P-Glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Patients With Cancer

Tore B. Stage*, Christina Mortensen, Sehbar Khalaf, Vivien Steffensen, Helen S. Hammer, Chenling Xiong, Flemming Nielsen, Oliver Poetz, Åsa Fex Svenningsen, Cristina Rodriguez-Antona, Deanna L. Kroetz*

*Kontaktforfatter for dette arbejde

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Abstrakt

Paclitaxel-induced peripheral neuropathy (PIPN) is a common and dose-limiting adverse event. The role of P-glycoprotein (P-gp) in the neuronal efflux of paclitaxel was assessed using a translational approach. SH-SY5Y cells were differentiated to neurons and paclitaxel toxicity in the absence and presence of a P-gp inhibitor was determined. Paclitaxel caused marked dose-dependent toxicity in SH-SY5Y-derived neurons. Paclitaxel neurotoxicity was exacerbated with concomitant P-gp inhibition by valspodar and verapamil, consistent with increased intracellular accumulation of paclitaxel. Patients with cancer treated with paclitaxel and P-gp inhibitors had a 2.4-fold (95% confidence interval (CI) 1.3–4.3) increased risk of peripheral neuropathy-induced dose modification while a 4.7-fold (95% CI 1.9–11.9) increased risk for patients treated with strong P-gp inhibitors was observed, and a 7.0-fold (95% CI 2.3–21.5) increased risk in patients treated with atorvastatin. Atorvastatin also increased neurotoxicity by paclitaxel in SH-SY5Y-derived neurons. Clinicians should be aware that comedication with P-gp inhibitors may lead to increased risk of PIPN.

OriginalsprogEngelsk
TidsskriftClinical Pharmacology and Therapeutics
Vol/bind108
Udgave nummer3
Sider (fra-til)671-680
ISSN0009-9236
DOI
StatusUdgivet - sep. 2020

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