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Abstract

In order to determine the role of different side groups in the interaction with different transporters, luminal and contraluminal stop-flow micro-perfusion was applied, and the apparent K_i values (mmol/l) of twelve morphine analogues were measured. Contraluminal organic cation transporter (K_{i, cl, NMeN}⁺; N’-methylnicotinamide): Those analogues which have an OH group on C atom 6 (normorphine, morphine, codeine, norcodeine) have higher K_idNMeN⁺ values (0.64-0.87 mmol/l) than those compounds which have an·group on C atom 6 (noroxymorphone, oxycodone, hydrocodone, hydromorphone (0.14-0.24 mmol/l). Luminal H⁺/organic cation exchanger (K_{i1, mpp}⁺; methylphenylpyridinium): analogues with both a OCH₃ group and a NCH₃ group on C atoms 3 and 6, respectively, have higher K_{i, 1mpp}⁺ values than those where one or both CH₃ groups were missing: codeine 5.1 → norcodeine 0.5 or morphine 1.15;hydrocodone 1.0 → hydromorphone 0.54; oxycodone 1.5 -→ noroxymorphone 0.63. The K_{i, cl, NMeN}⁺ and K_{i, 1, Mpp}⁺values of the 3β- and 6β-glucuronide conjugates of morphine were much higher ( > 10 mmol/l) than those of the other analogues. Luminal choline transporter (K_{i, 1, choiine}⁺): The tested analogues have K_{i, 1, Choline}⁺ values of between 6 and 25 mmol/l, except the glucuronide conjugates which do not inhibit at all. With the exception of the 14-OH compounds oxycodone and noroxymorphone, they show a similar inhibitory pattern as against the contraluminal NMeN⁺ transporter. Contraluminal organic anion transporter (K_{i cl pah};p-aminohippurate): 8 out of the 12 morphine analogues have K_{i, d, pah} values of between 5.7 and 7.3 mmol/l. Only the K_i values of codeine and the diacetyl and glucuronide conjugates are somewhat lower (2.1-3.5 mmol). The latter have K_i values against the cation transporters which are much higher than that of all other morphine analogues. The data indicate that the morphine analogues are ‘polysubstrates’ that interact with different organic cation transporters and the organic anion transporter. These transporters are, therefore, rather unspecific. Furthermore, each transporter has his preference for certain side groups in the substrate molecules.