Intestinal Drug Absorption After Subarachnoid Hemorrhage and Elective Neurosurgery: Insights From Esomeprazole Pharmacokinetics.

Objectives: Subarachnoid hemorrhage (SAH) may critically impair cardiovascular, metabolic, and gastrointestinal function. Previous research has demonstrated compromised drug absorption in this group of patients. This study aimed to examine the impact of SAH on gastrointestinal function and its subsequent effect on the absorption of enterally administered drugs, using esomeprazole as a probe drug.

An extended substrate spectrum of the proton organic cation antiporter and relation to other cation transporters.

Most central nervous system (CNS) active drugs are organic cations, which need carrier proteins for efficient transfer through the blood-brain barrier (BBB). A genetically still unidentified proton organic cation (H/OC) antiporter is found in several tissues, including endothelial cells of the BBB. We characterized the substrate spectrum of the H/OC antiporter and the overlap in substrate spectrum with OCTN1, OCTN2 or OCT3 by screening 87 potential substrates for transport activity.

Comprehensive characterization of the OCT1 phenylalanine-244-alanine substitution reveals highly substrate-dependent effects on transporter function.

Organic cation transporters (OCTs) can transport structurally highly diverse substrates. The molecular basis of this extensive polyspecificity has been further elucidated by cryo-EM. Apparently, in addition to negatively charged amino acids, aromatic residues may contribute to substrate binding and substrate selectivity.

Several orphan solute carriers functionally identified as organic cation transporters: Substrates specificity compared with known cation transporters.

Organic cations comprise a significant part of medically relevant drugs and endogenous substances. Such substances need organic cation transporters for efficient transfer via cell membranes. However, the membrane transporters of most natural or synthetic organic cations are still unknown.

Targeted mutagenesis of negatively charged amino acids outlining the substrate translocation path within the human organic cation transporter 3.

Recently published cryo-EM structures of human organic cation transporters of the SLC22 family revealed seven, sequentially arranged glutamic and aspartic acid residues, which may be relevant for interactions with positively charged substrates. We analyzed the functional consequences of removing those negative charges by creating D155N, E232Q, D382N, E390Q, E451Q, E459Q, and D478N mutants of OCT3. E232Q, E459Q, and D478N resulted in a lack of localization in the outer cell membrane and no relevant uptake activity.