Interactions of cationic drugs and cardiac glycosides at the hepatic uptake level: studies in the rat in vivo, isolated perfused rat liver, isolated rat hepatocytes and oocytes expressing oatp2.
This paper deals with a crucial mechanism for interaction of basic drugs and cardiac glycosides at the hepatic uptake level. Available literature data is provided and new material is presented to picture the differential transport inhibition of bulky (type2) cationic drugs by a number of cardiac glycosides in rat liver. It is shown that the so called organic anion transporting peptide 2 (oatp2) is the likely interaction site: differential inhibition patterns as observed in oocytes expressing oatp2, could be clearly identified also in isolated rat hepatocytes, isolated perfused rat liver and the rat in vivo. The anticipation of transport interactions at the hepatic clearance level should be based on data on the relative affinities of interacting substrates for the transport systems involved along with knowledge on the pharmacokinetics of these agents as well as the chosen dose regimen in the studied species. This review highlights the importance of multispecific tranporter systems such as OATP, accommodating a broad spectrum of organic compounds of various charge, implying potential transport interactions that can affect body distribution and organ clearance.
Meijer
Dirk K F
DK
Department of Pharmacokinetics and Drug Delivery, Groningen University Institute of Drug Exploration, The Netherlands. D.K.F.Meijer@farm.rug.nl
van Monffoort
Jessica E
JE
D000818:Animals; D001646:Bile / Q000378:metabolism; D002301:Cardiac Glycosides / Q000378:metabolism* / Q000494:pharmacology*; D002412:Cations; D004074:Digitoxin / Q000494:pharmacology; D004347:Drug Interactions; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013328:Strophanthins / Q000494:pharmacology; D014403:Tubocurarine / Q000378:metabolism; D014982:Xenopus laevis
D002301:Cardiac Glycosides; D002412:Cations; D027381:Liver-Specific Organic Anion Transporter 1; D013328:Strophanthins; D010042:Ouabain; C008240:K-strophanthoside; D004074:Digitoxin; D000254:Sodium-Potassium-Exchanging ATPase; D014403:Tubocurarine