Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I.V. infusion of [(14)C]CPT-11 in cancer patients.

This study determined the disposition of irinotecan hydrochloride trihydrate (CPT-11) after i.v. infusion of 125 mg/m(2) (100 microCi) [(14)C]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 beta-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.

• Publication year

  2000

• Venue

  Drug Metabolism And Disposition

• Publication date

  2000-04-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/s0090-9556(24)15060-xPMID 10725311
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2004cited by this paper
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  1998cited by this paper
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  1998cited by this paper
• Biliary excretion mechanism of CPT-11 and its metabolites in humans: involvement of primary active transporters.

  1998cited by this paper
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  1998cited by this paper
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  1998cited by this paper
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  1997cited by this paper
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  1997cited by this paper
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  1997cited by this paper
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  1997influential reference
• Pharmacokinetic interrelationships of irinotecan (CPT-11) and its three major plasma metabolites in patients enrolled in phase I/II trials.

  1997cited by this paper
• The transformation of irinotecan (CPT-11) to its active metabolite SN-38 by human liver microsomes Differential hydrolysis for the lactone and carboxylate forms

  1997cited by this paper
• CPT‐11 in human colon‐cancer cell lines and xenografts: Characterization of cellular sensitivity determinants

  1997cited by this paper
• Clinical Pharmacokinetics of Irinotecan

  1997influential reference
• Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients.

  1997cited by this paper
• Preclinical evaluation of CPT-11 and its active metabolite SN-38.

  1996cited by this paper
• Irinotecan (CPT-11) metabolites in human bile and urine.

  1996influential reference
• Identification and properties of a major plasma metabolite of irinotecan (CPT-11) isolated from the plasma of patients.

  1996cited by this paper
• Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials.

  1995cited by this paper
• The structural basis of camptothecin interactions with human serum albumin: impact on drug stability.

  1994cited by this paper
• Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea.

  1994cited by this paper
• Urinary and biliary disposition of the lactone and carboxylate forms of 20(S)-camptothecin in rats.

  1994cited by this paper
• A Regulatory and Industrial Perspective of the Use of Carbon-14 and Tritium Isotopes in Human ADME Studies

  1994cited by this paper
• Phase I and pharmacokinetic trial of weekly CPT-11.

  1993cited by this paper
• DNA Damage and Cell Killing by Camptothecin and Its Derivative in Human Leukemia HL‐60 Cells

  1993cited by this paper
• Canalicular organic anion transport after bile duct ligation and reconstructicn in the rat

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  1993cited by this paper
• Determination of Self-Association of Irinotecan Hydrochloride (CPT-11) in Aqueous Solution

  1992cited by this paper
• [Conversion of CPT-11 into SN-38 in human tissues].

  1991cited by this paper
• Application of chemical cytochrome P-450 model systems to studies on drug metabolism. IV. Mechanism of piperidine metabolism pathways via an iminium intermediate.

  1991cited by this paper
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  1991cited by this paper
• Nonlinear pharmacokinetics of CPT-11 in rats.

  1990cited by this paper
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  1990cited by this paper
• Hydroxy metabolites of phencyclidine. Identification and quantitation of two novel metabolites.

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• MIRD primer for absorbed dose calculations

  1988cited by this paper
• Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothec in, a novel water-soluble derivative of camptothecin, against murine tumors.

  1987cited by this paper
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  1987cited by this paper
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  1985cited by this paper

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