UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan

Ando, Yumiko; Sasaki, Hideo; Asai, G.; Sugiura, Shigeki; Shimokata, Kaoru; Kamataki, Tetsuya

doi:10.1023/a:1008438109725

Cited by 195 publications

(108 citation statements)

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“…In fact, Hosokawa et al 21) reported inter-individual variability of CCE activity in liver. Although our hypothesis was not supported by this study, other mechanisms such as hepatobiliary secretion, which has already been shown to have inter-individual variability, 11,12) might have interfered in some way. Although conversion from irinotecan to SN-38 is evident in liver, 1,13,14,17,18) small intestine, 13) colon, 14) plasma 15) and tumor tissue, 14,16) their mutual correlations have not been reported.…”

Section: Discussioncontrasting

confidence: 82%

“…4) Therefore, predicting its toxicity in any given patient has been difficult in contrast to other agents such as carboplatin, for which a sophisticated method for individualizing dosing is available. 10) As one of the mechanisms underlying this inter-individual variability of irinotecan metabolism, Ando et al 11,12) demonstrated that bilirubin UDP-glucuronosyltransferase 1 gene promoters with excessive TATAA elements were responsible for reduced conjugation of SN-38 to SN-38-glucuronide (SN-38G), resulting in a reduction of SN-38 detoxication in the liver. However, it is still unresolved whether this mechanism alone explains the entire inter-individual variability of the toxicity and pharmacokinetics of this drug.…”

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confidence: 99%

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In vitro conversion of irinotecan to SN‐38 in human plasma

et al. 2004

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Irinotecan is an active cytotoxic agent for various cancers, and is converted to SN-38, its most active metabolite, by carboxylesterase converting enzyme (CCE) in vivo. Although the primary metabolic site is in the liver, ex vivo studies have proven that irinotecan is also converted to SN-38 in intestines, plasma and tumor tissues. The present study attempted to elucidate the in vitro conversion efficiency in human plasma, and to examine possible inter-individual variability and its clinical significance. Plasma samples were taken from 57 patients with lung cancer, 3 patients with benign pulmonary diseases and 9 healthy volunteers. After addition of 157 µ µ µ µM irinotecan to plasma, time courses of SN-38 concentration, measured by high-performance liquid chromatography (HPLC), were investigated. All subjects showed linear increase in SN-38 concentration during the first 60-min period, followed by a plateau. Mean and standard deviation of the conversion rate in the first 60 min were 515.9 ± ± ± ±50.1 pmol/ml/h (n = = = =69), with a coefficient of variation of 0.097. Although most of the subjects showed comparable conversion rates, 3 subjects had significantly higher conversion rates. In conclusion, the results of this study suggest that the enzyme activity of CCE in human plasma may show inter-individual variability. rinotecan, a camptothecin analogue, has recently been introduced into clinical practice and used for treatment of various cancers including lung, colorectal, pancreatic and ovarian cancer. It is a pro-drug that is converted to SN-38 by carboxylesterase converting enzymes (CCE), 1) and SN-38 has 100-to 1000-fold higher cytotoxic activity when compared to the original chemical form.2, 3) In addition, irinotecan and its metabolites have an extremely complex pharmacokinetic profile that is dependent on many enzymes involved in metabolism and transporters associated with intestinal absorption and hepatobiliary secretion mechanisms. 4)The dose-limiting toxicity of the agent includes bone marrow suppression and diarrhea. These adverse effects are occasionally severe not only in high-risk patients, and can even be fatal, especially when diarrhea is accompanied by neutropenia. 5-8)One of the major clinical issues with this drug is that its toxicity and pharmacokinetic parameters ostensibly show inter-patient variability, 4,9) and the toxicity is not necessarily correlated to the pharmacokinetic parameters. 4) Therefore, predicting its toxicity in any given patient has been difficult in contrast to other agents such as carboplatin, for which a sophisticated method for individualizing dosing is available. 10)As one of the mechanisms underlying this inter-individual variability of irinotecan metabolism, Ando et al. 11,12) demonstrated that bilirubin UDP-glucuronosyltransferase 1 gene promoters with excessive TATAA elements were responsible for reduced conjugation of SN-38 to SN-38-glucuronide (SN-38G), resulting in a reduction of SN-38 detoxication in the liver. However, it is still unresolved whether this mec...

