03/30/2018 - Role of transporters in drug ADME

Role of efflux transporters in the absorption, distribution and elimination in rodents of a novel PDE4 inhibitor, CHF6001

Cenacchi V, Salvadori M, Riccardi B, Brogin G, Ghiglieri A, Messina M, Imre G, Puccini P.

Eur J Pharm Sci. 2018 Mar 30;115:100-108. doi: 10.1016/j.ejps.2017.12.030. Epub 2018 Jan 4.

PMID: 29307855


CHF6001 is a new and potent PDE4 inhibitor for the treatment of human lung diseases, designed for topical administration by inhalation. In preclinical assessment CHF6001 appeared safe and devoid of emetic effect, which is typical side effect of PDE4 inhibitors in humans. CHF6001 absorption, distribution and excretion were evaluated in rats by PO and IV administration of [14C]CHF6001; additionally the role of transporters was investigated by using transfected cells expressing either human transporters or MDR1 and BCRP KO mice. [14C]CHF6001 intravenously administered as bolus distributed in all the tissues (with very low levels in brain and fetus) and it was mainly eliminated in bile. Following oral administration [14C]CHF6001 about half of the dose was absorbed through the gut. In vitro, CHF6001 was a substrate of human membrane transporters MDR1 and BCRP. In wild and BCRP KO mice CHF6001 was not detectable in brain, whereas it was measurable in Mdr1a/b KO mice. Therefore, in animal species Mdr1a/b plays a significant role in CHF6001 disposition, limiting its distribution into brain and contributing to the safety profile observed in preclinical evaluation. This behavior was confirmed by the results of the first human studies, where CHF6001 was safe and with no emetic effect at all the evaluated doses.

Keywords: ADME; Membrane transporters; PDE4 inhibitors; Pharmacokinetics; Radiolabelled; Rodents.

Copyright © 2018 Elsevier B.V. All rights reserved.

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