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Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib

Camille TlemsaniParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

, MD,

Olivier HuillardParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

Jennifer ArrondeauParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

Pascaline Boudou-RouquetteParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

Anatole CessotParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

Benoit BlanchetParis Descartes University, Cochin Hospital, AP-HP, Pharmacokinetics and Pharmacochemistry Unit, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France

Audrey Thomas-SchoemannParis Descartes University, Cochin Hospital, AP-HP, Pharmacokinetics and Pharmacochemistry Unit, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France;Paris Descartes University, Paris Pharmaceutical Research Center, UMR 8638 CNRS, Faculty of Pharmacy, Paris, France

Romain CoriatParis Descartes University, Cochin Hospital, AP-HP, Gastroenterology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France

Jean-Philippe DurandParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

Julie GirouxParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

Jérôme AlexandreParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

François GoldwasserParis Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France33 1 58 41 17 46; 33 1 58 41 17 45; [email protected]

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Abstract

Introduction: UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes responsible for the glucuronidation reaction. Many therapeutic classes of drugs used in solid tumors are UGT substrates, including cancer therapies.

Areas covered: This article describes the tyrosine kinase inhibitors (TKIs) undergoing hepatic glucuronidation; its effect on transport and tissue accumulation and the clinical consequences of this particular metabolism. A PubMed search concerning the pharmacokinetics of the TKIs was performed. All are extensively metabolized by CYP450. Two TKIs, sorafenib and regorafenib, also have a major UGT-mediated metabolism and were therefore studied.

Expert opinion: The prescription of the same dose of sorafenib and regorafenib for all patients may be inappropriate since at each enzymatic step of this multistep metabolism inter-individual fluctuations exist. Having a non-exclusive CYP-mediated route of metabolism may reduce the risk of variability in drug exposure when CYP3A4 substrates are concomitantly given. Several clinical consequences derive from this pharmacokinetic particularity of sorafenib and regorafenib. Since no clear difference distinguishes TKIs in efficacy in large randomized trials, the differences for the clinical management of their toxicity is a critical aspect.

Keywords:

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

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Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib

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Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib

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