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PIII‐75
Author(s) -
Loos W. J.,
Jong F. A.,
Kitzen J. J.,
Verweij J.,
Bruijn P.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.283
Subject(s) - urine , irinotecan , excretion , chemistry , glucuronidation , cyp3a , feces , medicine , glucuronide , pharmacokinetics , endocrinology , enterohepatic circulation , pharmacology , metabolism , colorectal cancer , cancer , biology , enzyme , biochemistry , cytochrome p450 , microsome , paleontology
BACKGROUND Irinotecan (CPT‐11) is metabolized by various enzymes, including CE, CYP3A and UGT1A. Here we report on the disposition of irinotecan and its metabolites in plasma, urine, bile and feces of a cancer patient with a bile drain. METHODS Blood samples were collected up to 55h after infusion, while bile, feces and urine were collected during 6 consecutive days. RESULTS The plasma CL of CPT‐11 was 15.3 L/h, with relative metabolic conversions to SN‐38, APC and NPC of 0.022, 0.40 and 0.016 respectively and a relative extent of glucuronidation of 6.9. Overall, 84% of the administered dose was recovered (see table). The relative contribution of CPT‐11 to the excretion over the studied days in urine decreased, while those in bile was stable. The relative contribution of the metabolites to the excretion in bile and urine changes in time (see figure). CONCLUSION The PK of CPT‐11 and metabolites in plasma are equivalent to historical data, with a relative slow CL of CPT‐11 and relative high AUC of APC. The high percentage of the dose recovered in urine as compared to published data, the relative slow CL of CPT‐11 and the preferential urinary excretion over biliary excretion of APC is most likely related to reduced transport by ABC transporters in the liver. Differential affinities of CPT‐11 for substrate‐binding active sites on CYP3A may contribute to the changed metabolic excretion profile of CPT‐11 in time. Inhibition or decreased activity of CE, as well as sustained release from other compartments, also cannot be excluded.Recovery of administered dose CPT‐11 Excreta CPT‐11 SN‐38 SN‐38G APC NPC TotalUrine 29.2% 0.9% 4.6% 9.3% 0.5% 44.5% Bile 20.8% 0.9% 3.0% 5.2% 1.2% 31.0% Feces 7.1% 0.5% — 0.2% 0.1% 7.9% All 57.3% 2.4% 7.6% 14.6% 1.7% 83.5%Clinical Pharmacology & Therapeutics (2005) 79 , P79–P79; doi: 10.1016/j.clpt.2005.12.283