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

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.

[1]  P. MacEneaney,et al.  Body Composition by Computed Tomography as a Predictor of Toxicity in Patients With Renal Cell Carcinoma Treated With Sunitinib , 2017, American journal of clinical oncology.

[2]  Jaw-Yuan Wang,et al.  FOLFIRI and regorafenib combination therapy with dose escalation of irinotecan as fourth-line treatment for patients with metastatic colon cancer according to UGT1A1 genotyping , 2014, OncoTargets and therapy.

[3]  A. Paci,et al.  Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies. , 2014, European journal of cancer.

[4]  R. Paschke,et al.  Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial , 2014, The Lancet.

[5]  A. Palazzo,et al.  Incidence and relative risk of hepatic toxicity in patients treated with anti‐angiogenic tyrosine kinase inhibitors for malignancy , 2014, British journal of clinical pharmacology.

[6]  A. Sparreboom,et al.  Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro–in vivo correlations , 2014, British Journal of Cancer.

[7]  Andrew Rowland,et al.  The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. , 2013, The international journal of biochemistry & cell biology.

[8]  K. Brouwer,et al.  Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites , 2013, Drug Metabolism and Disposition.

[9]  Y. Pithavala,et al.  Clinical Pharmacology of Axitinib , 2013, Clinical Pharmacokinetics.

[10]  Y. Fujiyama,et al.  Pharmacokinetic interaction between sorafenib and prednisolone in a patient with hepatocellular carcinoma , 2013, Cancer Chemotherapy and Pharmacology.

[11]  O. Mir,et al.  Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients , 2013, British Journal of Cancer.

[12]  S. Baker,et al.  Contribution of OATP1B1 and OATP1B3 to the Disposition of Sorafenib and Sorafenib-Glucuronide , 2013, Clinical Cancer Research.

[13]  H. Gurney,et al.  Evidence for therapeutic drug monitoring of targeted anticancer therapies. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  O. Mir,et al.  Saturable absorption of sorafenib in patients with solid tumors: a population model , 2012, Investigational New Drugs.

[15]  O. Mir,et al.  Sorafenib exposure decreases over time in patients with hepatocellular carcinoma , 2012, Investigational New Drugs.

[16]  M. Loriot,et al.  Early Sorafenib-Induced Toxicity Is Associated with Drug Exposure and UGTIA9 Genetic Polymorphism in Patients with Solid Tumors: A Preliminary Study , 2012, PloS one.

[17]  O. Mir,et al.  Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma , 2012, PloS one.

[18]  Tingjun Hou,et al.  New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib , 2012, Molecular Cancer Therapeutics.

[19]  Martin Büchert,et al.  A Phase I Dose–Escalation Study of Regorafenib (BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors , 2012, Clinical Cancer Research.

[20]  G. Giaccone,et al.  Sorafenib Is an Inhibitor of UGT1A1 but Is Metabolized by UGT1A9: Implications of Genetic Variants on Pharmacokinetics and Hyperbilirubinemia , 2012, Clinical Cancer Research.

[21]  O. Mir,et al.  Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma , 2011, Investigational new drugs.

[22]  U. Fuhr,et al.  Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors , 2011, Clinical pharmacokinetics.

[23]  O. Mir,et al.  Functional and Clinical Evidence of the Influence of Sorafenib Binding to Albumin on Sorafenib Disposition in Adult Cancer Patients , 2011, Pharmaceutical Research.

[24]  Uwe Fuhr,et al.  Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors , 2011, Clinical pharmacokinetics.

[25]  J. Schellens,et al.  Moving towards dose individualization of tyrosine kinase inhibitors. , 2011, Cancer treatment reviews.

[26]  G. Szakács,et al.  Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance? , 2011, Expert opinion on drug metabolism & toxicology.

[27]  R. Kerbel,et al.  Antiangiogenic therapy: impact on invasion, disease progression, and metastasis , 2011, Nature Reviews Clinical Oncology.

