Unmasking the Role of Uptake Transporters for Digoxin Uptake Across the Barriers of the Central Nervous System in Rat

Abstract

The role of uptake transporter (organic anion–transporting polypeptide [Oatp]) in the disposition of a P-glycoprotein (P-gp) substrate (digoxin) at the barriers of central nervous system, namely, the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), and brain-cerebrospinal fluid barrier (BCSFB), was studied using rat as a preclinical species. In vivo chemical inhibition of P-gp and Oatp was achieved using elacridar and rifampicin, respectively. Our findings show that (1) digoxin had a low brain-to-plasma concentration ratio (B/P) (0.07) in rat; (2) in the presence of elacridar, the B/P of digoxin increased by about 12-fold; (3) rifampicin administration alone did not change the digoxin B/P significantly when compared with digoxin B/P alone; (4) rifampicin administration along with elacridar resulted only in 6-fold increase in the B/P of digoxin; (5) similar fold changes and trends were seen with the spinal cord-to-plasma concentration ratio of digoxin, indicating the similarity between BBB and the BSCB; and (6) unlike BBB and BSCB, the presence of rifampicin further increased the cerebrospinal fluid-to-plasma concentration ratio (CSF/P) for digoxin, suggesting a differential orientation of the uptake transporters at the BCSFB (CSF to blood) compared with the BBB (blood to brain). The observations for digoxin uptake, at least at the BBB and the BSCB, advocate the importance of uptake transporters (Oatps). However, the activity of such uptake transporters became evident only after inhibition of the efflux transporter (P-gp).

Imaging techniques to study drug transporter function in vivo

“…To our knowledge, no attempts have so far been made to image OATP1A2 and OATP2B1 at the BBB, the latter being considered as target transporters for facilitating brain entry of therapeutic drugs (Stieger & Gao, 2015). A potential complication in the development of PET tracers for these uptake transporters may be the fact that known transporter substrates are also recognized by efflux transporters at the BBB, which may mask the effect of the uptake transporters (Taskar et al, 2017;Tournier et al, 2013).…”

“…Substrates of influx transporters may also undergo efflux transport at the same interface. In this situation, the overall net flux of the drug results from the competition between the influx and efflux component, which is difficult to predict in the real-life situation (Chapy et al, 2016;Taskar et al, 2017).…”

Determinants of drug entry into the developing brain

“…The present paper describes experiments using three index drugs that are given to pregnant women and/or neonates (paracetamol, digoxin and cimetidine). Two of the drugs selected (digoxin and cimetidine) are used for their peripheral therapeutic effects (cardiovascular and alimentary systems respectively) but there is some evidence that they do enter the brain to a limited extent in adult animals (digoxin: Liu et al ., 2014; Mayer et al ., 1997; Taskar et al ., 2017 and cimetidine: Kodaira et al ., 2011). There are a few reports of entry of digoxin and cimetidine into the brains in fetal rodents (see Discussion).…”

Cardiac glycoside-mediated turnover of Na, K-ATPases as a rational approach to reducing cell surface levels of the cellular prion protein

“…Because neither ouabain nor digoxin are suitable for brain applications due to their relative low membrane permeability [44] and active extrusion from the brain by P-glycoproteins [45][46][47], we next explored alternative CGs known to have higher blood brain barrier (BBB) penetrance. Amongst several CGs we considered was oleandrin, a compound that can be extracted from the ornamental plant Nerium oleander.…”