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*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.

Original languageEnglish
JournalClinical Pharmacology and Therapeutics
Volume108
Issue number3
Pages (from-to)671-680
ISSN0009-9236
DOIs
Publication statusPublished - Sep 2020

Fingerprint Dive into the research topics of 'P-Glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Patients With Cancer'. Together they form a unique fingerprint.

Cite this