HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (49) Citing Articles via Google Scholar Google Scholar Articles by Paoluzzi, L. Articles by Sparreboom, A. Search for Related Content PubMed PubMed Citation Articles by Paoluzzi, L. Articles by Sparreboom, A. Social Bookmarking                   What's this?

Influence of Genetic Variants in UGT1A1 and UGT1A9 on the In Vivo Glucuronidation of SN-38

From the Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland (Dr. Paoluzzi, Dr. Figg, Dr. Sparreboom); Division of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy (Dr. Paoluzzi); Howard Hughes Medical Institute, Bethesda, Maryland (Mr. Singh); Molecular Pharmacology Section, National Cancer Institute, Bethesda, Maryland (Mr. Singh, Dr. Price); Department of Oncology, University of Pisa, Pisa, Italy (Dr. Danesi); and Erasmus MC—Daniel den Hoed Cancer Center, Rotterdam, the Netherlands (Dr. Mathijssen, Dr. Verweij). Dr. Paoluzzi and Mr. Singh contributed equally to this work. Dr. Figg is a member of the American College of Clinical Pharmacology (FCP). Mr. Singh is a Howard Hughes Medical Institute-National Institutes of Health Research Scholar.

Address for reprints: William D. Figg, PharmD, Clinical Pharmacology Research Core, National Cancer Institute, Building 10, Room 5A01, MSC 1910, 9000 Rockville Pike, Bethesda, MD 20892.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
The uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9 isoforms are involved in the phase II biotransformation of the irinotecan metabolite, SN-38. Recently, several variants in the UGT1A1 and UGT1A9 genes have been described with altered functionality in vitro. The aim of this study was to evaluate the functional consequence of the UGT1A1(TA)₇TAA (UGT1A1^*28), UGT1A9 766G>A (D256N; UGT1A9^*5), and UGT1A9 98T>C (M33T; UGT1A9^*3) variants in Caucasian patients treated with irinotecan. Pharmacokinetic studies were performed after the first course of irinotecan in 47 males and 47 females. The mean (SD) area under the curves (AUCs) of irinotecan and SN-38 were 20,348 ± 6466 ng•h/mL and 629 ± 370 ng•h/mL, respectively, which is in line with earlier findings. For UGT1A9^*5,novariant alleles were observed, whereas for UGT1A9^*3, 1 patient with the variant allele was found (allele frequency, 0.633%). The distribution of the UGT1A1^*28 variant showed 44 wild-type patients (Wt), 37 heterozygotes (Het), and 5 homozygotes (Var). The median AUC ratio of SN-38G to SN-38 was significantly reduced in carriers of the variant UGT1A1^*28 allele (7.00 [Wt] vs. 6.26 [Het] vs. 2.51 [Var]; p = .022). It is concluded that UGT1A9 functional variants are rare in Caucasians and likely to be clinically insignificant in irinotecan regimens. Screening for the UGT1A1^*28 polymorphism may identify patients with altered SN-38 pharmacokinetics.

Key Words: UGT1A1 • UGT1A9 • irinotecan • pharmacokinetics • genetic variants • SN-38

The UGT family is replete with polymorphisms, the functional significance of which is known for only a few. These genetic variants of the UGT enzymes engender some very clinically relevant problems. Gilbert's syndrome and Crigler-Najjar syndromes I and II, all nonhemolytic unconjugated hyperbilirubinemias, are due to mutations or a lack of UGT1A1 activity.^1,4 Furthermore, a polymorphism named ^*3 in the UGT1A7 allele, which is important in the elimination of benzo(a)pyrene and other polycyclic aromatic hydro-carbons, has been linked to an increased incidence in otolaryngeal cancers in smokers, spontaneous colorectal carcinomas, and hepatocellular carcinomas.^7-9 Moreover, these enzymes are involved in the metabolism of several important chemotherapy agents, including irinotecan, tamoxifen, and epirubicin.⁵

