OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Leblanc, A.; Sprowl, Jason A.; Alberti, Paola; Chiorazzi, A; Arnold, W. David; Gibson, Alice A.; Hong, Kristen; Pioso, Marissa S.; Chen, Mingqing; Huang, Kevin M.; Chodisetty, Vamsi; Costa, Olivia S.; Florea, Tatiana; Bruijn, Peter de; Mathijssen, Ron H.J.; Reinbolt, Raquel E.; Lustberg, Maryam B.; Sucheston‐Campbell, Lara E.; Cavaletti, Guido; Sparreboom, Alex; Hu, Shuiying

doi:10.1172/jci96160

Cited by 60 publications

(75 citation statements)

References 60 publications

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“…Recent investigations have demonstrated that regorafenib modestly inhibits the function of human OATP1B1, and that HEK293 cells overexpressing OATP1B1 exhibit increased sensitivity to regorafenib, suggesting that this multikinase inhibitor might be a transported substrate of Oatp1b‐type carriers in vivo . Our current studies, however, demonstrated that Oatp1b2 deficiency in mice does not cause differences in the pharmacokinetic profile of regorafenib after oral administration.…”

Section: Discussionmentioning

confidence: 99%

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

Chen

Anderson

et al. 2019

Clinical Translational Sci

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Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5′‐diphosphate glucuronosyltransferase (Ugt)1a9‐mediated glucuronidation to form regorafenib‐N‐β‐glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion‐transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM‐based, population‐based, parent‐metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with the metabolism of regorafenib occurring via two competing pathways, and the lack of Oatp1b2 results in decreased clearance of RG. The described model provides mechanistic insights into the in vivo disposition of regorafenib.

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Section: Discussionmentioning

confidence: 99%

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

Chen

Anderson

et al. 2019

Clinical Translational Sci

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“…13 Paclitaxel uptake is mediated by hepatic OATP1B3 (SLCO1B3) and OATP1B1 (SLCO1B1). 14,15 Recently, murine OATP1B2 was shown to play a key role in regulating paclitaxel distribution to sensory neurons and neurotoxicity 16 but the role of efflux transporters on intraneuronal accumulation of paclitaxel is unknown. Interestingly, pharmacogenetic studies have identified several associations between genetic variants in ABCB1 and risk of peripheral neuropathy, although these findings are not validated.…”

Section: P-glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicimentioning

confidence: 99%

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

Stage

Mortensen

Khalaf

et al. 2020

Clin Pharma and Therapeutics

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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.

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“…However, such strategies are rarely implemented and reported studies often fail to include positive and negative control inhibitors into the experimental design, which is recommended in the regulatory guidance documents. These issues complicate the interpretation of data and can result in discrepant views on extrapolating from in vitro studies to the clinical situation, as reported for ruxolitinib or crizotinib, where experimental data would suggest statistically significant but not clinically relevant degrees of inhibition [ 67 , 68 , 69 ]. Substrate selection: Since substrate-dependent inhibition by xenobiotics, including TKIs, has been well documented and is acknowledged expressly in the FDA guidance document, the degree to which findings obtained with one particular substrate can be extrapolated to other conditions is uncertain, and potentially accounts for several reported inconsistencies.…”

Section: Effects Of Tkis On the Function Of Oatp1b1 And Oatp1b3mentioning

confidence: 99%

Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

Garrison¹,

Talebi²,

Eisenmann³

et al. 2020

Pharmaceutics

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Failure to recognize important features of a drug’s pharmacokinetic characteristics is a key cause of inappropriate dose and schedule selection, and can lead to reduced efficacy and increased rate of adverse drug reactions requiring medical intervention. As oral chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) are particularly prone to cause drug-drug interactions as many drugs in this class are known or suspected to potently inhibit the hepatic uptake transporters OATP1B1 and OATP1B3. In this article, we provide a comprehensive overview of the published literature and publicly-available regulatory documents in this rapidly emerging field. Our findings indicate that, while many TKIs can potentially inhibit the function of OATP1B1 and/or OATP1B3 and cause clinically-relevant drug-drug interactions, there are many inconsistencies between regulatory documents and the published literature. Potential explanations for these discrepant observations are provided in order to assist prescribing clinicians in designing safe and effective polypharmacy regimens, and to provide researchers with insights into refining experimental strategies to further predict and define the translational significance of TKI-mediated drug-drug interactions.

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OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Cited by 60 publications

References 60 publications

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

Interaction Between Sex and Organic Anion‐Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib‐N‐Oxide and Regorafenib‐Glucuronide in Mice

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

Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

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