The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1

Fujita, Ken‐ichi; Sugiyama, Minako; Akiyama, Yoshitsugu; Ando, Yumiko; Sasaki, Yasutsuna

doi:10.1007/s00280-010-1445-3

Cited by 45 publications

(29 citation statements)

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“…In a clinical study for frontline treatment of CML-CP with dasatinib (the DASISION trial), the incidence of hyperbilirubinemia was only 1 %. In vitro analysis also confirmed that the inhibitory effect of dasatinib against UGT1A1 is ten times less than that of nilotinib [18]. This is a plausible reason why nilotinib but not dasatinib induced hyperbilirubinemia in the present case.…”

Section: Discussionsupporting

confidence: 66%

“…Preclinical studies revealed that nilotinib was not glucuronidated by UGT1A1; however, nilotinib inhibited UGT1A1 activity itself (unpublished data) [5]. Recently, Fujita et al [18] also identified that nilotinib was a potent noncompetitive inhibitor of UGT1A1 activity. Therefore, a plausible explanation of nilotinib-induced hyperbilirubinemia in patients with a UGT1A1 mutant allele such as UGT1A1*28 or *6 is that the lower activity of UGT1A1 due to allele mutation would be decreased further by its inhibitor, nilotinib.…”

Section: Discussionmentioning

confidence: 99%

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UGT1A128 and 6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

et al. 2012

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Nilotinib, a second-generation tyrosine kinase inhibitor of BCR-ABL, has shown superior efficacy compared with imatinib for the treatment of chronic myelogenous leukemia (CML). Unconjugated hyperbilirubinemia has been the most frequent adverse event with laboratory abnormality observed in clinical trials of nilotinib. The homozygosity for uridine diphosphate glucuronosyltransferase (UGT) 1A1*28 polymorphism has been reported to increase the risk of nilotinib-induced unconjugated hyperbilirubinemia in Caucasians. However, the frequency of UGT1A1*28 is low in Asians, including Japanese. On the other hand, the UGT1A1*6 allele mutation, which is extremely rare in Caucasians, is more frequent than the UGT1A1*28 allele in the Japanese population. Herein, we present a patient with CML who developed grade 3 unconjugated hyperbilirubinemia after being treated with nilotinib. We found that the patient was heterozygous for both UGT1A1*28 and *6. Our findings suggest that the compound heterozygosity for UGT1A1*28 and *6 could be a cause of unconjugated hyperbilirubinemia during nilotinib treatment.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

UGT1A128 and 6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

et al. 2012

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“…47) In particular, bilirubin is glucuronidated by UGT1A1 48) ; however, nilotinib inhibits bilirubin metabolism via UGT1A1, thereby increasing bilirubin levels. 49,50) In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients (ENESTnd) study, a higher nilotinib exposure was reported to be significantly correlated with greater incidence of all-grade bilirubin elevation.…”

Section: Nilotinib Tdmmentioning

confidence: 99%

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

Miura

2015

Biological & Pharmaceutical Bulletin

139

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Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). According to European LeukemiaNet recommendations, the clinical response of CML patients receiving TKI therapy should be evaluated after 3, 6, and 12 months. For patients not achieving a satisfactory response within 3 months, the mean plasma concentration for the three months of TKI administration must be considered. In TKI therapy for CML patients, therapeutic drug monitoring is a new strategy for dosage optimization to obtain a faster and more effective clinical response. The imatinib plasma trough concentration (C 0 ) should be set above 1000 ng/mL to obtain a response and below 3000 ng/mL to avoid serious adverse events such as neutropenia. For patients with a UGT1A1*6/*6, *6/*28, or *28/*28 genotype initially administered 300-400 mg/d, a target nilotinib C 0 of 500 ng/mL is recommended to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1*1 allele initially administered 600 mg/d, a target nilotinib C 0 of 800 ng/mL is recommended. For dasatinib, it is recommended that a higher C max or C 2 (above 50 ng/mL) to obtain a clinical response and a lower C 0 (less than 2.5 ng/mL) to avoid pleural effusion be maintained by once daily administration of dasatinib. Although at present clinicians consider the next pharmacotherapy from clinical responses (efficacy/ toxicity) obtained by a fixed dosage of TKI, the TKI dosage should be adjusted based on target plasma concentrations to maximize the efficacy and to minimize the incidence of adverse events.

