The eighth and ninth transmembrane domains in organic anion transporting polypeptide 1B1 affect the transport kinetics of estrone-3-sulfate and estradiol-17beta-D-glucuronide.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are responsible for the hepatic uptake of organic anions. They share similar sequences and structures with 12 putative transmembrane domains (TMs). Their substrate specificities are very broad and overlap each other, whereas each transporter specifically recognizes certain substrates.

Prediction of the effects of genetic polymorphism on the pharmacokinetics of CYP2C9 substrates from in vitro data.

Purpose: The *2 and *3 alleles of CYP2C9, with decreased enzymatic activity, are highly polymorphic and contribute to inter-individual differences in pharmacotherapy of CYP2C9 substrates. Here, we sought for a simplified theoretical method to predict the pharmacokinetic changes with minimal in vivo data.

Methods: The changes in clearances of CYP2C9 substrates in subjects with these alleles were quantitatively estimated by parameters from literature data: intrinsic metabolic clearance and the enzyme expression level of mutated CYP2C9, contribution of CYP2C9 to the CYP-mediated clearance (f (m2C9)), and the contribution of the dominant metabolic pathways to the total clearance (f (h)).

Functional characterization of single nucleotide polymorphisms with amino acid substitution in CYP1A2, CYP2A6, and CYP2B6 found in the Japanese population.

As a part of the studies conducted by the Pharma SNPs Consortium (PSC), the enzyme activities of CYP1A2, CYP2A6 and CYP2B6 variants with altered amino acids as a result of single nucleotide polymorphisms (SNPs) found among the Japanese population were analyzed under a unified protocol using the same lots of reagents by the laboratories participating in the PSC. Mutations in CYP1A2, CYP2A6 and CYP2B6 were introduced by site-directed mutagenesis and the wild type and mutated CYP molecules were expressed in Escherichia coli. The expressed cytochrome P450s were purified and the enzyme activities were measured in reconstitution systems.

2,3-Diphenylpropionic acids as potent VLA-4 antagonists.

The discovery and SAR of 2,3-diphenylpropionic acid derivatives as highly potent VLA-4 antagonists are described. One representative compound, 9cc has inhibited intercellular adhesion by a VCAM-1/VLA-4 interaction with an IC(50) of 1.7 nM, and has good pharmacokinetics and oral bioavailability.

Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration: role in preventing lung injury and fibrosis in bleomycin-challenged mice.

Background And Objective: Although the pathogenesis of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory cells, especially neutrophils, and the injurious substances produced by them play important roles in the progression of interstitial pneumonia and subsequent fibrosis. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis by antineutrophil and several other anti-inflammatory mechanisms. The present study was undertaken to investigate the effects of 14-MRMLs on an experimental model of bleomycin-induced acute lung injury and subsequent fibrosis in mice.

[Attenuated mRNA induction of molecules associated with neutrophil migration by 14-membered ring macrolides inhibits bleomycin induced acute lung injury in mice].

Background: Although the pathogeneses of interstitial pneumonia are not well understood, it has been reported that inflammatory cells, especially neutrophils, and their injurious substances play important roles in the progression of interstitial pneumonia. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to inhibit chronic airway inflammation by mechanisms of anti-neutrophil and several other anti-inflammatory activities. The present study was undertaken to investigate the effects and mechanisms of 14-MRMLs (erythromycin: EM; clarithromycin: CAM; roxithromycin: RXM) on an experimental model of bleomycin (BLM) -induced acute lung injury in mice.