Understanding Pharmacokinetic Disconnect in Preclinical Species for 4-Aminoquinolines: Consequences of Low Permeability and High P-glycoprotein Efflux Ratio on Rat and Dog Oral Pharmacokinetics.

Autor:	Mahajan MK; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA. Electronic address: mukesh.k.mahajan@gsk.com., Rivera EJ; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Sun HH; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Nagilla R; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., DeMartino MP; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Haile PA; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Casillas LN; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Marquis RW; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Votta BJ; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Bertin J; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA., Reilly MA; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2020 Oct; Vol. 109 (10), pp. 3160-3171. Date of Electronic Publication: 2020 Jun 18.
DOI:	10.1016/j.xphs.2020.06.013
Abstrakt:	Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies. Structurally similar analogues incorporating polarity at C-7 position of 4-aminoquinoline resulted in identification of GSKC - GSKF. Interestingly, following oral administration to rat at similar low dose, GSKC - GSKF demonstrated significantly low systemic drug exposure compared to GSKA and GSKB (3-17-fold difference). However, in dog, dose normalized oral systemic exposure for GSKC - GSKF was comparable to GSKA and GSKB (within 2-fold). A series of studies were conducted to understand the disconnect which highlighted that an intrinsic reduction in permeability and high P-glycoprotein (P-gp) efflux ratio for C-7 substituted analogues were driving pharmacokinetic disconnect between rat and dog. Oral absorption was minimally impacted in dog by P-gp mediated efflux compared to rat because the leakier gastrointestinal tract in dog likely overcomes this effect. (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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