Induction of transporters

As the examples cited above indicate, many clinical chug interactions have been considered to be mediated by inhibition or induction of transporters based only on circumstantial evidence. Because of the lack of potent and specific inhibitors for each transporter, it is difficult to accurately assess the relative contributions CYP enzymes and transporters in drug absorption and excretion. The mechanisms become even more complex when multiple CYP enzymes and drug transporters are involved in the processes of drug absorption and excretion. Therefore, care should be taken when exploring the underlying mechanism of drug interactions. 

Most drugs are not only transported but also metabolized, thus it is usually difficult to decide whether induction of transport plays a significant role in the increase in drug... 

The study of the influence of transporters on drug disposition is still pretty much in its infancy however, it is hecoming increasingly clear that the inhihition or induction of transporters other than PgP can significantly influence the absorption and/or excretion of many (victim) drugs. Table 12.4 provides some examples of clinically significant DDIs associated with the alteration of transporter function by some perpetrator drugs. 

Additional evidence for a glucagon-stimulated plasma membrane component of System A comes from the results of Barber et al. (65) who showed that the asparagine-linked, glycoprotein biosynthesis inhibitor tunicamycin blocked the hormone induction of System A. As shown previously for cycloheximide or puromycin (59, 61) if tunicamycin was added to hepatocytes after the hormone-mediated induction of transport activity had begun, inhibition of further stimulation occurred within 1 hour (65). These results demonstrate that the System A-associated glycoprotein responsible for the increased uptake activity must be continuously synthesized if the stimulation of transport is to be maintained. 

The relation between glucagon binding and stimulation of Na -depen-dent AIB uptake has been studied for isolated hepatocytes in suspension (25,50,67) or in monolayer culture (25). The dose-response curves for induction of transport were similar in both cell preparations despite the fact that the cultured cells contained more glucagon binding activity than did the freshly isolated hepatocytes (25). The half-maximal stimulation occurred at 0.5 to 1.5 nM glucagon (25, 62), whereas the maximal... 

Another way to increase the entry of Ca2+ across the plasma membrane is to hyperpolarize the plasma membrane by elevating active ion transport. Fischer et al. [130] demonstrated that hyperpolarization of colonic epithelial cells (HT-29) with carbachol elevates the intracellular levels of Ca2+, [Ca2+]i while depolarization with gramicidin D or elevation of K+ in the bathing fluid reverses it. Treatment with 0.1 mM carbachol produced a spontaneous increase in [Ca2+]i from 63 nM to 901 nM. This lasted for about 3 min, beyond which a plateau level of 309 nM was maintained. While the initial Ca2+ transient was present in Ca2+-free medium containing 0.1 mM EGTA, the plateau phase was suppressed to baseline levels, suggesting that carbachol initially releases Ca2+ from the intracellular stores and subsequently increases the Ca2+ entry across the plasma membrane. In cells hyperpolarized with carbachol, induction of depolarization by ele-... 

Little K., Elmer L., Zhong H., Scheys J., Zhang L. Cocaine induction of dopamine transporter trafficking to the plasma membrane. Mol. Pharmacol. 61 436, 2002. 

Fig. 11.4. Model for cholinergic signalling in the intestinal mucosa, providing a possible rationale for AChE secretion by parasitic nematodes. ACh released from enteric cholinergic motor neurons stimulates chloride secretion, mucus secretion and Paneth cell exocytosis through muscarinic receptors. Secretory responses may be modulated by mast cell mediators, either directly or via the induction of neural reflex programmes. The role of muscarinic receptor-positive cells in the lamina propria of rats infected with N. brasiliensis is undetermined, as are potential mechanisms of trans-epithelial transport of the enzymes. Adapted from Cooke (1984).

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