Transporter-mediated Efflux Influences CNS Side Effects: ABCB1, from Antitarget to Target.

Laboratory for Chemometrics, Department of Chemistry, University of Perugia, Via Elce di Soto 10, 06100 Perugia, Italy.
Molecular informatics 01/2010; 29(1-2):16-26. DOI: 10.1002/minf.200900075
Source: PubMed


We examined the relationship between sedation and orthostatic hypotension, two central side effects and ABCB1 transporter-mediated efflux for a set of 64 launched drugs that are documented as histamine H1 receptor antagonists. This relationship was placed in the context of passive diffusion (estimated using LogP, the octanol/water partition coefficient), receptor affinity, and the adjusted therapeutic daily dose, in order to account for side effect variability. Within this set, CNS permeability was not dependent on passive diffusion, as no significant differences were found for LogP and its pH-corrected equivalent, LogD(74). Sedation and orthostatic hypotension can be explained within the framework of ABCB1-mediated efflux and adjusted dose, while target potency has less influence. ABCB1, an antitarget for anti-cancer agents, acts in fact as a drug target for non-sedating antihistamines. An empirical set of rules, based on the incidence of these two side-effects, target affinity and dose was used to predict efflux effects for a number of drugs. Among them, azelastine and mizolastine are predicted to be effluxed via ABCB1-mediated transport, whereas aripiprazole, clozapine, cyproheptadine, iloperidone, olanzapine, and ziprasidone are likely to be non-effluxed.

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Available from: Fabio Broccatelli, Jul 09, 2014
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    • "In the absence of an ideal in vitro model of the BBB, surrogate screening tools have become very popular in industry which allows addressing two of the most critical BBB features, the ability of a compound to permeate across a very tight monolayer of cells and the ability to be recognised by efflux pumps, for instance P-glycoprotein (P-gp). P-gp is very highly active at the BBB and efficiently functions to keep many drugs out of the brain (Löscher and Potschka 2005; Broccatelli et al. 2010). MDCK-MDR1 cells have become the most widely used in vitro model screen compounds for their (i) permeability, and (ii) susceptibility to efflux by P-gp. "
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    • "After some other hypotheses, affinity for P-glycoprotein-mediated drug efflux at the level of the BBB has been identified as main reason why 2 nd generation antihistamines show little CNS side effects (Chishty et al. 2001; Obradovic et al. 2007). While this protecting mechanism was discovered only later on in the case of the antihistamines, it is now becoming a rational element in optimising the separation between the peripheral and the central activity of compounds in drug discovery projects aiming at a very low/no central activity to avoid CNS side effects (Broccatelli et al. 2010; Cole et al. 2012). "
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    • "Another anti-target is the drug efflux pump, ATP-binding cassette, sub-family B (MDR/TAP) member 1, ABCB1 [Swiss-Prot P08183] ranked at 313. However, a recent analysis suggests that, while an anti-target for anticancer agents, it can also be classified as a drug target for non-sedating antihistamines [26]. "
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