Assessing the Turnover of Intestinal Epithelia in Pre-clinical Animal Species and Human

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 metabolising 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 modelled more mechanistically. A literature review together with statistical analysis was employed in order to establish enterocyte turnover in human and pre-clinical species. A total of 85 studies were identified reporting enterocyte turnover in 1,602 subjects in six species. In mice, the weighted combined geometric 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). Human exhibited a WX enterocyte turnover of 3.48±1.55 days for the gastrointestinal (GI) epithelia (n=265), displaying comparable turnover to that of Cytochrome P450 enzymes in vitro (0.96-4.33 days). Statistical analysis indicated human to display longer enterocyte turnover as compared to pre-clinical species. Extracted data was too sparse to support regional differences in small intestinal enterocyte turnover in man despite being indicated in mouse. The utilisation of enterocyte turnover data, together with in vitro enzyme turnover in PBPK modelling may improve the predictions of metabolic DDIs 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.