Identification of the metabolites of irinotecan, a new derivative of camptothecin, in rat bile and its biliary excretion

Atsumi, Ryo; Suzuki, Wataru; Hakusui, Hideo

doi:10.3109/00498259109039556

Cited by 89 publications

(49 citation statements)

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“…On the other hand, the intestinal mucosa in mice in the NK012 treatment group was almost the same as that in the saline treatment group (14). CPT-11, SN-38, and SN-38G are excreted into the bile and eventually reach the small intestinal lumen (23,24). SN-38G is deconjugated in the cecum and colon to regenerate SN-38 through bacterial β-glucuronidase (25).…”

Section: Discussionmentioning

confidence: 94%

Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors

Hamaguchi

Doi

Eguchi-Nakajima

et al. 2010

Clinical Cancer Research

134

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Purpose: We conducted a first-in-human phase I study to determine the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38-incorporating micellar nanoparticle.Experimental Design: Patients with solid tumors refractory to standard therapy, or for which no standard therapy is available, were enrolled. NK012 was administered as a 30-minute infusion every 3 weeks. The starting dose was 2 mg/m 2 as SN-38 equivalent, and an accelerated titration schedule was used. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematologic toxicity, especially diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m 2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approximately 140 and 210 hours, respectively. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 months, respectively.Conclusions: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing. Clin Cancer Res; 16(20); 5058-66. ©2010 AACR.Irinotecan hydrochloride (CPT-11) has proven to be active against colorectal, lung, and ovarian cancers (1-5). CPT-11 is a prodrug that is converted to a biologically active metabolite, 7-ethyl-10-hydroxy-CPT (SN-38), by carboxylesterase (CE) enzymes. SN-38 is an analogue of the plant alkaloid camptothecin, which targets DNA topoisomerase I. Compared with CPT-11, SN-38 exhibits up to 1,000-fold more potent cytotoxic activity against various cancer cells in vitro (6). Although CPT-11 is converted to SN-38 in the liver and tumor, the metabolic conversion rate is <10% of the original volume of 8). Moreover, the conversion of CPT-11 to SN-38 depends on the genetic interindividual variability of CE activity (9). Thus, more efficient use of SN-38 might be highly advantageous and quite attractive for cancer treatment.Drugs categorized under the drug delivery system (DDS) are made primarily by using nanotechnology (10). In the field of oncology, DDS drugs have been produced and evaluated in preclinical or clinical trials, with some already approved for clinical use (11,12). NK012 categorized in DDS is a micelle-forming macromolecular prodrug prepared by binding SN-38 to the polyglutamate of a block copolymer via an ester bond (Fig. 1). The amphiphilic block copolymers consist of polyethylene glycol and partially SN-38-bound polyglutamate. Polyethylene glycol is hydrophilic a...

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Section: Discussionmentioning

confidence: 94%

Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors

Hamaguchi

Doi

Eguchi-Nakajima

et al. 2010

Clinical Cancer Research

134

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“…32). CPT-11, SN-38, and SN-38-Glu are excreted into the bile and then reach the small intestinal lumen (32,33). SN-38-Glu is Fig.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of NK012 Combined with Cisplatin against Small Cell Lung Cancer and Intestinal Mucosal Changes in Tumor-Bearing Mouse after Treatment

