Hepatobiliary Disposition of Atovaquone: A Case of Mechanistically Unusual Biliary Clearance.

Autor:	Patel M; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)., Johnson M; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)., Sychterz CJ; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)., Lewis GJ; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)., Watson C; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)., Ellens H; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)., Polli JW; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.)., Zamek-Gliszczynski MJ; Mechanistic Safety and Disposition (M.P., M.J., C.W., H.E., J.W.P., M.J.Z.-G.) and Bioanalysis, Immunogenicity, and Biomarkers (C.J.S.), GlaxoSmithKline, King of Prussia, Pennsylvania; and Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, United Kingdom (G.J.L.) maciej.x.zamek-gliszczynski@gsk.com.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2018 Jul; Vol. 366 (1), pp. 37-45. Date of Electronic Publication: 2018 Apr 13.
DOI:	10.1124/jpet.117.247254
Abstrakt:	Atovaquone, an antiprotozoal and antipneumocystic agent, is predominantly cleared by biliary excretion of unchanged parent drug. Atovaquone is ≥10,000-fold concentrated in human bile relative to unbound plasma. Even after correcting for apparent nonspecific binding and incomplete solubility in bile, atovaquone is still concentrated ≥100-fold in bile, consistent with active biliary excretion. Mechanisms of atovaquone hepatobiliary disposition were studied using a multiexperimental in vitro and in vivo approach. Atovaquone uptake was not elevated in HEK293 cells singly overexpressing OATP1B1, OATP1B3, OATP2B1, OCT1, NTCP, or OAT2. Hepatocyte uptake of atovaquone was not impaired by OATP and OCT inhibitor cocktail (rifamycin and imipramine). Atovaquone liver-to-blood ratio at distributional equilibrium was not reduced in Oatp1a/1b and Oct1/2 knockout mice. Atovaquone exhibited efflux ratios of approximately unity in P-gp and BCRP overexpressing MDCK cell monolayers and did not display enhanced uptake in MRP2 vesicles. Biliary and canalicular clearance were not decreased in P-gp, Bcrp, Mrp2, and Bsep knockout rats. In the present study, we rule out the involvement of major known basolateral uptake and bile canalicular efflux transporters in the hepatic uptake and biliary excretion of atovaquone. This is the first known example of a drug cleared by biliary excretion in humans, with extensive biliary concentration, which is not transported by the mechanisms investigated herein. (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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