Irinotecan (CPT-11) is a particularly important drug because it is included in the first-line regimen for advanced metastatic colorectal cancer as well as regimens for lung cancer.¹⁰ It is a prodrug that is transformed to the highly active topoisomerase 1 inhibitor, SN-38, by carboxylesterase enzymes. However, its major dose-limiting side effect is diarrhea.¹¹ Irinotecan's metabolism is particularly relevant in the context of the UGT family because the main route of elimination for SN-38 is through glucuronidation and biliary excretion. Furthermore, it is theorized that the glucuronidation of SN-38 is important for decreasing the toxicity of SN-38 to the intestinal mucosa, which leads to diarrhea.^12,13

The UGT1A1, UGT1A7, and UGT1A9 isoforms are responsible for most of the glucuronidation of SN-38.^14-16 The UGT1A1(TA)₇TAA (UGT1A1^*28) polymorphism¹⁷ has been correlated in small studies with an increased incidence of diarrhea and neutropenia; it has also been proposed to be of utility as a pretreatment test to predict irinotecan-associated toxicities.^18,19 But other studies have pointed out that the correlation is not absolute; interindividual differences in levels of UGT1A isoforms, environmental effects on enzyme levels, and the contribution of other UGT isoforms to SN-38 glucuronidation have been postulated to contribute to the missing link.^15,20 The UGT1A7 isoform and its variants were shown not to correlate with irinotecan-associated diarrhea or neutropenia.²¹ Recently, groups have begun to study the contribution of UGT1A9 polymorphisms to individual variability in SN-38 glucuronidation. While Vogel et al⁹ failed to find UGT1A9 polymorphisms in a group of German patients, Jinno et al²² found the novel UGT1A9 766G>A (D256N; UGT1A9^*5) variant in 1 of 61 Japanese cancer patients being treated with irinotecan, and Villeneuve et al²³ found 4.4% of a Caucasian population to have a previously undescribed UGT1A9 98T>C (M33T; UGT1A9^*3) variant and 1 of 20 African American patients to have the UGT1A9^*2 mutation. Only the UGT1A9^*3 allele exhibited a diminished glucuronidating ability for SN-38. Here, we explored the allelic frequencies and functional consequence of the UGT1A1^*28, UGT1A9^*3,and UGT1A9^*5 variants in a Caucasian population treated with irinotecan.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Patients and Treatment
A group of 94 adult Caucasian patients (47 males and 47 females) with histologically confirmed diagnosis of a malignant solid tumor (e.g., gastrointestinal cancers), for which there was no effective standard regimen and irinotecan was a reasonable treatment option, were treated with irinotecan administered as a 90-minute intravenous infusion at a median dose of 600 mg. The patients had a median age of 54 years (range: 34-75 years) and good marrow reserve (i.e., absolute neutrophil count 2.0 x 10⁹/L and platelet count 100.0 x 10⁹/L). None of the patients received any other concurrent chemotherapy or other drugs, food supplements, and/or herbal preparations known to interfere with the pharmacokinetics of irinotecan. The clinical protocol, including blood sampling for the purpose of pharmacokinetic and pharmacogenetic analyses, was approved by the institutional review board, and all patients provided written informed consent.

Irinotecan Disposition
Pharmacokinetic studies were performed after the first course of irinotecan. Blood samples of about 5 mL each were collected at serial time points up to 500 hours after drug administration and were centrifuged to obtain plasma. Pharmacokinetic data obtained in a subset of 53 patients were described previously.²⁴ Concentrations of irinotecan, SN-38, and SN-38 glucuronide (SN-38G) were determined using a validated method based on liquid chromatography with fluorescence detection, as described elsewhere.²⁵ Previously developed population models were used to predict the pharmacokinetic parameters of irinotecan, SN-38, and SN-38G.²⁶

