title: Atypical dose-route-dependent food effects of eplerenone in the dog: presence of food effects following intravenous dosing and lack of food effects of following oral dosing.
abstract: This study was conducted to investigate why a food effect was observed following an intravenous dose of eplerenone (EP) in the dog, but not following oral dosing. Three female dogs were implanted with a chronic portal vein access port and received radiolabeled EP doses orally (15 mg/kg in solution) and intravenously (7.5 mg/kg via cephalic and portal veins) under fasted and fed conditions. Mean AUC values for EP after infusion through the cephalic vein were 23.0 +/- 2.7 and 18.2 +/- 1.1 h.microg/mL under fasted and fed conditions, respectively. Corresponding values after infusion through the portal vein were 20.7 +/- 3.2 and 12.9 +/- 1.3 h.microg/mL, respectively. After oral administration, EP was absorbed 82.0 +/- 6.9 and 98.0 +/- 8.3% under fasted and fed conditions; corresponding mean AUC values were 32.0 +/- 2.0 and 30.8 +/- 3.6 h.microg/mL, respectively. The AUC value for SC-70303 acid (the open lactone form of EP) was lower under fed conditions after cephalic vein infusion, but was greater under fed conditions after portal vein infusion or oral solution administration. The hepatic first-pass effect of EP was 12.6 +/- 6.3% under fasted conditions and 27.1 +/- 6.0% under fed conditions. Pharmacokinetic analysis of EP concentrations after portal vein infusion and oral administration showed that under fed conditions the rate constants for bile excretion and for liver metabolism and urinary excretion were increased while the rate constant for elimination and/or metabolism in the gastrointestinal tract was reduced. In conclusion, the apparent lack of food effect after oral administration was observed because enhanced clearance was compensated by increased absorption.
authors.affiliation: Global Drug Metabolism, Pharmacia Corporation, 4901 Searle Parkway, Skokie, Illinois 60077, USA. chyung.s.cook@pharmacia.com
authors.forename: Chyung S
authors.initials: CS
authors.lastname: Cook
authors.forename: Liming
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004285:Dogs; D000077545:Eplerenone; D018565:Food-Drug Interactions / Q000502:physiology*; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism; D013058:Mass Spectrometry; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011169:Portal Vein; D013148:Spironolactone / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; C424563:SC70303; D013148:Spironolactone; D000077545:Eplerenone