Category: Preclinical Development
Purpose: The purpose of the study is to investigate reliability and reproducibiity of in vitro models and its use in predicting the drug absorption. Characterization of the microtissues included evaluation of structural features, barrier properties, and expression of drug transporters and drug metabolizing enzymes.
Methods: The quality and reproducibiity of tissue production was compared in two independent production facilities (MatTek, Ashland, MA, USA and IVLSL, Bratislava, Slovakia) by measuring TEER and Lucifer Yellow (LY) leakage. To evaluate the suitability of the microtissues for drug absorption, the apparent permeability coefficient (Papp) values for a panel of benchmark drugs with known human absorption values were measured. Drug-drug interactions were examined using drugs known to be substrates or inhibitors of efflux transporters. Structural features were monitored by histology
Results: Results showed that tissues are highly reproducible with physiological TEER values averaging 146.4±20.8 Ω*cm2 (% CV=14.2%) in the USA (N=128 lots) and 162.6±10.2 Ω*cm2 in Slovakia (N=60 lots) facilities. The real-time PCR analysis revealed that microtissues expressed all tested drug transporters and metabolizing enzymes known to be present in vivo. Drug permeation analysis with 18 selected drugs showed that the intestinal microtissues could discriminate between low and high permeability drugs with 94% accuracy. The in vitro Papp values correlated well with human absorption data. SMI microtissues show an active efflux transport as when exposed to substrates of ABC pumps, the resulting drug efflux ratios were > 2.0. Moreover, addition of efflux transporter inhibitors reduced the drug efflux ratio while increasing the bioavaiabilty of the test drugs, providing further evidence of ABC transporter activity.
Conclusion: The SMI microtissues appear to be a promising tool for predicting safety and bioavailability of orally administered drugs.