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Section: Discussioncontrasting

confidence: 82%

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confidence: 99%

In vitro conversion of irinotecan to SN‐38 in human plasma

et al. 2004

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“…9 In addition, UGT1A1*28 has been identified as a risk factor for unwanted drug side effects exemplified by the possibility of severe toxicity of the anti-cancer drug irinotecan. [10][11][12][13] Gilbert's disease can therefore be regarded as a sentinal phenotype pointing to a pharmacogenetic risk constellation of UGT1A1*28-carrying individuals. 13 UGT1A1 is a member of the UGT1A family of transferases encoded on human chromosome 2.…”

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confidence: 99%

Gilbert's disease and atazanavir: From phenotype to UDP-glucuronosyltransferase haplotype

et al. 2006

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Gilbert's disease leads to intermittent non-hemolytic hyperbilirubinemia by a reduction of hepatic bilirubin glucuronidation associated with the presence of the UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism. It is considered benign because it does not result in hepatocellular damage. However, pharmacogenetic analyses have linked UGT1A1*28 to drug toxicity and cancer predisposition. The protease inhibitor atazanavir (ATV) is an inhibitor of hepatic UGT activity leading to hyperbilirubinemia in individual patients. Whether this is linked specifically to UGT1A1*28 or to more complex variants influencing glucuronidation is unclear. One hundred and six ATV-treated patients were characterized and genotyped for UGT1A1*28, the UGT1A3 (-66C) and UGT1A7 (-57G) promoter variants, and UGT1A7 129K/131K . ATV treatment increased median bilirubin levels from 10 to 41 mol/L (P ‫؍‬ .001) with hyperbilirubinemia exceeding 43 mol/L in 37%. Hyperbilirubinemia over 43 mol/L was significantly associated not only with UGT1A1*28 but also with UGT1A3-66C, UGT1A7-57G, and UGT1A7 129K/131K , although these variants do not naturally occur in linkage dysequilibrium in blood donors. Homozygous combinations of UGT1A1*28 with the other variants increased from 7.4% (normal bilirubin to 42 mol/L) to 41% to 46.1% (43 to >85 mol/L), and 100% (>85 mol/L). All six patients with hyperbilirubinemia greater than 85 mol/L were homozygous for all four variants identifying a haplotype inherited on a single allele. In conclusion, the genetic variant associated with Gilbert's disease is identified as part of a haplotype of four UGT1A variants spanning three genes at the UGT1A gene locus. This haplotype predisposes to hyperbilirubinemia in ATV treatment and may have an additional role as a pharmacogenomic risk factor for drug therapy. (HEPATOLOGY 2006;44:1324-1332

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“…The variable number of TA repeats ranges from five to eight copies, six TA repeats represent the most common allele, with up to 33% in Caucasians having a variant allele containing seven repeats (UGT1A1*28) (Iyer et al, 1999). Significant associations between patients with the UGT1A1*28 allele and reduced UGT1A1 expression, and, consequently, reduced SN38 glucuronidation have been shown in several studies (Ando et al, 1998;Iyer et al, 1999;Iyer et al, 2002). Assessment of the presence of the UGT1A1*28 allele in patients prior to irinotecan treatment may predict individuals at risk for severe toxicity from irinotecan, allowing the selection of lower doses or alternative therapies.…”

Section: Udp-glucuronosyltransferase 1a1 (Ugt1a1)mentioning

confidence: 99%

Cancer pharmacogenetics

2004

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The large number of active combination chemotherapy regimens for most cancers has led to the need for better information to guide the 'standard' treatment for each patient. In an attempt to individualise therapy, pharmacogenetics and pharmacogenomics (a polygenic approach to pharmacogenetic studies) encompass the search for answers to the hereditary basis for interindividual differences in drug response. This review will focus on the results of studies assessing the effects of polymorphisms in drugmetabolising enzymes and drug targets on the toxicity and response to commonly used chemotherapy drugs. In addition, the need for polygenic pharmacogenomic strategies to identify patients at risk for adverse drug reactions will be highlighted.

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UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan

Abstract: These results support the idea that the patient with 7/7 genotype has an impaired capacity for glucuronidation of SN-38.

Cited by 195 publications

References 6 publications

In vitro conversion of irinotecan to SN‐38 in human plasma

In vitro conversion of irinotecan to SN‐38 in human plasma

Gilbert's disease and atazanavir: From phenotype to UDP-glucuronosyltransferase haplotype

Cancer pharmacogenetics

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