RT Journal Article
SR Electronic
T1 Hepatobiliary disposition of atovaquone: A case of mechanistically unusual biliary clearance
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.247254
DO 10.1124/jpet.117.247254
A1 Mitesh Patel
A1 Marta Johnson
A1 Caroline J. Sychterz
A1 Gareth J Lewis
A1 Cory Watson
A1 Harma Ellens
A1 Joseph W. Polli
A1 Maciej J. Zamek-Gliszczynski
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/04/13/jpet.117.247254.abstract
AB Atovaquone, an anti-protozoal and anti-pneumocystic 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 non-specific 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 multi-experimental 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.