title: Meta-analysis of the turnover of intestinal epithelia in preclinical animal species and humans.
abstract: Due to the rapid turnover of the small intestinal epithelia, the rate at which enterocyte renewal occurs plays an important role in determining the level of drug-metabolizing enzymes in the gut wall. Current physiologically based pharmacokinetic (PBPK) models consider enzyme and enterocyte recovery as a lumped first-order rate. An assessment of enterocyte turnover would enable enzyme and enterocyte renewal to be modeled more mechanistically. A literature review together with statistical analysis was employed to establish enterocyte turnover in human and preclinical species. A total of 85 studies was identified reporting enterocyte turnover in 1602 subjects in six species. In mice, the geometric weighted combined mean (WX) enterocyte turnover was 2.81 ± 1.14 days (n = 169). In rats, the weighted arithmetic mean enterocyte turnover was determined to be 2.37 days (n = 501). Humans exhibited a geometric WX enterocyte turnover of 3.48 ± 1.55 days for the gastrointestinal epithelia (n = 265), displaying comparable turnover to that of cytochrome P450 enzymes in vitro (0.96-4.33 days). Statistical analysis indicated humans to display longer enterocyte turnover as compared with preclinical species. Extracted data were too sparse to support regional differences in small intestinal enterocyte turnover in humans despite being indicated in mice. The utilization of enterocyte turnover data, together with in vitro enzyme turnover in PBPK modeling, may improve the predictions of metabolic drug-drug interactions dependent on enzyme turnover (e.g., mechanism-based inhibition and enzyme induction) as well as absorption of nanoparticle delivery systems and intestinal metabolism in special populations exhibiting altered enterocyte turnover.
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (A.S.D., U.A., D.M.A., A.R.-H.); and Simcyp (a Certara company), Sheffield, United Kingdom (A.R.-H.) adam.darwich@manchester.ac.uk.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Darwich
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (A.S.D., U.A., D.M.A., A.R.-H.); and Simcyp (a Certara company), Sheffield, United Kingdom (A.R.-H.).
authors.forename: Umair
authors.initials: U
authors.lastname: Aslam
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (A.S.D., U.A., D.M.A., A.R.-H.); and Simcyp (a Certara company), Sheffield, United Kingdom (A.R.-H.).
authors.forename: Darren M
authors.initials: DM
authors.lastname: Ashcroft
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, United Kingdom (A.S.D., U.A., D.M.A., A.R.-H.); and Simcyp (a Certara company), Sheffield, United Kingdom (A.R.-H.).
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: D000818:Animals; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D020895:Enterocytes / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System