title: In Vitro-In Vivo Extrapolation of Intestinal Availability for Carboxylesterase Substrates Using Portal Vein-Cannulated Monkey.
abstract: Prediction of intestinal availability (FaFg) of carboxylesterase (CES) substrates is of critical importance in designing oral prodrugs with optimal properties, projecting human pharmacokinetics and dose, and estimating drug-drug interaction potentials. A set of ester prodrugs were evaluated using in vitro permeability (parallel artificial membrane permeability assay and Madin-Darby canine kidney cell line-low efflux) and intestinal stability (intestine S9) assays, as well as in vivo portal vein-cannulated cynomolgus monkey. In vitro-in vivo extrapolation (IVIVE) of FaFgwas developed with a number of modeling approaches, including a full physiologically based pharmacokinetic (PBPK) model as well as a simplified competitive-rate analytical solution. Both methods converged as in the PBPK simulations enterocyte blood flow behaved as a sink, a key assumption in the competitive-rate analysis. For this specific compound set, the straightforward analytical solution therefore can be used to generate in vivo predictions. Strong IVIVE of FaFgwas observed for cynomolgus monkey with R2of 0.71-0.93. The results suggested in vitro assays can be used to predict in vivo FaFgfor CES substrates with high confidence.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Trapa
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beaumont
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06345.
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06345.
authors.forename: Heather
authors.initials: H
authors.lastname: Eng
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06345.
authors.forename: Amanda
authors.initials: A
authors.lastname: King-Ahmad
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Scott
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Cambridge, Massachusetts 02139.
authors.forename: Tristan S
authors.initials: TS
authors.lastname: Maurer
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, Connecticut 06345. Electronic address: Li.Di@Pfizer.Com.
authors.forename: Li
authors.initials: L
authors.lastname: Di
mesh_terms: D000284:Administration, Oral; D000818:Animals; D043182:Carboxylesterase / Q000008:administration & dosage* / Q000097:blood*; D002404:Catheterization / Q000379:methods; D004285:Dogs; D005260:Female; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology*; D008252:Macaca fascicularis; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D011169:Portal Vein / Q000187:drug effects* / Q000378:metabolism*; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D043182:Carboxylesterase
keywords: In vitro–in vivo extrapolation; carboxylesterase; fraction absorbed; gut first-pass extraction; intestine S9; portal vein–cannulated monkey