The area under the plasma-concentration time curve (AUC) normalized to the recommended single-agent dose of 600 mg was simulated for irinotecan and its metabolites in all patients from time 0 to 100 hours after start of infusion. This analysis was performed using NONMEM version VI (S. L. Beal and L. B. Sheiner, San Francisco). Metabolic conversion ratios were calculated as the AUC ratio of SN-38 to irinotecan and the AUC ratio of SN-38G to SN-38. Previously, it was shown that the AUC of irinotecan, SN-38, and SN-38G is dose proportional over a large dose range in the tested 3-week regimen with irinotecan administered as a 90-minute intravenous infusion, indicating a linear pharmacokinetic behavior.^15,20 Therefore, values for all AUC ratios were compared directly without any correction for differences in drug dose administered between patients. Previous investigations have shown that both age and sex are not significant covariates on irinotecan clearance or exposure to the metabolites.²⁶

Genotyping Techniques
Deoxyribonucleic acid (DNA) was extracted from the serum using a QiaBlood extraction kit (Qiagen, Valencia, CA) and stored at 4°C.²⁷ The UGT1A1^*28 polymorphism was analyzed by direct sequencing as described previously.²⁸ For UGT1A9, primers were selected that overlapped the portion of the UGT1A9 gene containing the UGT1A9^*5 and UGT1A9^*3 variants (Table I).^22,23 The DNA products were amplified with primers obtained from Invitrogen (Carlsbad, CA) using 1.25-U Platinum Taq DNA polymerase. Samples were subject to an initial 40-cycle reaction using 40-pmol primers with the following temperature cycle: 5 minutes at 94°C, 30 seconds at 94°C, 30 seconds at 62°C, 30 seconds at 72°C, and 7 minutes at 72°C. The samples were checked via 4% agarose gel electrophoresis for the presence of products. Those samples that did not amplify were subjected to a nested polymerase chain reaction (PCR) amplification. The nested PCR reaction consisted of a primary 20-cycle round of amplification using 20 pmol of the forward (F)1 and reverse (R)1 primers with the same conditions as above. The second round of amplification was carried out using 40 pmol of the F2 and R2 primers for 40 cycles (see settings above). All reactions were verified for product using 4% agarose gel electrophoresis.

All samples were cleaned with the Microcon YM-100 DNA purification kit (Millipore, Billerica, MA) in preparation for PCR for sequencing. Sequencing PCR was done with 3.2 pmol of F3 or R3 primers using dRhodamine terminator cycle sequencing reaction reagents (ABI Prism 403042) under the following cycle sequence: 5 minutes at 94°C, 10 seconds at 96°C, 5 seconds at 50°C, and 4 minutes at 60°C. The PCR products were then sequenced on an ABI Prism 310 Genetic Analyzer as per the manufacturer's instructions.

Pharmacodynamic Evaluation
Complete blood cell counts and chemistry were obtained for each patient prior to study entry, prior to each chemotherapy course, and was repeated once weekly during the patients' outpatient visits. In case of severe hematologic toxicity, blood cell counts were measured daily or as clinically indicated. Diarrhea was scored using the National Cancer Institute common toxicity criteria (NCI-CTC) version 2.0 (accessed May 4, 2004, at http://ctep.info.nih.gov/reporting/ctc.html).

Statistical Analysis
Pharmacokinetic data were presented as mean values ± SD unless otherwise indicated. Correlations between SN-38G or SN-38 pharmacokinetic parameters and the variant genotypes were assessed by a nonparametric Kruskal-Wallis test followed by a comparison of all means with a Tukey-Kramer multiple-comparison test (NCSS v2001; J. Hintze, Number Cruncher Statistical Systems, Kaysville, UT). Also, a separate nonparametric Mann-Whitney U test was used to compare the UGT1A1^*28 homozygotes with wild types plus heterozygotes. The a priori cutoff for statistical significance was set at p < 0.05.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Genotypic and Allelic Frequencies
For UGT1A1^*28, 86 patients had nonambiguous electropherograms; 44 patients (51.2%) were wild-type (TA6/TA6), 37 (43.0%) were heterozygous (TA6/TA7), and 5 (5.80%) were homozygous variant (TA7/TA7) (Table II). This corresponds to an allele frequency of 72.6% for the wild-type allele (p) and 27.3% for the variant (q). Of the 94 patients tested for the UGT1A9^*5 variant, all showed amplification products, with 82 of the patients having nonambiguous sequencing electropherograms, and each of these had a wild-type sequence. Of the 94 subjects tested for the UGT1A9^*3 variant, 79 showed amplification products, with 78 patients having nonambiguous sequencing electropherograms. With the exception of 1 patient carrying the heterozygote sequence for UGT1A9^*3, only wild types were observed (allele frequency, 0.633%).

