Effects of membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver of drugs: A microdialysis study in rats

Wang, Shuyao; Chen, Chun; Guan, Chi; Qiu, Liping; Zhang, Lei; Zhang, Shaofeng; Zhou, Hongyu; Du, Hongwen; Li, Chen; Wu, Yaqiong; Chang, Hang; Wang, Tao

doi:10.1002/prp2.879

Cited by 2 publications

(3 citation statements)

References 47 publications

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“…The drug concentration asymmetry across the BSMI observed herein indicates that drug transport into the SM is governed by both, active influx and efflux, and should not be assumed to be a passive process. Indeed, recent advances in the understanding of the molecular makeup of endothelial cells of the endomysium and accumulating evidence on the potential differences in molecular transport therein support it being a potential barrier for drugs [39][40][41][42]. Our findings are also in line with a recent microdialysis study where predominant efflux or influx transport across the SM endothelial barrier (K p,uu,SM < 1 or > 1) was also found for 14 marketed drugs [42].…”

Section: Discussionsupporting

confidence: 91%

“…Indeed, recent advances in the understanding of the molecular makeup of endothelial cells of the endomysium and accumulating evidence on the potential differences in molecular transport therein support it being a potential barrier for drugs [39][40][41][42]. Our findings are also in line with a recent microdialysis study where predominant efflux or influx transport across the SM endothelial barrier (K p,uu,SM < 1 or > 1) was also found for 14 marketed drugs [42]. Similar findings were also reported for 56 tested compounds where 15 out of 56 compounds showed rather limited penetration at BSMI with K p,uu,SM below 0.3 and also 2 out of 56 compounds demonstrated active uptake with K p,uu,SM higher than 2 [43].…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy

Hu,

Girdenyté,

Roest

et al. 2024

Fluids Barriers CNS

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Background Chemotherapy-induced peripheral neuropathy (CIPN) represents a major unmet medical need that currently has no preventive and/or curative treatment. This is, among others, driven by a poor understanding of the contributive role of drug transport across biological barriers to target-site exposure. Methods Here, we systematically investigated the transport of 11 small-molecule drugs, both, associated and not with CIPN development, at conventional (dorsal root ganglia, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN sites. We developed a Combinatory Mapping Approach for CIPN, CMA-CIPN, combining in vivo and in vitro elements. Results Using CMA-CIPN, we determined the unbound tissue-to-plasma concentration ratio (Kp,uu) and the unbound intracellular-to-extracellular concentration ratio (Kp,uu,cell), to quantitatively assess the extent of unbound drug transport across endothelial interfaces and parenchymal cellular barriers of investigated CIPN-sites, respectively, in a rat model. The analysis revealed that unique pharmacokinetic characteristics underly time-dependent accumulation of the CIPN-positive drugs paclitaxel and vincristine at conventional (dorsal root ganglia and sciatic nerve) and non-conventional (skeletal muscle) CIPN sites. Investigated CIPN-positive drugs displayed intracellular accumulation contrary to CIPN-negative drugs nilotinib and methotrexate, which lacked this feature in all investigated tissues. Conclusions Hence, high unbound drug intracellular and extracellular exposure at target sites, driven by an interplay of drug transport across the endothelial and parenchymal cellular barriers, is a predisposing factor to CIPN development for CIPN-positive drugs. Critical drug-specific features of unbound drug disposition at various CIPN- sites provide invaluable insights into understanding the pharmacological/toxicological effects at the target-sites which will inform new strategies for monitoring and treatment of CIPN.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy

Hu,

Girdenyté,

Roest

et al. 2024

Fluids Barriers CNS

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“…Memantine stands out as a distinct medication for AD treatment, which functions by blocking NMDA receptors related to glutamate signaling in the brain [ 30 ]. Memantine is eliminated mainly through the kidneys and remains in the system for approximately 70 h [ 31 ]. The FDA has approved memantine to treat moderate and severe AD alone or combined with AChEIs.…”

Section: Current Treatments and Their Limitationsmentioning

confidence: 99%

Mesoporous Silica Nanoparticles: Types, Synthesis, Role in the Treatment of Alzheimer’s Disease, and Other Applications

Sivamaruthi,

Kapoor,

Kukkar

et al. 2023

Pharmaceutics

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Globally, many individuals struggle with Alzheimer’s disease (AD), an unrelenting and incapacitating neurodegenerative condition. Despite notable research endeavors, effective remedies for AD remain constrained, prompting the exploration of innovative therapeutic avenues. Within this context, silica-based nanoplatforms have emerged with pronounced potential due to their unique attributes like expansive surface area, customizable pore dimensions, and compatibility with living systems. These nanoplatforms hold promise as prospective interventions for AD. This assessment provides a comprehensive overview encompassing various forms of mesoporous silica nanoparticles (MSNs), techniques for formulation, and their applications in biomedicine. A significant feature lies in their ability to precisely guide and control the transport of therapeutic agents to the brain, facilitated by the adaptability of these nanoplatforms as drug carriers. Their utility as tools for early detection and monitoring of AD is investigated. Challenges and prospects associated with harnessing MSNs are studied, underscoring the imperative of stringent safety evaluations and optimization of how they interact with the body. Additionally, the incorporation of multifunctional attributes like imaging and targeting components is emphasized to enhance their efficacy within the intricate milieu of AD. As the battle against the profound repercussions of AD persists, MSNs emerge as a promising avenue with the potential to propel the development of viable therapeutic interventions.

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Effects of membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver of drugs: A microdialysis study in rats

Abstract: One of the most important concepts in clinical pharmacology is the free drug hypothesis. This concept stipulates that only the unbound (free) drug is able to distribute from the blood circulation across cell membranes to tissues and that only unbound drug can

Cited by 2 publications

References 47 publications

Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy

Analysis of the contributing role of drug transport across biological barriers in the development and treatment of chemotherapy-induced peripheral neuropathy

Mesoporous Silica Nanoparticles: Types, Synthesis, Role in the Treatment of Alzheimer’s Disease, and Other Applications

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