OCT1 is the most highly expressed cation transporter in the liver and affects pharmacokinetics and pharmacodynamics. Newly marketed drugs have previously been screened as potential OCT1 substrates and verified by virtual docking. Here, we used machine learning with transport experiment data to predict OCT1 substrates based on classic molecular descriptors, pharmacophore features, and extended-connectivity fingerprints and confirmed them by in vitro uptake experiments. We virtually screened a database of more than 1000 substances. Nineteen predicted substances were chosen for in vitro testing. Sixteen of the 19 newly tested substances (85%) were confirmed as, mostly strong, substrates, including edrophonium, fenpiverinium, ritodrine, and ractopamine. Even without a crystal structure of OCT1, machine learning algorithms predict substrates accurately and may contribute not only to a more focused screening in drug development but also to a better molecular understanding of OCT1 in general.

Older persons may particularly benefit from pharmacogenetic diagnostics, but there is little clinical evidence on that question. We quantitatively analyzed the effects of age and genotype in drugs with consensus on a therapeutically relevant impact of a genotype. Assuming additive effects of age and genotype, drugs may be classified in groups with different priorities to consider either age, or genotype, or both, in therapy. Particularly interesting were those studies specifically analyzing the age-by-genotype interaction.

The organic cation transporter 1 (OCT1, SLC22A1) transports a large number of structurally diverse endogenous and exogenous substrates. There are numerous known competitive and non-competitive inhibitors of OCT1, but there are no studies systematically analyzing the relationship between transport, stimulation, and inhibition. Here, we tested in vitro OCT1 inhibition by OCT1 substrates and transport of OCT1 inhibitors under uniform analytical conditions. Beyond inhibition testing with two model substrates, we tested nine additional OCT1 substrates for their mutual inhibition. Inhibition of ASP+ uptake by most OCT1 substrates was weak. The model substrate sumatriptan, with its moderately stronger inhibitability, was used to confirm this. Interestingly, OCT1 substrates exhibiting stronger OCT1 inhibition were mainly biaromatic β-agonistic drugs, such as dobutamine, fenoterol, ractopamine and ritodrine. Biaromatic organic cations were both, strong inhibitors and good substrates, but many OCT1 substrates showed little pairwise inhibition. Surprisingly, sumatriptan did significantly enhance dobutamine uptake. This effect was concentration dependent and additional experiments indicated that efflux inhibition may be one of the underlying mechanisms. Our data suggests, that OCT1 substrates are mainly weak OCT1 inhibitors and among those inhibiting well, noncompetitive inhibition could be responsible. Weak competitive inhibition confirms that OCT1 inhibition screenings poorly predict OCT1 substrates. Additionally, we showed that the OCT1 substrate sumatriptan can enhance uptake of some other OCT1 substrates. OCT1 transport stimulation was already observed earlier but is still poorly understood. Low OCT1 uptake inhibition and strong OCT1 efflux inhibition could be mechanisms exploitable for enhancing transport.

Human monoamine transporters (MATs) are cation transporters critically involved in neuronal signal transmission. While inhibitors of MATs have been intensively studied, their substrate spectra have received far less attention. Polyspecific organic cation transporters (OCTs), predominantly known for their role in hepatic and renal drug elimination, are also expressed in the central nervous system and might modulate monoaminergic signaling. Using HEK293 cells overexpressing MATs or OCTs, we compared uptake of 48 compounds, mainly phenethylamine and tryptamine derivatives including matched molecular pairs, across noradrenaline, dopamine and serotonin transporters and OCTs (1, 2, and 3). Generally, MATs showed surprisingly high transport activities for numerous analogs of neurotransmitters, but their substrate spectra were limited by molar mass. Human OCT2 showed the broadest substrate spectrum, and also the highest overlap with MATs substrates. Comparative kinetic analyses revealed that the radiotracer meta-iodobenzylguanidine had the most balanced uptake across all six transporters. Matched molecular pair analyses comparing MAT and OCT uptake using the same methodology could provide a better understanding of structural determinants for high cell uptake by MATs or OCTs. The data may result in a better understanding of pharmacokinetics and toxicokinetics of small molecular organic cations and, possibly, in the development of more specific radiotracers for MATs.

The sensitivity of small-bowel capsule endoscopy in visualizing a single finding present in everyone, the duodenal papilla, is limited. In this retrospective case series study we evaluated whether the duodenal papilla can be better visualized by a capsule endoscope equipped with cameras on both ends. The recordings of 45 colonic capsule endoscopies (PillCam Colon) performed in a single tertiary center were re-evaluated seeking for the duodenal papilla. The two-hour sleeping period of the colon capsule endoscopy system led to the imaging of duodenum in 10 / 45 patients. The duodenal papilla was identified in 6 / 10 (60 %) patients while the number of frames where the papilla was clearly visualized ranged from 2 - 9. Consequently, a small-bowel capsule endoscope containing two cameras could better identify the duodenal papilla and theoretically other obscure areas of the small bowel, expanding its diagnostic accuracy.