Genotypes-Pharmacokinetics Correlations
The mean AUCs for irinotecan, SN-38, and SN-38G, as well as the metabolic ratios, were consistent with previously reported estimates (Table III).²⁶ The kinetic values were derived from a population kinetic approach, with AUC values being predicted at a dose of 600 mg/patient, using an assumption of linear kinetics.²⁰ The median AUC ratio of SN-38G to SN-38 was significantly reduced in patients with the variant UGT1A^*28 allele: 7.00 for wild-type patients versus 6.26 for heterozygous versus 2.51 for homozygous (p = 0.022) (Table IV and Figure 1). A separate nonparametric Mann-Whitney U test showed that median values for the AUC ratio of SN-38G to SN-38 in patients homozygous for UGT1A1^*28 were significantly different from that observed in wild-type and heterozygous patients combined (p = 0.012). As a result, circulating concentrations of unconjugated SN-38 were substantially increased in patients carrying the homozygous variant sequence (Table IV). The other pharmacokinetic parameters tested were not significantly affected by the UGT1A1^*28 genotype.

View larger version (10K): [in this window] [in a new window]   Figure 1. Comparison of the AUC ratio of SN-38G to SN-38 among those patients who are wild type (TA6/TA6), heterozygous (TA6/TA7), or homozygous variant (TA7/TA7) for UGT1A1*28. Each point represents an individual patient. The horizontal lines indicate mean values. The x-axis positions were artificially manipulated to allow better visibility.

The UGT1A9^*3 genotype was found in only 1 patient, and it did not significantly affect the pharmacokinetics of irinotecan in this patient. This patient's SN-38G to SN-38 AUC ratio was 11.4, which is within 1 standard deviation of the mean value (7.49 ± 5.50) of this ratio in the entire patient population. Furthermore, this patient did not experience diarrhea or neutropenia and was wild type with respect to UGT1A1^*28. Diarrhea graded 2, 3, and 4 on the NCI-CTC scale was observed in 18%, 11%, and 2% of patients, respectively, and was not significantly associated with the UGT1A1^*28 genotype (p = 0.74).

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Irinotecan is an antitumor prodrug of the topoisomerase I inhibitor SN-38 with a complex metabolism that involves several phase I and II enzymes. Glucuronidation is the major route of biotransformation responsible for the elimination and inactivation of SN-38.² UGT1A1 was previously suggested to be the main human UGT isoform involved in the formation of SN-38G.^{16,18,19,29,30} The metabolic clearance of SN-38 in patients with cancer is of considerable clinical significance since increased concentrations of SN-38 are correlated with the incidence and severity of diarrhea, irinotecan's main dose-limiting side effect, as well as with neutropenia.^29,31

In a retrospective case control study of 26 Japanese patients who experienced greater toxicity following irinotecan treatment, multivariate analysis suggested that a heterozygous or homozygous genotype for UGT1^*28 would be a significant risk factor for severe toxicity by this drug.¹⁸ Shortly thereafter, a prospective clinical pharmacogenetic study of 20 patients being treated with irinotecan for solid tumors observed that 1 of 7 heterozygotes experienced grade 4 diarrhea, 1 of 4 of the homozygote variant demonstrated grade 3 neutropenia, and another homozygote demonstrated both grade 3 diarrhea and grade 4 neutropenia.¹⁹ The findings from these studies have been propagated as a rationale for performing pretreatment genetic testing on patients receiving irinotecan, despite the small sample sizes tested. One aim of the current work was to analyze the frequency of the UGT1A1^*28 polymorphism in a larger set of Caucasian patients and its relevance to SN-38 glucuronidation.

