Determination of camptothecin analogs in biological matrices by high-performance liquid chromatography

Several analogs of the topoisomerase I inhibitor camptothecin (CPT) have been introduced in clinical practice in the last decade. All CPT analogs are sensitive to a pH-dependent reversible conversion between a pharmacologically active lactone form and its inactive, lactone ring-opened, carboxylate form. The reversible conversion is also dependent on the, sometimes species-dependent, protein binding properties of the two forms, resulting in different lactone to carboxylate plasma ratios for the various analogs. Pharmacokinetic analysis of the CPT analogs is helpful in understanding the pharmacodynamic outcome of drug treatment, in clinical as well preclinical studies. Measurement of these analogs is habitually complicated by the chemical instability of the lactone moiety and necessitates a rapid centrifugation of the blood sample, preferably at the bedside of the patient, to collect the plasma supernatant. Since the lactone forms of these drugs are able to diffuse across cell membranes, including those of the red blood cells, rapid collection and processing is even necessary in the case where only the total concentrations of the CPT analogs are to be measured. Sample pretreatment procedures of the CPT analogs topotecan, irinotecan, 9-aminocamptothecin and lurtotecan are summarized and discussed in this review.