying DIS and MCAEs. Here, we investigated the neuropharmacokinetics of pyrilamine, diphenhydramine, bupropion, tramadol, oxycodone, and memantine. Using the Combinatory Mapping Approach for Regions of Interest (CMA-ROI), we characterized the transport of unbound drugs across the BBB in specific CNS regions, as well as the blood-spinal cord barrier (BSCB) and the blood-cerebrospinal fluid barrier (BCSFB). Our findings demonstrated active net uptake across the BBB and BSCB, with unbound ROI-to-plasma concentration ratio, Kp,uu,ROI, values consistently exceeding unity in all assessed regions. Despite minor regional differences, no significant distinctions were found when comparing the whole brain to investigated regions of interest, indicating region-independent active transport. Furthermore, we observed intracellular accumulation via lysosomal trapping for all studied drugs. These results provide new insights into the CNS regional neuropharmacokinetics of these drugs, suggesting that while the brain uptake is region-independent, the active transport mechanism enables high extracellular and intracellular drug concentrations, potentially contributing to neurotoxicity. This finding emphasizes the necessity of thorough neuropharmacokinetic evaluation and neurotoxicity profiling in the development of drugs that utilize this transport pathway. [ABSTRACT FROM AUTHOR]