The current UGT1^*28 genotype analysis revealed the presence of three different groups of patients carrying the wild-type (n = 44), heterozygous (n = 37), or homozygous (n = 5) variant sequence. The wild-type and the heterozygous variant populations exhibited similar median glucuronidation efficiencies: 7.00 and 6.26, respectively. However, the homozygous variants exhibited only 35% of the efficiency of the other two groups, which was significant at p = 0.012. The allele frequencies of the patients in our study were 0.727 for wild type and 0.273 for the variant, comparable with the allele frequencies observed by Iyer et al¹⁹ of 0.625 and 0.375, respectively. The frequency of UGT1A^*28 homozygotes has been reported to be about 0.5% to 23% in different populations and to be much lower in the Asians compared to Caucasians and Africans.^5,28,32

A previous study showed a slightly impaired SN-38 glucuronidation in 2 homozygous variant patients with the UGT1A^*28 genotype without a statistically significant difference (p = 0.22).²⁴ These results could be due to a low allele frequency of the variant allele in that Caucasian population. That study did note, however, that there was a downward trend in the AUC ratio for the homozygous variants versus the wild-type and heterozygous populations.

Recent data have suggested a major role of UGT1A9 in addition to UGT1A1 in the biotransformation of SN-38. In vitro studies identified two novel, functional nonsynonymous single-nucleotide polymorphisms in UGT1A9 exon 1.^22,23 Jinno et al²² found 1 of 61 Japanese cancer patients with the 766G>A variant, which results in the amino acid substitution D256N (UGT1A9^*5), and Villeneuve et al²³ found 4.4% of a population of 201 French Canadians to be heterozygous for the variant UGT1A9^*3, which results in the amino acid substitution M33T. These two variants showed less than 5% of SN-38 glucuronidation efficiency in comparison with their wild-type proteins.

In our study, we did not find any cases of the UGT1A9^*5 variant in a group of 82 patients, although for UGT1A9^*3, we observed 1 of 78 patients with the heterozygous 98T>C mutation. The glucuronidation ratio of the patients in this study ranged from 1.70 to 37.5. The 1 patient with the UGT1A9^*3 variant allele did not exhibit decreased glucuronidation as would be predicted according to the in vitro data.²³ In fact, this patient's SN-38G to SN-38 AUC ratio was 11.4, which was higher than the mean value of 7.49. This patient also turned out to be wild type for UGT1A1^*28. Surprisingly, the patient who showed the lowest value of SN-38 glucuronidation (i.e., 1.70) revealed a wild-type genotype for the three UGT1A variants evaluated in this study. These results point to the importance of additional factors involved in SN-38 inactivation and toxicity. For example, two recent studies have indicated that variations in genes encoding MDR1 P-glycoprotein (ABCB1) may increase exposure to irinotecan and SN-38, as well as influence renal excretion of the drug.^24,33 In addition, the complexity of irinotecan metabolism indicates the likelihood of additional factors being responsible for its side effects, including environmental and physiologic factors.²⁰

In conclusion, the UGT1A1^*28 polymorphism seems to be only one of few identified causes of altered SN-38 pharmacokinetics and possibly of irinotecan-induced toxicities. In addition, the present data indicate that in a Caucasian population, the UGT1A9^*5 and UGT1A9^*3 variants are infrequent and of unlikely significance in relation to irinotecan metabolism and toxicity. It is concluded that screening for the UGT1A^*28 polymorphism may identify patients with altered SN-38 pharmacokinetics and may aid in individualizing chemotherapeutic treatment with irinotecan. It is possible that a study comparing the haplotypes of the UGT1A1 and UGT1A9 genes with irinotecan's pharmacodynamics and pharmacokinetics may provide more precise information.³⁴ Further studies focusing on analysis of additional functional variants in genes involved in irinotecan elimination are warranted.

