Determination of Free and Liposome-Associated Doxorubicin and Vincristine Levels in Plasma under Equilibrium Conditions Employing Ultrafiltration Techniques

✍ Scribed by Lawrence D. Mayer; Ginette St.-Onge

• Book ID: 102560051
• Publisher: Elsevier Science
• Year: 1995
• Tongue: English
• Weight: 117 KB
• Volume: 232
• Category: Article
• ISSN: 0003-2697
• DOI: 10.1006/abio.1995.0001

✦ Synopsis

tion procedure is rapid, versatile, and can be used for a wide range of drug and liposome concentra-A thorough understanding of the pharmacodynamic relationships associated with toxicity and ef-tions and free drug/liposomal drug ratios. ᭧ 1995 Aca- demic Press, Inc. ficacy behavior of liposome-encapsulated anticancer agents such as doxorubicin and vincristine will rely on the ability to accurately separate and quantify the free and liposome-associated drug fractions in Numerous studies by various laboratories have docuplasma after administration. We have investigated mented the therapeutic benefits of encapsulating antithe use of ultrafiltration as a method of isolating free cancer drugs such as doxorubicin and vincristine in doxorubicin and vincristine from liposomal drug unliposomes using preclinical models (1-4). These reports der equilibrium conditions and compared it to prehave revealed a consistent ability of appropriately deviously developed nonequilibrium procedures based signed liposomes to reduce the toxicity of the encapsuon solid-phase extraction. Adsorption of drugs dislated agents to healthy tissue while maintaining or solved in saline to the ultrafiltration devices resulted in concentration-dependent ultrafiltrate drug recov-increasing their antitumor potency. The ability of lipoeries ranging from 41 to 96%. However, concentra-somes to buffer the toxicity of doxorubicin and vincristion-independent quantitative recovery of vincristine appears related to the fact that liposomes do not tine in saline solutions could be obtained by accumulate in many of the target organs associated passivating the ultrafiltration devices with PEGwith toxic side effects and thereby minimize exposure 8000 and device drug adsorption was ameliorated for of these tissues to free drug (5-7). In contrast, the both agents by plasma. The ultrafiltration method antitumor activity of liposomal anticancer drug formuprovided a more reliable separation of free and prolations correlates with delivery of encapsulated cytotein-bound drug, whereas solid-phase extraction toxic agents by the lipid carriers directly to tumors yielded artificially high free drug concentrations where the vasculature permeability to small (100 nm) due to process-induced protein-bound drug complex liposomes is increased relative to nonmalignant tissue dissocation. Also, coelution of liposomes with the (8)(9)(10)(11). More recent reports on clinical trials with lipofree drug fraction using solid-phase extraction was somal formulations of doxorubicin and daunorubicin 64-to 418-fold higher than observed with ultrafiltrahave provided encouraging indications that the imtion. Taken together, these properties indicated a proved therapeutic index of liposome-encapsulated ansignificantly increased degree of accuracy in meaticancer drugs observed in preclinical studies will be suring the amount of free doxorubicin and vincristranslated into meaningful improvements in the treattine in samples containing liposomal formulations ment of clinical malignancies (12,13). employing ultrafiltration compared to solid-phase Although such phenomenological comparisons have extraction. The importance of this improvement was demonstrated significant reduction in toxicity and imhighlighted by observations that determinations of provement of efficacy profiles of liposome-encapsulated free drug concentrations in the plasma of mice inanticancer drugs compared to their free drug counterjected with liposomal doxorubicin and vincristine parts, a clear understanding of the pharmacodynamic were 3-to 12-fold higher using solid-phase extraction compared to ultrafiltration. Finally, the ultrafiltra-relationships underlying these effects has been lacking. 149