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“…Taking all above findings into consideration, it is suggested that a detergent/alamethicin-caused decrease in adenine nucleotides in the ER is one possible mechanism that explains the latency of UGT. The inhibitors of EGFR-protein tyrosine kinase have an undesired inhibitory effect on UGT (Liu et al, 2010;Fujita et al, 2011;Piu et al, 2011). This may cause a drug-drug interaction in UGT-dependent metabolism (Fujita et al, 2011).…”

Section: Release Of Atp From Rlm By Brij-58 and Alamethicin Treatmentmentioning

confidence: 99%

“…Through these experiments, we hypothesized that a change in the concentration of adenine nucleotides within the ER is the reason for the latency of UGT. In contrast, agents such as Gefitinib (Iressa; Tocris Bioscience, Bristol, UK), which inhibits epidermal growth factor receptor (EGFR)-protein tyrosine kinase, are UGT inhibitors (Liu et al, 2010;Fujita et al, 2011;Piu et al, 2011). However, the reason why Gefitinib and related compounds exhibit an inhibitory effect on UGT has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

ATP Serves as an Endogenous Inhibitor of UDP-Glucuronosyltransferase (UGT): A New Insight into the Latency of UGT

Ishii

Nishimura

et al. 2012

Drug Metab Dispos

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ABSTRACT:We have suggested that adenine-related compounds are allosteric inhibitors of UGT in rat liver microsomes (RLM) treated with detergent. To clarify whether the same occurs with a pore-forming peptide, alamethicin, the effects of adenine-related compounds on 4-metylumbelliferone (4-MU) glucuronidation were examined using RLM and human liver microsomes (HLM). ATP inhibited 4-MU glucuronidation when polyoxyethylene cetyl alcohol ether (Brij-58)-treated RLM were used (IC 50 ‫؍‬ approximately 70 M). However, alamethicin-treated RLM exhibited a lower susceptibility (IC 50 ‫؍‬ approximately 460 M) than Brij-58-treated RLM. A similar phenomenon was observed when pooled HLM were used. Then, the endogenous ATP content of RLM was determined in the presence and absence of alamethicin or detergent, and although no ATP remained in the microsomal pellets after Brij-58 treatment, more than half of the microsomal ATP remained even after treatment with alamethicin. Furthermore, the V max in the absence of an adenine-related compound was approximately three times higher in Brij-58-treated than in alamethicin-treated RLM. The difference in the inhibitory potency observed was due to the difference in remaining endogenous ATP and the accessibility of exogenous ATP to the luminal side of the endoplasmic reticulum (ER), where the active site of UDP-glucuronosyltransferase (UGT) is located. Gefitinib (Iressa), a protein tyrosine kinase inhibitor, markedly inhibited human UGT1A9 activity. It is interesting to note that AMP antagonized Gefitinib-provoked inhibition of UGT1A9, and ATP exhibited an additive inhibitory effect at a lower concentration. Therefore, Gefitinib inhibits UGT1A9 at the common ATP-binding site shared with ATP and AMP. Releasing adenine nucleotide from the ER is suggested to be one of the mechanisms that explain the "latency" of UGT.

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The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1

Abstract: We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.

Cited by 45 publications

References 10 publications

UGT1A128 and 6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

UGT1A128 and 6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

ATP Serves as an Endogenous Inhibitor of UDP-Glucuronosyltransferase (UGT): A New Insight into the Latency of UGT

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The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1

Abstract: We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.

Cited by 45 publications

References 10 publications

UGT1A1*28 and *6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

UGT1A1*28 and *6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

ATP Serves as an Endogenous Inhibitor of UDP-Glucuronosyltransferase (UGT): A New Insight into the Latency of UGT

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UGT1A128 and 6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

UGT1A128 and 6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia