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Stereoselectivity can be most relevant in drug metabolism and receptor binding. Although drug membrane transport might be equally important for small-molecule pharmacokinetics, the extent of stereoselectivity in membrane transport is largely unknown. Here, we characterized the stereoselective transport of 18 substrates of SLC22 organic cation transporters (OCTs) 1, 2, and 3. OCT2 and OCT3 showed highly stereoselective cell uptake with several substrates and, interestingly, often with opposite stereoselectivity. In contrast, transport by OCT1 was less stereoselective, although (R)-tamsulosin was transported by OCT1 with higher apparent affinity than the (S)-enantiomer. Using OCT1 and CYP2D6 co-overexpressing cells, an additive effect of the stereoselectivities was demonstrated. This indicates that pharmacokinetic stereoselectivity may be the result of combined effects in transport and metabolism. This study …