Pharmacokinetic analysis of ramatroban using a recirculatory model with enterohepatic circulation by measuring portal and systemic blood concentration difference in Sprague-Dawley and Eisai hyperbilirubinemic rats.
OBJECTIVE
The aim of this study was to characterize the in vivo pharmacokinetics with the enterohepatic circulation (EHC) and identify the role of multidrug resistance-associated protein 2 (MRP2/Mrp2) in biliary excretion and absorption of ramatroban, a thromboxane A2 antagonist using a recirculatory model.


METHODS
Ramatroban was intravenously or orally administered to Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic rats (EHBR). Portal and systemic blood and bile samples were collected, and the drug concentrations were analyzed by high-performance liquid chromatography (HPLC) to estimate various global and local moments.


RESULTS
The bioavailability (BA) of ramatroban was estimated at 21.0% in SDR and 61.9% in EHBR. The local absorption ratio for the dosage after oral administration (Fa(dosage)) and the single-pass local absorption ratio for EHC (Fa') in the rats were similar and nearly 100%. The hepatic recovery ratio (Fh) and the single-pass biliary excretion ratio through the liver for the sum of ramatroban and its glucuronides (Fb) in EHBR were 61.4% and 8.88%, respectively, which differed considerably from those in SDR (15.0% and 22.4%). The difference in hepatic elimination between these strains would be caused, at least in part, by the reduced biliary excretion in EHBR, although the biliary excretion was not completely impaired.


CONCLUSIONS
Ramatroban may be excreted by multiple transport systems, followed by efficient enterohepatic reabsorption in both strains. The results suggest that ramatroban may not be susceptible to drug-drug interaction involving MRP2/Mrp2 in biliary excretion and absorption.
Moriwaki
Toshiya
T
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
Yasui
Hiroyuki
H
Yamamoto
Akira
A
D000284:Administration, Oral; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism*; D001646:Bile / Q000737:chemistry; D002227:Carbazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004764:Enterohepatic Circulation / Q000187:drug effects* / Q000502:physiology*; D020719:Glucuronides / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007275:Injections, Intravenous; D026901:Membrane Transport Proteins / Q000097:blood / Q000737:chemistry; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000097:blood / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology
D002227:Carbazoles; D020719:Glucuronides; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; D013928:Thromboxane A2; C063119:ramatroban