The 8-state free-exchange model of generalized transport. The transporter can assume four different binding states (apo, E; proton-bound, EH; drug-bound, ED; and proton/drug-bound, EHD). All states can perform alternating access. The pathways leading to antiport or symport are shown in B and C, respectively. In either case, proton and drug can bind in any order. However, different pairs of key states must alternate access to achieve coupled antiport (ED and EH) or coupled symport (E and EHD). Colors and labeling are as in Figs. 1 and 2.