	FOOTNOTES

 
The authors report no relationships that are conflicts of interest in the carrying out of these experiments or in the presentation of the data in this article. This project was funded, in part, by the intramural program of the National Cancer Institute (Bethesda, MD) and the Italian Foundation for Cancer Research (Milano, Italy).

DOI: 10.1177/0091270004267159

Submitted for publication March 17, 2004; Revised version accepted May 10, 2004.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 

1. Tukey RH, Strassburg CP: Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2000;40: 581-616.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

2. Bock KW: Vertebrate UDP-glucuronosyltransferases: functional and evolutionary aspects. Biochem Pharmacol 2003;66: 691-696.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Tukey RH, Strassburg CP, Mackenzie PI: Pharmacogenomics of human UDP-glucuronosyltransferases and irinotecan toxicity. Mol Pharmacol 2002;62: 446-450.[Free Full Text]

4. Miners JO, McKinnon RA, Mackenzie PI: Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. Toxicology 2002;181-182: 453-456.

5. Desai AA, Innocenti F, Ratain MJ: UGT pharmacogenomics: implications for cancer risk and cancer therapeutics. Pharmacogenetics 2003;13: 517-523.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Basu NK, Ciotti M, Huang MS, et al: Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical up-take. J Biol Chem 2003;279: 1429-1441.[Medline] [Order article via Infotrieve]

7. Zheng Z, Fang JL, Lazarus P: Glucuronidation: an important mechanism for detoxification of benzo[a]pyrene metabolites in aerodigestive tract tissues. Drug Metab Dispos 2002;30: 397-403.[Abstract/Free Full Text]

8. Strassburg CP, Nguyen N, Manns MP, et al: UDP-glucuronosyltransferase activity in human liver and colon. Gastroenterology 1999;116: 149-160.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Vogel A, Kneip S, Barut A, et al: Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene. Gastroenterology 2001;121: 1136-1144.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Rothenberg ML: Irinotecan (CPT-11): recent developments and future directions—colorectal cancer and beyond. Oncologist 2001;6: 66-80.[Abstract/Free Full Text]

11. Rothenberg ML: Efficacy and toxicity of irinotecan in patients with colorectal cancer. Semin Oncol 1998;25: 39-46.[Web of Science][Medline] [Order article via Infotrieve]

12. Kehrer DF, Yamamoto W, Verweij J, et al: Factors involved in prolongation of the terminal disposition phase of SN-38: clinical and experimental studies. Clin Cancer Res 2000;6: 3451-3458.[Abstract/Free Full Text]

13. Takasuna K, Hagiwara T, Hirohashi M, et al: Involvement of betaglucuronidase in intestinal microflora in the intestinal toxicity of the antitumor camptothecin derivative irinotecan hydrochloride (CPT-11) in rats. Cancer Res 1996;56: 3752-3757.[Abstract/Free Full Text]

14. Ciotti M, Basu N, Brangi M, et al: Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38) by the human UDP-glucuronosyltransferases encoded at the UGT1 locus. Biochem Biophys Res Commun 1999;260: 199-202.[CrossRef][Medline] [Order article via Infotrieve]

15. Gagne JF, Montminy V, Belanger P, et al: Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Mol Pharmacol 2002;62: 608-617.[Abstract/Free Full Text]

16. Iyer L, King CD, Whitington PF, et al: Genetic predisposition to the metabolism of irinotecan (CPT-11): role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 1998;101: 847-854.[Web of Science][Medline] [Order article via Infotrieve]

17. Ando Y, Saka H, Asai G, et al: UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol 1998;9: 845-847.[Abstract/Free Full Text]

