Interactions of chlorpromazine and imipramine with artificial membranes investigated by equilibrium dialysis, dual-wavelength photometry, and fluorimetry

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT3Receptors in Raft-Like Domains

“…Only clozapine has been shown to accumulate in the "very low-density lipoprotein" fraction of plasma samples with highly elevated lipoprotein levels, but no such accumulation occurred in standard plasma (Procyshyn et al, 2001). Generally, basic lipophilic compound such as antidepressants, e.g., fluoxetine and imipramine, may bind nonspecifically to membrane phospholipids (Bickel and Steele, 1974;Di Francesco and Bickel, 1977;Romer and Bickel, 1979). Thus, an accumulation of such drugs in phospholipid-rich membrane microdomains such as lipid rafts is highly probable.…”

Commentary: Nonspecific Protein Binding versus Membrane Partitioning: It Is Not Just Semantics

“…Nonspecific binding to proteins or apparatus can be erratic (Minder et al, 1970;Palmgrén et al, 2006), whereas partitioning into membranes is governed by physicochemical interactions (Francesco and Bickel, 1977;Römer and Bickel, 1979;Austin et al, 2002;Hallifax and Houston, 2006;Abraham and Austin, 2012). In fact, partitioning into membranes is an integral part of membrane permeability.…”

“…Evidence suggests that, by far, the most common cause of drug sequestration is partitioning into phospholipid membranes. Early work by Bickel showed that basic lipophilic drugs such as imipramine, chlorpromazine, and other drugs predominantly sequester into phospholipid membranes, specifically via hydrophobic interactions with membrane lipids such as phosphatidylcholine (Bickel and Steele, 1974;Francesco and Bickel, 1977;Römer and Bickel, 1979). Margolis and Obach (2003) compared binding of a number of drugs to microsomes and phospholipid vesicles and determined that sequestration was associated with the phospholipid component.…”

Ion-Trapping, Microsomal Binding, and Unbound Drug Distribution in the Hepatic Retention of Basic Drugs

“…The main mechanisms of such a distribution pattern are nonspecific binding to membrane phospholipids (Bickel and Steele, 1974;Francesco and Bickel, 1977;Romer and Bickel, 1979), binding to microsomal protein (Hung et al, 2002), and the sequestration of the compounds into acidic vesicular compartments such as lysosomes or mitochondria (Daniel et al, 1995). A potential consequence of an apparent irreversible sequestration of basic drugs into acidic vesicles is a potentially reduced drug bioavailability (de Duve et al, 1974;Ohkuma and Poole, 1978) or drug interactions (Daniel and Wojcikowski, 1999b;Nebbia et al, 1999).…”