High-performance liquid chromatographic determination of irinotecan (CPT-11) and its active metabolite (SN-38) in human plasma

Sumiyoshi, Hiromichi; Fujiwara, Yasuhiro; Ohune, Terumasa; Yamaoka, Naoki; Tamura, Keiko; Yamakido, Michio

doi:10.1016/0378-4347(95)00130-1

Cited by 49 publications

(18 citation statements)

References 10 publications

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“…Each blood sample was centrifuged immediately and the plasma was stored at -20°C until analysis. CPT-l 1 and SN-38, an active metabolite of CPT-I 1, were assayed by high-performance liquid chromatography (HPLC) with fluorescent detection, using a procedure that allowed the simultaneous determination of both compounds (Sumiyoshi et al, 1995). The detection limits for CPIT-11 and SN-38 were 50 and 1 ng ml' respectively.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer

Ando¹,

Eguchi²,

Shinkai³

et al. 1997

Br J Cancer

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Summary We conducted a phase I study of irinotecan (CPT-11) and etoposide (VP-16) given sequentially to untreated patients with metastatic non-small-cell lung cancer. Arm A: CPT-11 was given over 90 min on days 1-3 and VP-16 was given over 60 min on days 4-6. Arm B: VP-16 was given on days 1-3 and CPT-11 on days 4-6. G-CSF was given to all patients daily on days 7-17. Twenty-seven patients were entered randomly at the two arms. The major dose-limiting toxicities in arms A and B were granulocytopenia and diarrhoea. Transient elevations of transaminases and bilirubin were observed in both arms. The degree of the toxicities did not differ between the two arms. The maximum tolerated doses (MTDs) were 60 mg m-2 CPT-11 and 60 mg m-2 VP-16 in both arms. Of the 13 patients who received more than two cycles, two out of five achieved partial response (PR) at the first level of arm A and one out of four achieved PR at the second level of arm B. We conclude that these schedules of sequential CPT-11 and VP-16 administration were inappropriate because of severe toxicities.Keywords: irinotecan; Topo I and 11 inhibitors; sequential administration Topoisomerase (Topo) inhibitors have played an important role in cancer chemotherapies (Pommier, 1993).hIinotecan (CPT-1) is a new camptothecin derivative, which has shown anti-tumour activity against several malignancies in clinical trials (Fukuoka et al, 1992;Shimada et al, 1993).Some investigators have reported that simultaneous exposure to Topo I and II inhibitors results in a synergistic effect in vivo (Kano et al, 1992). However, antagonistic effects of simultaneous exposure to Topo I and II inhibitors have been reported by other investigators (Kaufmann, 1991). The sequential administration of camptothecin and etoposide (VP-16) separated by 6-8 h has been reported to show an additive effect in vitro (Bertrand et al, 1991). In some human tumour xenografts, the cytotoxicity of doxorubucin is enhanced when it is sequentially administered 24 h after CPT-l 1 treatment, and tumour cells treated with CPT-11 show an increase in Topo-II mRNA expression after 24 and 48 h (Kim et al, 1992). These results suggest that sequential administration of Topo I and II inhibitors may enhance their anti-tumour effects.We previously conducted a phase I trial of daily simultaneous administration of CPT-l 1 and VP-16, for 3 consecutive days, for patients with refractory solid tumours (Karato et al, 1993). Granulocytopenia was so severe that this regimen required supportive therapy with granulocyte colony-stimulating factor (G-CSF). The major dose-limiting toxicities (DLT) were diarrhoea and weight loss. The recommended dose of CPT-lIIVP-16 for this regimen with G-CSF support is 60/60 mg m-2 on days 1-3 every Correspondence to: Kenji Eguchi 3 or 4 weeks. A phase II trial of this regimen for metastatic nonsmall-cell lung cancer (NSCLC) without previous chemotherapy has been conducted: 13 out of 55 patients (23.6%) showed a partial response (Goto et al, 1995).To improve the therapeutic effect, we conducted ...

