{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:16:38Z","timestamp":1792196198793,"version":"4.4.0"},"reference-count":40,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCO"],"published-print":{"date-parts":[[2009,6,1]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg\/m<jats:sup>2<\/jats:sup> (n = 20) and 350 mg\/m<jats:sup>2<\/jats:sup> (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 \u201348C&gt;T, SLCO1B1*1b, ANC baseline levels, sex, and race (P &lt; .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 \u201324C&gt;T, SLCO1B1*5, HNF1A 79A&gt;C, age, and CPT-11 dose (P &lt; .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T&gt;C, ABCB1 IVS9 \u201344A&gt;G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G\/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.2008.20.6300","type":"journal-article","created":{"date-parts":[[2009,4,7]],"date-time":"2009-04-07T01:28:03Z","timestamp":1239067683000},"page":"2604-2614","source":"Crossref","is-referenced-by-count":233,"title":["Comprehensive Pharmacogenetic Analysis of Irinotecan Neutropenia and Pharmacokinetics"],"prefix":"10.1200","volume":"27","author":[{"given":"Federico","family":"Innocenti","sequence":"first","affiliation":[{"name":"From The University of Chicago, Chicago, IL; University of California, San Francisco, CA; St. Jude's Children Research Hospital, Memphis, TN; and The University of Texas M. D. Anderson Cancer Center, Houston, TX."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deanna L.","family":"Kroetz","sequence":"additional","affiliation":[{"name":"From The University of Chicago, Chicago, IL; University of California, San Francisco, CA; St. Jude's Children Research Hospital, Memphis, TN; and The University of Texas M. D. Anderson Cancer Center, Houston, TX."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Schuetz","sequence":"additional","affiliation":[{"name":"From The University of Chicago, Chicago, IL; University of California, San Francisco, CA; St. Jude's Children Research Hospital, Memphis, TN; and The University of Texas M. D. Anderson Cancer Center, Houston, TX."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Eileen","family":"Dolan","sequence":"additional","affiliation":[{"name":"From The University of Chicago, Chicago, IL; University of California, San Francisco, CA; St. Jude's Children Research Hospital, Memphis, TN; and The University of Texas M. D. Anderson Cancer Center, Houston, TX."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"From The University of Chicago, Chicago, IL; University of California, San Francisco, CA; St. Jude's Children Research Hospital, Memphis, TN; and The University of Texas M. D. Anderson Cancer Center, Houston, TX."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Relling","sequence":"additional","affiliation":[{"name":"From The University of Chicago, Chicago, IL; University of California, San Francisco, CA; St. Jude's Children Research Hospital, Memphis, TN; and The University of Texas M. D. 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