Application of a Modified In Situ Perfusion Model to Quantify Intestinal Drug Excretion and Transporter-Mediated...

Intestinal excretion (IE), one of the under-investigated mechanisms of drug elimination, has been identified as the loci of drug-drug interactions (DDIs) within the intestinal tract. Here, we employed a modified rat in situ intestinal perfusion model to examine of the drug clearance of apixaban, talinolol, and irinotecan in the short time drug recovery study. The influence of specific efflux transporter inhibitors, including P-glycoprotein (P-gp) inhibitor elacridar, multidrug resistance-associated protein 2 (Mrp2) inhibitor MK571, and breast cancer resistance protein (Bcrp) inhibitor KO143, on IE, systemic exposure and metabolite ratio were accessed using a 2.5-h constant-rate intravenous infusion. IE plays a major role in the elimination of apixaban (36 ± 14% of the total amount eliminated estimated using the sum of biliary, renal, and intestinal excretion), but only a minor role in the excretion of talinolol (11 ± 3.9%) and irinotecan (22 ± 3.1%). Efflux transporter inhibitors of P-gp/Mrp2 significantly reduced the apixaban's intestine clearance without substantially affecting its biliary excretion or metabolite ratio, accompanied by increased systemic exposure or plasma area under the curve (AUC). However, the systemic PKs of talinolol and irinotecan were not altered, likely due to low IE. The drug's IE was temperature- and dose-dependent but not intestinal segmental-dependent. The modified perfusion model provides a robust framework for characterizing intestinal clearance and assessing transporter-mediated interactions for drugs undergoing intestinal clearance following i.v. administration. Similar to other routes, intestinal clearance can be a critical elimination pathway, and apixaban is a suitable reference "victim" drug for intestinal clearance inhibition studies.