Nagano

Yasunaga²,

Goto

et al. 2009

Clinical Cancer Research

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Purpose: To investigate the advantages of treatment with the SN-38^incorporating polymeric micelles NK012 over CPT-11 in combination with cisplatin [cis-dichlorodiammineplatinum (II) (CDDP)] in mice bearing a small cell lung cancer xenograft in terms of antitumor activity and toxicity, particularly intestinal toxicity. Experimental Design: Cytotoxic effects were evaluated in human small cell lung cancer cell lines [H69, H82, and vascular endothelial growth factor (VEGF)^secreting cells (SBC-3/VEGF and its mock transfectant SBC-3/Neo)]. In vivo antitumor effects were evaluated in SBC-3/Neob earing and SBC-3/VEGF^bearing mice after NK012/CDDP or CPT-11/CDDP administration on days 0, 7, and 14. Drug distribution was analyzed by high-performance liquid chromatography or fluorescence microscopy, and the small intestine was pathologically examined. Results:The in vitro growth-inhibitory effects of NK012 were 198-to 532-fold more potent than those of CPT-11. A significant difference in the relative tumor volume on day 30 was found between NK012/CDDP and CPT-11/CDDP treatments (P = 0.0058). Inflammatory changes in the small intestinal mucosa were rare in all NK012-treated mice but were commonly observed in CPT-11^treated mice. Moreover, a large amount of CPT-11was excreted into the feces and high CPT-11concentration was detected in the small intestinal epithelium. On the other hand, a small amount of NK012 was found in the feces and NK012 was weakly and uniformly distributed in the mucosal interstitium. Conclusions: NK012/CDDP combination may be a promising candidate regimen against lung cancer without severe diarrhea toxicity and therefore warrants further clinical evaluation.SN-38 or 7-ethyl-10-hydroxy-camptothecin is a biologically active metabolite of irinotecan hydrochloride (CPT-11) and is formed through CPT-11 conversion by carboxylesterases. SN-38 is active against various human cancers, such as colorectal, lung, and ovarian cancer (1 -4). Although SN-38 shows up to 1,000-fold more potent cytotoxic activity against various cancer cell lines than CPT-11 in vitro (5), it has been clinically unavailable because of its water-insoluble nature, and the conversion rate from CPT-11 to SN-38 is <10% of the original CPT-11 volume in the body (6, 7).The SN-38 -incorporating polymeric micelles NK012 seem to have the advantage of passive targeting of the drug delivery system. In this passive targeting of drug delivery system, the drug accumulates in tumor tissue by using the enhanced permeability and retention effect (8 -11). This enhanced permeability and retention effect is based on several pathologic mechanisms, which include hypervascularity, secretion of tumor vascular permeability factors stimulating extravasation of macromolecules including nanoparticles such as liposomes and micelles, and the absence of an effective lymphatic drainage of macromolecules accumulated in solid tumor tissue. Recent studies showed that NK012 has a significantly more potent antitumor activity than CPT-11 against small cell lung can...

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“…2). The liver compartment, as described in the Introduction, has UGT as a key enzyme 11,12) . In the intestinal compartment 15) , CPT-11, SN-38 and SN-38G are secreted into bile by hepatocytes with subsequent excretion into the intestine 16,17) .…”

Section: Discussionmentioning

confidence: 99%

“…CPT-11 is metabolized to an active form, 7-ethyl-10-hydroxycamptothecin (SN-38), by carboxyl esterase 10) , and SN-38 is deactivated to SN-38 glucuronide (SN38-Glu) by UDPglucuronosyltransferase (UGT) in the liver 11) . The UGT gene has a polymorphism of its gene, and gene analysis of UGT-1A1 can predict leucopenia 12) .…”

Section: Discussionmentioning

confidence: 99%

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Biweekly Administration of Irinotecan (Cpt-11) Plus Cisplatin With an Antidiarrheal Program of Intestinal Alkalization to Reduce Diarrhea in Cancer Patients

Kobayashi

Sakuyama

Koizumi

et al. 2012

Ann. Cancer Res. Therap.

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Identification of the metabolites of irinotecan, a new derivative of camptothecin, in rat bile and its biliary excretion

Cited by 89 publications

References 5 publications

Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors

Phase I Study of NK012, a Novel SN-38–Incorporating Micellar Nanoparticle, in Adult Patients with Solid Tumors

Antitumor Activity of NK012 Combined with Cisplatin against Small Cell Lung Cancer and Intestinal Mucosal Changes in Tumor-Bearing Mouse after Treatment

Biweekly Administration of Irinotecan (Cpt-11) Plus Cisplatin With an Antidiarrheal Program of Intestinal Alkalization to Reduce Diarrhea in Cancer Patients

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