7 research outputs found
Key Role for the 12-Hydroxy Group in the Negative Ion Fragmentation of Unconjugated C24 Bile Acids
Host-gut microbial
interactions contribute to human health and
disease states and an important manifestation resulting from this
cometabolism is a vast diversity of bile acids (BAs). There is increasing
interest in using BAs as biomarkers to assess the health status of
individuals and, therefore, an increased need for their accurate separation
and identification. In this study, the negative ion fragmentation
behaviors of C24 BAs were investigated by UPLC-ESI-QTOF-MS. The step-by-step
fragmentation analysis revealed a distinct fragmentation mechanism
for the unconjugated BAs containing a 12-hydroxyl group. The unconjugated
BAs lacking 12-hydroxylation fragmented via dehydration and dehydrogenation.
In contrast, the 12-hydroxylated ones, such as deoxycholic acid (DCA)
and cholic acid (CA), employed dissociation routes including dehydration,
loss of carbon monoxide or carbon dioxide, and dehydrogenation. All
fragmentations of the 12-hydroxylated unconjugated BAs, characterized
by means of stable isotope labeled standards, were associated with
the rotation of the carboxylate side chain and the subsequent rearrangements
accompanied by proton transfer between 12-hydroxyl and 24-carboxyl
groups. Compared to DCA, CA underwent further cleavages of the steroid
skeleton. Accordingly, the effects of stereochemistry on the fragmentation
pattern of CA were investigated using its stereoisomers. Based on
the knowledge gained from the fragmentation analysis, a novel BA,
3β,7β,12α-trihydroxy-5β-cholanic acid, was
identified in the postprandial urine samples of patients with nonalcoholic
steatohepatitis. The analyses used in this study may contribute to
a better understanding of the chemical diversity of BAs and the molecular
basis of human liver diseases that involve BA synthesis, transport,
and metabolism
Electrophoretically induced aqueous flow through single-walled carbon nanotube membranes
Diabetes mellitus and other metabolic disturbances induced by atypical antipsychotic agents
Renal Drug Transporters and Drug Interactions.
Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers