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

¹ Oncopharmacology Department, Pharmacy Service, and
² Department of Medicine, Val d’Aurelle Anticancer Centre, Parc Euromédecine, 34298 Montpellier, Cedex 5 France.

³ Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, 15 Avenue Ch. Flahault, University Montpellier I, 34093 Montpellier Cedex 5, France.

^aAddress correspondence to this author at: Laboratoire de Pharmacocinétique Clinique, Faculté de Pharmacie, BP 14491, 34093 Montpellier Cedex 5, France. Fax 33-4-6754-8075; e-mail Fbressolle{at}aol.com.

Background: We developed gradient HPLC methods for quantification of the antimitotic drug irinotecan (CPT-11) and its four metabolites, SN-38, SN-38 G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4amino-1-piperidino]-carbonyloxycamptothecin (NPC), as the sum of the lactone and carboxylate forms, in human plasma and saliva. Camptothecin was used as internal standard.

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 µg/L. For the five analytes, limits of quantification were 0.5 µg/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%.

Conclusion: The developed assay can be used to determine pharmacokinetic parameters for CPT-11, SN-38, SN-38 G, APC, and NPC in plasma and saliva from patients with metastatic colorectal cancer.

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