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ANESTHETIC PHARMACOLOGY

The Role of Drug-Lipid Interactions on the Disposition of Liposome-Formulated Opioid Analgesics In Vitro and In Vivo

Claudette R. Bethune, PhD^*, Christopher M. Bernards, MD, Tot Bui-Nguyen, BS^*, Danny D. Shen, PhD^*, and Rodney J. Y. Ho, PhD^*

Departments of *Pharmaceutics and Anesthesiology, University of Washington, Seattle, Washington

Address correspondence and reprint requests to Rodney J. Y. Ho, PhD, Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA 98195-7610. Address e-mail to Rodneyho{at}u.washington.edu

Although liposome encapsulation prolongs the duration of action of epidurally administered drugs, little is known about how liposome encapsulation affects opioids differently, or about how lipid content of liposomes alters the bioavailability of epidurally-administered opioids. To address these issues, morphine, alfentanil, fentanyl, and sufentanil were loaded into D--dipalmitoyl phosphatidylcholine multilamellar liposomes, and incorporation efficiency and in vitro release rates were determined. We then determined epidural morphine and sufentanil liposomes, at two different lipid/opioid ratios, in vivo in a pig model in which epidural and intrathecal spaces were continuously sampled via microdialysis. Liposome encapsulation efficiency was significantly more for sufentanil (100%) than for the other opioids (25%–30%). The in vitro release rate was slowest for morphine, intermediate for fentanyl and alfentanil, and fastest for sufentanil. In vivo, morphine was released more slowly than sufentanil. It is most important to note that increasing the lipid content of morphine liposomes increased the proportion of drug reaching the intrathecal space. In contrast, increasing the lipid content of sufentanil liposomes did not alter intrathecal movement but did decrease movement into plasma. Therefore, increasing drug hydrophobicity and lipid content of the liposomes modulates drug distribution in vivo.

IMPLICATIONS: The degree of interaction between opioids and lipid bilayers in liposome-formulated opioids dictates the rates at which epidurally-administered drugs distribute into the intrathecal compartment and blood in potentiating analgesic effects.