Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET

Abstract

The radiotracer [ 11 C]N-desmethyl-loperamide (dLop) images the in vivo function of P-glycoprotein (P-gp), a transporter that blocks the entry of drugs that are substrates into brain. When P-gp is inhibited, [ C]dLop uptake before and after tariquidar preadministration in lysosome-rich organs of P-gp KO mice and humans. After tariquidar pretreatment in both species, radioactivity uptake in these organs decreased by 35% to 40%. Our results indicate that dLop is trapped in lysosomes and that tariquidar competes with dLop for lysosomal accumulation in vitro and in vivo. Although tariquidar and dLop compete for lysosomal trapping in the periphery, such competition does not occur in brain because tariquidar has negligible entry into brain. In summary, tariquidar and [ 11 C]dLop can be used in combination to selectively measure the function of P-gp at the blood-brain barrier.ATP-binding cassette | efflux

Lysosomal Sequestration (Trapping) of Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells)

“…There are limited examples in the literature of similar findings, such as the inhibition (40-70%) of the in vitro partitioning of imipramine by other lipophilic amines in isolated rat hepatocytes (Hallifax and Houston, 2006;Hallifax and Houston, 2007) and ion-trapping in lysosomes accounting for approximately 50% of propranolol hepatic sequestration during in situ perfusions of isolated rat livers (Siebert et al, 2004), consistent with data in this study (;50% propranolol partitioning). More recently, the P-glycoprotein inhibitor tariquidar has been shown to significantly decrease the in vitro and in vivo accumulation of the positron emission tomography imaging agent [ 11 C]-N-desmethyl-loperamide in lysosome-rich tissues through competition for lysosomal trapping (Kannan et al, 2011). However, the clinical significance of lysosomal trapping-based DDIs is not well understood and requires further study.…”

Whole-Body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans

“…Consistent with previous studies, the lowest distribution of radioactivity was to the brain, as can be explained by ABCB1-and ABCG2-mediated efflux transport at the BBB (6,7). The time-activity curves for 11 C-elacridar and 11 C-tariquidar in all studied organs except spleen were characterized by a slow washout, which may be due to intracellular acidic trapping of the weak bases elacridar and tariquidar in lysosomes (16).…”

Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution

“…b Student's t test: Significantly different compared with the group that received only one P-gp modulator, whether elacridar at 1.0 mg/kg or tariquidar at 1.0 mg/kg. Nevertheless, when the two compounds are coadministered, elacridar may reduce or delay the active transport of tariquidar by both proteins (Kannan et al, 2011), thus significantly increasing the K p of tariquidar. An important issue to consider when comparing the distribution of low doses of P-gp modulators in the brain is the species differences in P-gp transport activity, which appear to be substrate-dependent (Lin and Yamazaki, 2003).…”