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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    • "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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    • "Polypharmacology is not always beneficial, as it often causes side effects: Cisapride, which acts as a serotonergic 5-HT4 receptor agonist, as well as astemizole, which blocks histamine H1 receptors (H1Rs), have both been withdrawn from all markets due to the risk of fatal cardiac arrhythmia associated with their blockade of the hERG potassium ion channel, an unanticipated and undesirable ‘anti-target’ associated to QT prolongation and ‘torsades de pointes’ (5). However, ‘target’ and ‘anti-targets’ are dynamic attributes, as exemplified by the case of H1R antagonists and their (in)ability to achieve clinically significant levels in the brain, influenced by the ATP-binding cassette transporter ABCB1 (also known as P-glycoprotein), which effluxes some of these drugs from the brain (6). Acquiring knowledge of the complete pharmacology profile has inspired new strategies to predict and to characterize drug-target associations in order to improve the success rates of current drug discovery paradigms, i.e. increase the efficacy and reduce toxicity and adverse effects (2). "
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