18. Ando Y, Saka H, Ando M, et al: Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 2000;60: 6921-6926.[Abstract/Free Full Text]

19. Iyer L, Das S, Janisch L, et al: UGT1A1^*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002;2: 43-47.[CrossRef][Medline] [Order article via Infotrieve]

20. Mathijssen RH, van Alphen RJ, Verweij J, et al: Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 2001;7: 2182-2194.[Abstract/Free Full Text]

21. Ando M, Ando Y, Sekido Y, et al: Genetic polymorphisms of the UDP-glucuronosyltransferase 1A7 gene and irinotecan toxicity in Japanese cancer patients. Jpn J Cancer Res 2002;93: 591-597.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

22. Jinno H, Saeki M, Saito Y, et al: Functional characterization of human UDP-glucuronosyltransferase 1A9 variant, D256N, found in Japanese cancer patients. J Pharmacol Exp Ther 2003;306: 688-693.[Abstract/Free Full Text]

23. Villeneuve L, Girard H, Fortier LC, et al: Novel functional polymorphisms in the UGT1A7 and UGT1A9 glucuronidating enzymes in Caucasian and African-American subjects and their impact on the metabolism of 7-ethyl-10-hydroxycamptothecin and flavopiridol anticancer drugs. J Pharmacol Exp Ther 2003;307: 117-128.[Abstract/Free Full Text]

24. Mathijssen RH, Marsh S, Karlsson MO, et al: Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res 2003;9: 3246-3253.[Abstract/Free Full Text]

25. Sparreboom A, de Bruijn P, de Jonge MJ, et al: Liquid chromatographic determination of irinotecan and three major metabolites in human plasma, urine and feces. J Chromatogr B Biomed Sci Appl 1998;712: 225-235.[CrossRef][Medline] [Order article via Infotrieve]

26. Xie R, Mathijssen RH, Sparreboom A, et al: Clinical pharmacokinetics of irinotecan and its metabolites: a population analysis. J Clin Oncol 2002;20: 3293-3301.[Abstract/Free Full Text]

27. Dixon SC, Horti J, Guo Y, et al: Methods for extracting and amplifying genomic DNA isolated from frozen serum. Nat Biotechnol 1998;16: 91-94.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

28. Monaghan G, Ryan M, Seddon R, et al: Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet 1996;347: 578-581.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

29. Innocenti F, Undevia SD, Iyer L, et al.: Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004;22: 1382.[Abstract/Free Full Text]

30. Ando M, Kitagawa C, Ando Y, et al: Genetic polymorphisms in the phenobarbital-responsive enhancer module of the UDP-Glucuronosyltransferase (UGT) 1A1 gene and irinotecan toxicity in Japanese patients. Proc ASCO 2003;22(abstr 496): 124.

31. Gupta E, Mick R, Ramirez J, et al: Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 1997;15: 1502-1510.[Abstract]

32. Burchell B: Genetic variation of human UDP-glucuronosyltransferase: implications in disease and drug glucuronidation. Am J Pharmacogenomics 2003;3: 37-52.[CrossRef][Medline] [Order article via Infotrieve]

33. Sai K, Kaniwa N, Itoda M, et al: Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 2003;13: 741-757.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

34. Yamanaka H, Nakajima M, Katoh M, et al: A novel polymorphism in the promoter region of human UGT1A9 gene (UGT1A9^*22) and its effects on the transcriptional activity. Pharmacogenetics 2003;14: 329-332.
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. W. J. Wang, K. H. Kulkarni, L. Tang, J. R. Wang, T. Yin, T. Daidoji, H. Yokota, and M. Hu Disposition of Flavonoids via Enteric Recycling: UDP-Glucuronosyltransferase (UGT) 1As Deficiency in Gunn Rats Is Compensated by Increases in UGT2Bs Activities J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1023 - 1031. [Abstract] [Full Text] [PDF]

