Abstract
This study determined the disposition of irinotecan hydrochloride trihydrate (CPT-11) after i.v. infusion of 125 mg/m2 (100 μCi) [14C]CPT-11 in eight patients with solid tumors. Mean ± S.D. recovery of radioactivity in urine and feces was 95.8 ± 2.7% (range 92.2–100.3%, n = 7) of dose. Radioactivity in blood, plasma, urine, and feces was determined for at least 168 h after dosing. Fecal excretion accounted for 63.7 ± 6.8 (range 54.2–74.9%, n = 7) of dose, whereas urinary excretion accounted for 32.1 ± 6.9% (range 21.7–43.8%; n = 7) of dose. One patient with a biliary T-tube excreted 30.1% of dose in bile, 14.2% in feces, and 48.2% in urine. Quantitative radiometric HPLC revealed that CPT-11 was the major excretion product in urine, bile, and feces. Aminopentane carboxylic acid (APC) and SN-38 glucuronide (SN-38G) were the most significant metabolites in urine and bile, whereas SN-38 and NPC, a primary amine metabolite, were relatively minor excretion products. SN-38 and APC were the most significant metabolites in feces. The relatively higher amount of SN-38 in feces compared with bile is presumably due to hydrolysis of SN-38G to SN-38 by enteric bacterial β-glucuronidases. There was close correspondence between quantitative fluorescence HPLC and mass balance findings. CPT-11 was the major circulating component in plasma (55% of the mean radiochemical area under the curve), and CPT-11, SN-38, SN-38G, and APC accounted for 93% of the mean radiochemical AUC. These results show that the parent drug and its three major metabolites account for virtually all CPT-11 disposition, with fecal excretion representing the major elimination pathway.
Footnotes
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Send reprint requests to: Dr. J. Greg Slatter, Drug Metabolism Research, Pharmacia & Upjohn Co., 301 Henrietta Street, Kalamazoo MI 49007. E-mail: john.g.slatter{at}am.pnu.com
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Presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology (ASCO Proceedings), Volume 18, Abstract 633, Page 164a, Atlanta, May 15–18, 1999. Methodological aspects were presented at the 12th Central US Meeting of the International Isotope Society (IIS), Kalamazoo MI, May 20–21, 1999 (J Labelled Compd Radiopharm 1999: 42: 915–916.)
- Abbreviations used are::
- CPT-11
- irinotecan hydrochloride trihydrate
- APC
- aminopentane carboxylic acid metabolite of CPT-11
- ARE
- amount remaining to be excreted
- cMOAT
- canalicular multiple organic anion transporter
- MS
- mass spectrometry
- LC-MS
- liquid chromatography-mass spectrometry
- LSC
- liquid scintillation counting
- NPC
- primary amine metabolite of CPT-11
- SN-38
- active metabolite of CPT-11
- SN-38G
- SN-38 glucuronide
- SPE
- solid-phase extraction
- AUC
- area under the curve
- Rt
- retention time
- QC
- quality control
- CL
- total systemic clearance
- Vz
- terminal phase volume of distribution, LLOQ, lower limit of quantitation
- ULOQ
- upper limit of quantitation
- Received July 23, 1999.
- Accepted December 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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