title: Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.
abstract: The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.
authors: Bristol-Myers Squibb, F13-01, Princeton, NJ 08543, USA. zhang4422@gmail.com
authors: Donglu
authors: D
authors: Zhang
authors: Charles E
authors: CE
authors: Frost
authors: Kan
authors: K
authors: He
authors: A David
authors: AD
authors: Rodrigues
authors: Xiaoli
authors: X
authors: Wang
authors: Lifei
authors: L
authors: Wang
authors: Theunis C
authors: TC
authors: Goosen
authors: W Griffith
authors: WG
authors: Humphreys
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics; D000166:Acridines / Q000494:pharmacology; D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D002606:Charcoal / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055786:Gene Knockout Techniques; D007408:Intestinal Absorption / Q000187:drug effects* / Q000235:genetics; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014018:Tissue Distribution / Q000235:genetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D000166:Acridines; D000931:Antidotes; D005343:Fibrinolytic Agents; D049990:Membrane Transport Modulators; D011720:Pyrazoles; D011728:Pyridones; D044005:Tetrahydroisoquinolines; D002606:Charcoal; C522181:apixaban; C083501:Elacridar