Human Enteroid Monolayers: A Novel, Functionally-Stable Model for Investigating Oral Drug Disposition.

To further the development of an in vitro model which faithfully recapitulates drug disposition of orally administered drugs, we investigated the utility of human enteroid monolayers to simultaneously assess intestinal drug absorption and first-pass metabolism processes. We cultured human enteroid monolayers from three donors, derived via biopsies containing duodenal stem cells that were propagated and then differentiated atop permeable Transwell® inserts, and confirmed transformation into a largely enterocyte population via RNA-seq analysis and immunocytochemical (ICC) assays. Proper cell morphology was assessed and confirmed via bright field microscopy and ICC imaging of tight junction proteins and other apically and basolaterally localized proteins.

An Integrative Approach to Elucidate Mechanisms Underlying the Pharmacokinetic Goldenseal-Midazolam Interaction: Application of In Vitro Assays and Physiologically Based Pharmacokinetic Models to Understand Clinical Observations.

The natural product goldenseal is a clinical inhibitor of CYP3A activity, as evidenced by a 40%-60% increase in midazolam area under the plasma concentration versus time curve (AUC) after coadministration with goldenseal. The predominant goldenseal alkaloids berberine and (-)--hydrastine were previously identified as time-dependent CYP3A inhibitors using human liver microsomes. Whether these alkaloids contribute to the clinical interaction, as well as the primary anatomic site (hepatic vs.

Gutsy science: In vitro systems of the human intestine to model oral drug disposition.

The intestine has important gate-keeping functions that can profoundly affect the systemic blood exposure of orally administered drugs. Thus, characterizing a new molecular entity's (NME) disposition within the intestine is of utmost importance in drug development. While currently used in vitro systems, such as Ussing chamber, precision-cut intestinal slices, immortalized cell lines, and primary enterocytes provide substantial knowledge about drug absorption and the intestinal first-pass effect, they remain sub-optimal for quantitatively predicting this process and the oral bioavailability of many drugs.

Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail.

The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P-glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter-expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity.