Protocols of in vitro protein covalent binding studies in liver.

Xenobiotics, including therapeutic agents, can produce a variety of beneficial, as well as adverse, effects in mammals. One potential source of drug-mediated toxicity stems from metabolic activation of the parent compound, typically catalyzed by one or more members of the cytochrome P450 family of enzymes. The resulting electrophile, if not quenched by low molecular weight endogenous nucleophiles, can form covalent adducts to cellular proteins, potentially resulting in enzyme inactivation, cell death, or formation of an immunogenic species.

Metabolism and excretion of [14C]taranabant, a cannabinoid-1 inverse agonist, in humans.

Taranabant (N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5 mg/201 μCi [14C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (∼92%), with the majority of the dose (∼87%) excreted into faeces and a much smaller fraction (∼5%) into urine.

Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans.

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites.

Characterization of a novel calibration method for mineral density determination of dentine by X-ray micro-tomography.

Laboratory micro-CT systems, although limited by beam hardening effect and instability of the source, have been utilized to measure mineral density in combination with specific image processing methods. However, few attempts have been made to accurately determine mineral density profiles in dentine due to the lack of suitable calibration standards. The aim of this study was to develop a calibration method to evaluate mineral density profiles in dentine including changes associated with dentinal caries.

Absorption, metabolism, and excretion of [(14)C]MK-0524, a prostaglandin D(2) receptor antagonist, in humans.

[(3R)-4-(4-Chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopentaindol-3-yl]acetic acid (MK-0524) is a potent orally active human prostaglandin D(2) receptor 1 antagonist that is currently under development for the prevention of niacin-induced flushing. The metabolism and excretion of [(14)C]MK-0524 in humans were investigated in six healthy human volunteers following a single p.o.

Absorption, metabolism, and excretion of [14C]MK-0767 (2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in humans.

MK-0767 (KRP-297; 2-methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) is a thiazolidinedione (TZD)-containing dual agonist of the peroxisome proliferator-activated receptors alpha and gamma that has been studied as a potential treatment for patients with type 2 diabetes. The metabolism and excretion of [14C]MK-0767 were evaluated in six human volunteers after a 5-mg (200 microCi) oral dose. Excretion of 14C radioactivity was found to be nearly equal into the urine (approximately 50%) and feces (approximately 40%).

Pharmacological characterization and radioligand binding properties of a high-affinity, nonpeptide, bradykinin B1 receptor antagonist.

Compound A (N-[2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl]-2-[(2R)-1-(2-napthylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetamide) is a member of a new class of aryl sulfonamide dihydroquinoxalinone bradykinin B1 receptor antagonists that should be useful pharmacological tools. Here we report on some of the pharmacological properties of compound A as well as the characterization of [35S]compound A as the first nonpeptide bradykinin B1 receptor radioligand. Compound A inhibited tritiated peptide ligand binding to the cloned human, rabbit, dog, and rat bradykinin B1 receptors expressed in CHO cells with Ki values of 0.

A small molecule alpha4beta1/alpha4beta7 antagonist differentiates between the low-affinity states of alpha4beta1 and alpha4beta7: characterization of divalent cation dependence.

An alpha4beta1/alpha4beta7 dual antagonist, 35S-compound 1, was used as a model ligand to study the effect of divalent cations on the activation state and ligand binding properties of alpha4 integrins. In the presence of 1 mM each Ca2+/Mg2+, 35S-compound 1 bound to several cell lines expressing both alpha4beta1 and alpha4beta7, but 2S-[(1-benzenesulfonyl-pyrrolidine-2S-carbonyl)-amino]-4-[4-methyl-2S-(methyl-[2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl]-amino) pentanoylamino]-butyric acid (BIO7662), a specific alpha4beta1 antagonist, completely inhibited 35S-compound 1 binding, suggesting that alpha4beta1 was responsible for the observed binding. 35S-Compound 1 bound RPMI-8866 cells expressing predominantly alpha4beta7 with a KD of 1.