[28]  Sagar Agarwal,et al.  The Role of the Breast Cancer Resistance Protein (ABCG2) in the Distribution of Sorafenib to the Brain , 2011, Journal of Pharmacology and Experimental Therapeutics.

[29]  E. Heath,et al.  A Phase I Study of the Pharmacokinetic and Safety Profiles of Oral Pazopanib With a High‐Fat or Low‐Fat Meal in Patients With Advanced Solid Tumors , 2010, Clinical pharmacology and therapeutics.

[30]  L. Birdsell,et al.  Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[31]  P. Casali,et al.  Gastrointestinal stromal tumours : ESMO Clinical Practice Guidelines for diagnosis , treatment and follow-up , 2010 .

[32]  Tae Won Kim,et al.  Cross-sectional study of imatinib plasma trough levels in patients with advanced gastrointestinal stromal tumors: impact of gastrointestinal resection on exposure to imatinib. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  Jos H. Beijnen,et al.  Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation , 2010, Molecular Cancer Therapeutics.

[34]  J. Magdalou,et al.  Insights on membrane topology and structure/function of UDP-glucuronosyltransferases , 2010, Drug metabolism reviews.

[35]  S. Baker,et al.  Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters , 2009, Clinical Cancer Research.

[36]  Jos H Beijnen,et al.  The biological and clinical role of drug transporters at the intestinal barrier. , 2009, Cancer treatment reviews.

[37]  A. Stead,et al.  Effects of food on the relative bioavailability of lapatinib in cancer patients. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  S. Paggi,et al.  Sorafenib in Advanced Hepatocellular Carcinoma , 2008 .

[39]  M. Ratain,et al.  Pharmacogenetic Pathway Analysis of Irinotecan , 2008, Clinical pharmacology and therapeutics.

[40]  Jeffrey W. Clark,et al.  Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. , 2007, The oncologist.

[41]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[42]  M. Radtke,et al.  Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics , 2006, Cancer Chemotherapy and Pharmacology.

[43]  John Smeraglia,et al.  Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects , 2006, Anti-cancer drugs.

[44]  D. Hirata,et al.  Mutational analysis of the yeast multidrug resistance ABC transporter Pdr5p with altered drug specificity , 2005, Genes to cells : devoted to molecular & cellular mechanisms.

[45]  Kathleen M Sakamoto.  Su-11248 Sugen. , 2004, Current opinion in investigational drugs.

[46]  S. Wilhelm,et al.  BAY 43-9006: preclinical data. , 2002, Current pharmaceutical design.

[47]  H. Hirte,et al.  BAY 43-9006: early clinical data in patients with advanced solid malignancies. , 2002, Current pharmaceutical design.

[48]  Nancy Woods,et al.  Cancer and comorbidity , 2000, Cancer.

[49]  A. Di Rienzo,et al.  Phenotype‐genotype correlation of in vitro SN‐38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism , 1999, Clinical pharmacology and therapeutics.

[50]  F. Goldwasser,et al.  Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports. , 1997, Annals of oncology : official journal of the European Society for Medical Oncology.

[51]  M. Ratain,et al.  Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea. , 1994, Cancer research.

[52]  A. M. Hilliard.  AFFILIATION , 1910 .

[53]  F. Goldwasser,et al.  Drug interactions with solid tumour-targeted therapies. , 2014, Critical reviews in oncology/hematology.

[54]  N. Gray,et al.  Targeting cancer with small molecule kinase inhibitors , 2009, Nature Reviews Cancer.

[55]  Armando Santoro,et al.  Sorafenib: a review of its use in advanced hepatocellular carcinoma. , 2009, Drugs.

[56]  Peter Lloyd,et al.  Clinical Pharmacokinetics of Imatinib , 2005, Clinical pharmacokinetics.

[57]  P. Borst,et al.  Mammalian ABC transporters in health and disease. , 2002, Annual review of biochemistry.