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

Overview

Journal Mol Inform

Specialties Biochemistry
Biology
Chemistry
Molecular Biology

Date 2012 Feb 21

PMID 22347894

Citations 15

Authors

Fabio Broccatelli

Emanuele Carosati

Gabriele Cruciani

Tudor I Oprea

Affiliations

Soon will be listed here.

Abstract

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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References

Hindmarch I, Shamsi Z . Antihistamines: models to assess sedative properties, assessment of sedation, safety and other side-effects. Clin Exp Allergy. 1999; 29 Suppl 3:133-42. DOI: 10.1046/j.1365-2222.1999.0290s3133.x. View

. Discussion: mechanisms of antihistamines . Clin Exp Allergy. 1999; 29 Suppl 3:37-8. View

Polli J, Wring S, Humphreys J, Huang L, Morgan J, Webster L . Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001; 299(2):620-8. View

Chishty M, Reichel A, Siva J, Abbott N, Begley D . Affinity for the P-glycoprotein efflux pump at the blood-brain barrier may explain the lack of CNS side-effects of modern antihistamines. J Drug Target. 2001; 9(3):223-8. DOI: 10.3109/10611860108997930. View

Yamashita M, Fukui H, Sugama K, Horio Y, Ito S, Mizuguchi H . Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc Natl Acad Sci U S A. 1991; 88(24):11515-9. PMC: 53166. DOI: 10.1073/pnas.88.24.11515. View

Summerfield S, Stevens A, Cutler L, del Carmen Osuna M, Hammond B, Tang S . Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, P-glycoprotein efflux, and free fractions in blood and brain. J Pharmacol Exp Ther. 2005; 316(3):1282-90. DOI: 10.1124/jpet.105.092916. View

Wada M . Single nucleotide polymorphisms in ABCC2 and ABCB1 genes and their clinical impact in physiology and drug response. Cancer Lett. 2005; 234(1):40-50. DOI: 10.1016/j.canlet.2005.06.050. View

Dewan M, Koss M . The clinical impact of reported variance in potency of antipsychotic agents. Acta Psychiatr Scand. 1995; 91(4):229-32. DOI: 10.1111/j.1600-0447.1995.tb09773.x. View

Chen C, Hanson E, Watson J, Lee J . P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists. Drug Metab Dispos. 2003; 31(3):312-8. DOI: 10.1124/dmd.31.3.312. View

10.

Yanai K, Okamura N, Tagawa M, Itoh M, Watanabe T . New findings in pharmacological effects induced by antihistamines: from PET studies to knock-out mice. Clin Exp Allergy. 1999; 29 Suppl 3:29-36; discussion 37-8. View

11.

Leonard G, Fojo T, Bates S . The role of ABC transporters in clinical practice. Oncologist. 2003; 8(5):411-24. DOI: 10.1634/theoncologist.8-5-411. View

12.

Schinkel A, Jonker J . Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev. 2003; 55(1):3-29. DOI: 10.1016/s0169-409x(02)00169-2. View

13.

Tatsumi M, Groshan K, Blakely R, Richelson E . Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1998; 340(2-3):249-58. DOI: 10.1016/s0014-2999(97)01393-9. View

14.

Quach T, Duchemin A, Rose C, Schwartz J . In vivo occupation of cerebral histamine H1-receptors evaluated with 3H-mepyramine may predict sedative properties of psychotropic drugs. Eur J Pharmacol. 1979; 60(4):391-2. DOI: 10.1016/0014-2999(79)90250-4. View

15.

Austin C, Brady L, Insel T, Collins F . NIH Molecular Libraries Initiative. Science. 2004; 306(5699):1138-9. DOI: 10.1126/science.1105511. View

16.

Leurs R, Church M, Taglialatela M . H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy. 2002; 32(4):489-98. DOI: 10.1046/j.0954-7894.2002.01314.x. View

17.

Chen C, Chin J, Ueda K, Clark D, Pastan I, Gottesman M . Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986; 47(3):381-9. DOI: 10.1016/0092-8674(86)90595-7. View

18.

HANSCH C, Bjorkroth J, Leo A . Hydrophobicity and central nervous system agents: on the principle of minimal hydrophobicity in drug design. J Pharm Sci. 1987; 76(9):663-87. DOI: 10.1002/jps.2600760902. View

19.

Brosen K, Klysner R, Gram L, Otton S, Bech P, Bertilsson L . Steady-state concentrations of imipramine and its metabolites in relation to the sparteine/debrisoquine polymorphism. Eur J Clin Pharmacol. 1986; 30(6):679-84. DOI: 10.1007/BF00608215. View

20.

Olsson T, Oprea T . Cheminformatics: a tool for decision-makers in drug discovery. Curr Opin Drug Discov Devel. 2001; 4(3):308-13. View