Transport and metabolism of tyrosine kinase inhibitors associated with chronic myeloid leukemia therapy: a review

• Published in: Molecular and cellular biochemistry Vol. 477; no. 4; pp. 1261 - 1279
• Main Authors: Kumar, Veerandra, Singh, Priyanka, Gupta, Sonu Kumar, Ali, Villayat, Verma, Malkhey
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2022; Springer; Springer Nature B.V
• Subjects: Abl protein; Anemia; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; BCR protein; Binding sites; Biochemistry; Biomedical and Life Sciences; Biomolecules; Cancer; Cardiology; Care and treatment; Chronic myeloid leukemia; Cytochrome P-450; Diarrhea; Dimethylaniline monooxygenase (N-oxide-forming); Drug approval; Drug Resistance, Neoplasm - drug effects; Efflux; Flavin; Fusion protein; Glucuronosyltransferase; Glutathione; Health risks; Hematology; Humans; Imatinib; Inhibitors; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Life Sciences; Medical Biochemistry; Metabolism; Mutation; Myeloid leukemia; Nausea; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Neutropenia; Nilotinib; Oncology; Pancreatitis; Patients; Pharmacokinetics; Pharmacology; Phenols; Physiological aspects; Pleural effusion; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Risk analysis; Risk factors; Side effects; Thrombocytopenia; Toxicity; Tyrosine; Tyrosine kinase inhibitors; Uridine; Vomiting; Cytochrome P450 (CYP450); T315I mutation; BCR-ABL oncoprotein; Pharmacokinetics; Multidrug resistance; ATP-binding cassette (ABC) transporters
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-022-04376-6

Imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib are FDA-approved tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML), each of which has a specific pharmacological profile. Asciminib has been recently (2021) approved for patients resistant to former TKIs, and because the binding site of this drug (the myristoyl pocket in the ABL1 kinase) is different from that of other TKIs (ATP-binding sites), it is, therefore, effective against T315I mutation of BCR-ABL oncoprotein. All TKIs have a different pharmacological profile due to different chemical structures. Imatinib is the only TKI whose absorption depends on both influx (OCT1 and OATP1A2) and efflux (ABCB1 and ABCG2) transporters, whereas the others rely only on efflux transporters. The efflux of dasatinib is also regulated by ABCC4 and ABCC6 transporters. Nilotinib and ponatinib are transported passively, as no role of transporters has been found in their case. A phenomenon common to all in the metabolic aspect is that the CYP3A4 isoform of CYP450 primarily metabolizes TKIs. Not only does CYP3A4, flavin-containing monooxygenase 3 (FMO3), and uridine 5'-diphospho-glucuronosyltransferase (UGT) also metabolize dasatinib, and similarly, by glucuronidation process, asciminib gets metabolized by UGT enzymes (UGT1A3, UGT1A4, UGT2B7, and UGT2B17). Additionally, the side effects of TKIs are categorized as hematological (thrombocytopenia, neutropenia, anemia, and cardiac dysfunction) and non-hematological (diarrhea, nausea, vomiting, pleural effusion, and skin rash). However, few toxicities are drug-specific, like degradation of biomolecules by ponatinib-glutathione (P-GSH) conjugates and clinical pancreatitis (dose-limited toxicity and manageable by dosage alterations) are related to ponatinib and asciminib, respectively. This review focuses on the pharmacokinetics of approved TKIs related to CML therapy to comprehend their specificity, tolerability, and off-target effects, which could help clinicians to make a patient-specific selection of CML drugs by considering concomitant diseases and risk factors to the patients.