				R. M. Balliet, G. Chen, C. J. Gallagher, R. W. Dellinger, D. Sun, and P. Lazarus Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype Cancer Res., April 1, 2009; 69(7): 2981 - 2989. [Abstract] [Full Text] [PDF]

				G B McDonald and D Frieze A problem-oriented approach to liver disease in oncology patients Gut, July 1, 2008; 57(7): 987 - 1003. [Full Text] [PDF]

				J. A. Williams, T. Andersson, T. B. Andersson, R. Blanchard, M. O. Behm, N. Cohen, T. Edeki, M. Franc, K. M. Hillgren, K. J. Johnson, et al. PhRMA White Paper on ADME Pharmacogenomics J. Clin. Pharmacol., July 1, 2008; 48(7): 849 - 889. [Abstract] [Full Text] [PDF]

				L. R. Bomgaars, M. Bernstein, M. Krailo, R. Kadota, S. Das, Z. Chen, P. C. Adamson, and S. M. Blaney Phase II Trial of Irinotecan in Children With Refractory Solid Tumors: A Children's Oncology Group Study J. Clin. Oncol., October 10, 2007; 25(29): 4622 - 4627. [Abstract] [Full Text] [PDF]

				J. M. Hoskins, R. M. Goldberg, P. Qu, J. G. Ibrahim, and H. L. McLeod UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters J Natl Cancer Inst, September 5, 2007; 99(17): 1290 - 1295. [Abstract] [Full Text] [PDF]

				C. F. Stewart, J. C. Panetta, M. A. O'Shaughnessy, S. L. Throm, C. H. Fraga, T. Owens, T. Liu, C. Billups, C. Rodriguez-Galindo, A. Gajjar, et al. UGT1A1 Promoter Genotype Correlates With SN-38 Pharmacokinetics, but Not Severe Toxicity in Patients Receiving Low-Dose Irinotecan J. Clin. Oncol., June 20, 2007; 25(18): 2594 - 2600. [Abstract] [Full Text] [PDF]

				R. P. Ramchandani, Y. Wang, B. P. Booth, A. Ibrahim, J. R. Johnson, A. Rahman, M. Mehta, F. Innocenti, M. J. Ratain, and J. V. S. Gobburu The Role of SN-38 Exposure, UGT1A1*28 Polymorphism, and Baseline Bilirubin Level in Predicting Severe Irinotecan Toxicity J. Clin. Pharmacol., January 1, 2007; 47(1): 78 - 86. [Abstract] [Full Text] [PDF]

				K. K. Hahn, J. J. Wolff, and J. M. Kolesar Pharmacogenetics and irinotecan therapy Am. J. Health Syst. Pharm., November 15, 2006; 63(22): 2211 - 2217. [Abstract] [Full Text] [PDF]

				G. Toffoli, E. Cecchin, G. Corona, A. Russo, A. Buonadonna, M. D'Andrea, L. M. Pasetto, S. Pessa, D. Errante, V. De Pangher, et al. The Role of UGT1A1*28 Polymorphism in the Pharmacodynamics and Pharmacokinetics of Irinotecan in Patients With Metastatic Colorectal Cancer J. Clin. Oncol., July 1, 2006; 24(19): 3061 - 3068. [Abstract] [Full Text] [PDF]

				J.-Y. Han, H.-S. Lim, E. S. Shin, Y.-K. Yoo, Y. H. Park, J.-E. Lee, I.-J. Jang, D. Ho Lee, and J. Soo Lee Comprehensive Analysis of UGT1A Polymorphisms Predictive for Pharmacokinetics and Treatment Outcome in Patients With Non-Small-Cell Lung Cancer Treated With Irinotecan and Cisplatin J. Clin. Oncol., May 20, 2006; 24(15): 2237 - 2244. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (49) Citing Articles via Google Scholar Google Scholar Articles by Paoluzzi, L. Articles by Sparreboom, A. Search for Related Content PubMed PubMed Citation Articles by Paoluzzi, L. Articles by Sparreboom, A. Social Bookmarking                   What's this?