Investigations of hydrazine cleavage of eltrombopag in humans.

After oral administration to humans, eltrombopag undergoes extensive cleavage of its hydrazine linkage to metabolites, which are exclusively eliminated in urine. In vitro, the cleavage pathway was not detected in systems using cytochrome P450 enzymes, renal or hepatic microsomes, or hepatocytes but was readily evident after anaerobic incubation with rodent cecal contents or human fecal homogenate. Antibiotic treatment in vitro and in vivo inhibited eltrombopag cleavage, further indicating that cleavage is via gut microbes.

Evaluation of a chimeric (uPA+/+)/SCID mouse model with a humanized liver for prediction of human metabolism.

A model that predicts human metabolism and disposition of drug candidates would be of value in early drug development. In this study, a chimeric (uPA+/+)/SCID mouse model was evaluated with three structurally distinct compounds (GW695634, a benzophenone, SB-406725, a tetrahydroisoquinoline and GW823093, a fluoropyrrolidine) for which human metabolism and disposition was characterized. Human metabolite profiles in plasma and/or urine were compared to those of chimeric (uPA+/+)/SCID and control CD-1 or (uPA+/+)/SCID) mice.

The disposition and metabolism of GW695634: a non-nucleoside reverse transcriptase inhibitor (NNRTi) for treatment of HIV/AIDS.

GW695634 is the prodrug of GW678248, a novel non-nucleoside reverse transcriptase inhibitor with potent antiviral activity against HIV/AIDS efavirenz- and nevirapine-resistant viruses. In mice, rats, and monkeys following oral administration of [(14)C]GW695634, the primary pathway of metabolic clearance was by amide hydrolysis and the main route of elimination (46%-75% of the dose) was in the feces. The primary metabolic pathway of clearance for GW695634 and GW678248 in the preclinical species was by amide hydrolysis.

The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions.

Lapatinib [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine, GW572016, Tykerb] is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers overexpressing HER2 (ErbB2). In this work we investigated the role of efflux and uptake transporters in lapatinib disposition and drug interactions. In vitro studies evaluated whether lapatinib is a substrate for efflux transporters or an inhibitor of efflux/uptake transporters.

In vitro p-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: a recommendation for probe substrates.

Because modulation of P-glycoprotein (Pgp) through inhibition or induction can lead to drug-drug interactions by altering intestinal, central nervous system, renal, or biliary efflux, it is anticipated that information regarding the potential interaction of drug candidates with Pgp will be a future regulatory expectation. Therefore, to be able to utilize in vitro Pgp inhibition findings to guide clinical drug interaction studies, the utility of five probe substrates (calcein-AM, colchicine, digoxin, prazosin, and vinblastine) was evaluated by inhibiting their Pgp-mediated transport across multidrug resistance-1-transfected Madin-Darby canine kidney cell type II monolayers with 20 diverse drugs having various degrees of Pgp interaction (e.g.

In vitro absorption and secretory quotients: practical criteria derived from a study of 331 compounds to assess for the impact of P-glycoprotein-mediated efflux on drug candidates.

The absorptive (AQ) and secretory (SQ) quotients have been proposed as a novel experimental approach to quantify the modulation of intestinal absorption and secretion by P-glycoprotein (Pgp). Because these unidirectional assays inherently assess for the impact of Pgp, conclusions as to whether a compound is a Pgp substrate will be made from the data. Therefore, the objective of this study was to establish the relationship between AQ/SQ and the bidirectional efflux assay and to derive criteria to classify a compound as a Pgp substrate.

Steady-state brain concentrations of antihistamines in rats: interplay of membrane permeability, P-glycoprotein efflux and plasma protein binding.

The purpose of this study was to measure the in vivo brain distribution of antihistamines and assess the influence of in vitro permeability, P-glycoprotein (Pgp) efflux, and plasma protein binding. Six antihistamines (acrivastine, chlorpheniramine, diphenhydramine doxylamine, fexofenadine, terfenadine) were selected based on previously reported in vitro permeability and Pgp efflux properties and dosed intravenously to steady-state plasma concentrations of 2-10 micromol/l in rats. Plasma and brain concentrations were measured by LC/MS/MS, and protein binding determined by ultrafiltration.

The systemic exposure of an N-methyl-D-aspartate receptor antagonist is limited in mice by the P-glycoprotein and breast cancer resistance protein efflux transporters.

GV196771 [E-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-glydenemethyl)-1H-indole-2 carboxylic acid] is a potent antagonist of the modulatory glycine site of the N-methyl-d-aspartate receptor. GV196771 has low oral bioavailability (<10%) and plasma clearance ( approximately 2 ml/min/kg) in rats. P-Glycoprotein (Pgp) and breast cancer resistance protein (Bcrp) are ATP-binding cassette (ABC) transporters that limit the oral absorption of drugs and dietary constituents.

Predicting P-glycoprotein substrates by a quantitative structure-activity relationship model.

A quantitative structure-activity relationship (QSAR) model has been developed to predict whether a given compound is a P-glycoprotein (Pgp) substrate or not. The training set consisted of 95 compounds classified as substrates or non-substrates based on the results from in vitro monolayer efflux assays. The two-group linear discriminant model uses 27 statistically significant, information-rich structure quantifiers to compute the probability of a given structure to be a Pgp substrate.

P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine.

Recent in vitro studies have suggested that P-glycoprotein (Pgp) and passive membrane permeability may influence the brain concentrations of non-sedating (second-generation) antihistamines. The purpose of this study was to determine the importance of Pgp-mediated efflux on the in vivo brain distribution of the non-sedating antihistamine cetirizine (Zyrtec), and the structurally related sedating (first-generation) antihistamine hydroxyzine (Atarax). In vitro MDR1-MDCKII monolayer efflux assays demonstrated that cetirizine was a Pgp substrate (B-->A/A-->B + GF120918 ratio = 5.

Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs.

Membrane permeability and P-glycoprotein (Pgp) can be limiting factors for blood-brain barrier penetration. The objectives of this study were to determine whether there are differences in the in vitro permeability, Pgp substrate profiles, and physicochemical properties of drugs for central nervous system (CNS) and non-CNS indications, and whether these differences are useful criteria in selecting compounds for drug development. Apparent permeability (P(app)) and Pgp substrate profiles for 93 CNS (n = 48) and non-CNS (n = 45) drugs were determined by monolayer efflux.