•We propose properties related to drug–transporter interactions and drug attrition.•This space consists of compounds with PSA>75 and clogP<3.•This space overlaps with BDDCS class III and known drug-transporters interaction.•We demonstrate differences between physical-property and drug–transporter attrition.•We propose an index to identify compounds at risk of drug-transporter interactions. Improving the efficiency of drug discovery remains a major focus for the pharmaceutical industry. Toxicity accounts for 90% of withdrawals and major early-stage terminations relate to suboptimal efficacy and safety. Traditional oral drug space is well defined with respect to physicochemical properties and ADMET risks but increased focus on ligand-lipophilicity efficiency, maximizing enthalpy contributions and new target classes challenge this paradigm. A hybrid space has been identified that combines physical properties and key interactions attributable to drug transporters. A novel algorithm is proposed that incorporates drug–transporter interactions and its utility evaluated against popular ligand efficiency indices. Simply reducing the bulk properties of compounds can exchange one problem for another and creates high-risk areas that challenge the successful delivery from a balanced portfolio. The traditional physical-property-based argument for drug attrition is developed and extended to one that incorporates drug–transporter interactions. A new algorithm is proposed that facilitates the evaluation of this hybrid property space.