Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irinotecan is widely used in the treatment of colorectal, gastric, and lung cancers. However, adverse drug reactions such as severe diarrhea and neutropenia limit the dose of this drug. Irinotecan is metabolized by carboxylesterase to form an active metabolite, 7-ethyl-10-hydroxycamptothecin(SN-38), which in turn is subsequently conjugated by UGT-glucuronosyltransferase 1A1(UGT1A1)to yield an inactive form, SN-38 glucuronide(SN-38 G). The UGT1A1 gene polymorphisms contribute to the individual variation in adverse events among patients administered irinotecan. However, the distribution of polymorphisms shows large interethnic differences. The distribution of UGT1A1*28 greatly differs between Caucasians and Japanese; the frequency of UGT1A1*28 is high in Caucasians, whereas it is low in Asians including Japanese. Recently, it has been demonstrated that genetic variants of UGT1A1*6 in addition to UGT1A1*28 are associated with the occurrence of adverse events in irinotecan chemotherapy in Asians. This review summarizes recent studies to outline the role of UGT1A1*28 and UGT1A1*6 for irinotecan-induced adverse drug reaction in Japanese cancer patients.
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PMID:[Role of UGT1A1*28 and UGT1A1*6 for irinotecan-induced adverse drug reaction]. 1863 45

After the rapid development of new classes of antineoplastic drugs, research activities have focused their efforts to the identification of predictive markers of drug activity and tolerability. Irinotecan (CPT-11) may induce severe toxicities (diarrhea, neutropenia) that limit its clinical use, but the increasing knowledge of its pharmacokinetics offered a potential approach to treatment optimization. Pharmacokinetics, the first area of investigation, has identified markers such as biliary index, the relative extent of conversion and the glucuronidation ratio, which are capable to define the risk for severe adverse effects. Because of the existence of some issues concerning the adoption of pharmacokinetic strategies to optimize CPT-11 dose and schedule, analyses of genetic polymorphisms seemed to offer a more reliable and safer approach for the identification of patients at risk than pharmacokinetics. In this view, the uridine diphosphate glucuronosil transferase isoform 1A1 (UGT1A1) was associated with significant changes in disposition of CPT-11 and its metabolites, and consequently with treatment-induced toxicities. However, the complex pharmacokinetics of irinotecan and the involvement of several enzymes other than UGT (i.e., carboxyl estherases, CYP450 isoforms), and transmembrane transporters (ABCB1, ABCC1, ABCG2, SLCO1B1) make difficult the identification of patients with an optimal sensitivity and specificity, and a large part of variability among patients still remains unexplained. Furthermore, prospective clinical studies that should demonstrate the reliability of those pharmacokinetic and pharmacogenetic markers are still lacking. In the present review, pharmacokinetic and pharmacogenetic markers will be discussed.
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PMID:Pharmacokinetic and pharmacogenetic predictive markers of irinotecan activity and toxicity. 2178 64