Predicting Oral Absorption for Compounds Outside the Rule of Five Property Space.

The estimation of the extent of absorption of drug candidates intended for oral drug delivery is an important selection criteria in drug discovery. The use of cell-based transwell assays examining flux across cell-monolayers (e.g.

Transport properties of valsartan, sacubitril and its active metabolite (LBQ657) as determinants of disposition.

1. The potential for drug-drug interactions of LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) was investigated in vitro. 2.

Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.

Objective: An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted.

Methods: The study used cell lines that stably expressed or over-expressed the respective transporters.

A plasma concentration of α-ketoglutarate influences the kinetic interaction of ligands with organic anion transporter 1.

The purpose of the present study was to determine whether a physiologic plasma concentration of α-ketoglutarate (αKG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular αKG on the kinetics of para-aminohippurate (PAH) and cidofovir transport was examined along with its effect on the potency of 10 drugs in five different classes (uricosuric, nonsteroidal anti-inflammatories, loop diuretics, angiotensin II receptor antagonists, and β-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular αKG competitively inhibited PAH and cidofovir transport with Ki values (∼5 μM) approximating its unbound plasma concentration (determined by equilibrium dialysis).

Expression of organic anion transporter 2 in the human kidney and its potential role in the tubular secretion of guanine-containing antiviral drugs.

The organic anion transporters 1 and 3 (OAT1 and OAT3) and organic cation transporter 2 (OCT2) are important for renal tubular drug secretion. In contrast, evidence for OAT2 expression in the human kidney is limited, and its role in renal drug transport is unknown. Both mRNA (real-time polymerase chain reaction) and protein (Western blotting) for OAT2 were detected in renal cortex from eight donors, and interindividual variability in protein levels was 3-fold.

Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects.

Purpose: To conduct a mechanistic investigation of the interaction between aliskiren and grapefruit juice in healthy subjects.

Methods: Twenty-eight subjects received an oral dose of aliskiren 300 mg (highest recommended clinical dose) with 300 mL of either water or grapefruit juice in a two-way crossover design. Safety and pharmacokinetic analyses were performed.