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Section: Pharmacokineticsmentioning

confidence: 99%

Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer

Ando¹,

Eguchi²,

Shinkai³

et al. 1997

Br J Cancer

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“…These methods involve the simultaneous quantification of the lactone and carboxylate forms (27,29,32,37 ) or quantification of the total forms, i.e., lactone plus carboxylate (26,28,30,31,(33)(34)(35)(36). In most of these methods, both CPT-11 and SN-38 were quantified and the related compound camptothecin was used as the internal standard.…”

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confidence: 99%

Sensitive HPLC-Fluorescence Method for Irinotecan and Four Major Metabolites in Human Plasma and Saliva: Application to Pharmacokinetic Studies

Poujol¹,

Pinguet²,

Malosse³

et al. 2003

Clinical Chemistry

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Methods:The sample pretreatment involved protein precipitation with methanol-acetonitrile (50:50 by volume) followed by acidification with hydrochloric acid to convert the lactone ring-opened form into its lactone form, quantitatively. HPLC separation was performed on a Xterra RP18 column. The excitation wavelength was 370 nm, and the emission wavelength was set at 470 nm for the first 24 min and then at 534 nm for the next 4 min. The stabilities of irinotecan and its four metabolites in plasma, saliva, and acidic extracts were also investigated under various conditions. Results: Assays were linear in the tested range of 0.5-1000 g/L. For the five analytes, limits of quantification were 0.5 g/L in both matrices. The interassay imprecision (as relative standard deviation) was 3.2-14% in plasma and 2.6 -5.6% in saliva. Assay recoveries ranged from 92.8% to 111.2% for plasma and 100.1% to 104.1% for saliva. Mean extraction recovery from plasma or saliva was 90%.

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“…Irinotecan and its major metabolite SN38 were measured by HPLC using previously described methods. 20,21 A limited sampling strategy was applied for the prediction of the total AUC for both irinotecan and SN38. 22 …”

Section: Irinotecan Pharmacokineticsmentioning

confidence: 99%

Phase 2 study of gemcitabine and irinotecan in metastatic breast cancer with correlatives to determine topoisomerase I localization as a predictor of response

Moulder

Valkov

Neuger

et al. 2008

Cancer

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BACKGROUND.Gemcitabine incorporation into DNA enhances cleavage complexes in vitro when combined with topoisomerase I inhibitors and demonstrates synergy in cancer cells when given with irinotecan. Topoisomerase I inhibitors require that topoisomerase I interacts with DNA to exert activity.METHODS.Patients who had received previous anthracycline therapy or were not candidates for anthracycline therapy received gemcitabine at a dose of 1000 mg/m2 intravenously over 30 minutes followed by irinotecan at a dose of 100 mg/m2 over 90 minutes on Days 1 and 8 of a 21‐day cycle. The primary endpoint was improvement in response from that historically observed with gemcitabine (from 25% to 45%) as measured by Response Evaluation Criteria in Solid Tumors. Correlative studies included characterization of cellular levels and nuclear distribution of topoisomerase I and pharmacokinetic analysis of gemcitabine and irinotecan.RESULTS.Forty‐nine patients were assessed for response. The response rate was approximately 25% (all partial responses [PRs], 12 patients; 95% confidence interval [95% CI], 13‐39). Six patients had stable disease (SD) for ≥6 months for a clinical benefit rate (PR + SD) of 39%. The median time to disease progression was 3.7 months (95% CI, 2.5 months‐4.6 months), and median survival was 11.6 months (95% CI, 8.9 months‐15 months). Toxicities included neutropenia, nausea, and vomiting. Seven of 9 tissue biopsies were assessable for topoisomerase I. Tumors with the 2 lowest nuclear to cytoplasmic ratios demonstrated no response to irinotecan.CONCLUSIONS.Gemcitabine and irinotecan are active in metastatic breast cancer, but response did not meet predetermined response parameters, and the null hypothesis was accepted. Topoisomerase I localization can be measured in metastatic breast cancer. Further validation is needed to determine whether this assay can predict response. Cancer 2008. © 2008 American Cancer Society.

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High-performance liquid chromatographic determination of irinotecan (CPT-11) and its active metabolite (SN-38) in human plasma

Cited by 49 publications

References 10 publications

Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer

Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer

Sensitive HPLC-Fluorescence Method for Irinotecan and Four Major Metabolites in Human Plasma and Saliva: Application to Pharmacokinetic Studies

Phase 2 study of gemcitabine and irinotecan in metastatic breast cancer with correlatives to determine topoisomerase I localization as a predictor of response

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