Inhibition of transporters

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Interestingly, we have recently identified a mutation of a tyrosine in the third intracellular loop of the hDAT that causes a major alteration in the conformational equilibrium of the transport cycle, and thus as such is comparable to mutants on G protein-coupled receptors causing constitutive isomerization of the receptor to the active state (66). Most importantly, this conclusion is based on the observation that mutation of the tyrosine completely reverts the effect of Zn2+ at the endogenous Zn2+ binding site in the hDAT (50,51) from potent inhibition of transport to potent stimulation of transport (Fig. 6). In the absence of Zn2+, transport capacity is reduced to less than 1% of that observed for the wild-type, however, the presence of Zn2+ in only micromolar concentrations causes a close to 30-fold increase in uptake (66). Moreover, it is found that the apparent affinities for cocaine and several other inhibitors are substantially decreased, whereas the apparent affinities for substrates are markedly increased (66). Notably, the decrease in apparent cocaine affinity was around 150-fold and thus to date the most dramatic alteration in cocaine affinity reported upon mutation of a single residue in the monoamine transporters (66). 

Kidney failure not only decreases renal clearance of nicotine and cotinine, but also metabolic clearance of nicotine (Molander et al. 2000). Metabolic clearance of nicotine is reduced by 50% in subjects with severe renal impairment compared to healthy subjects. It is speculated that accumulation of uremic toxins may inhibit CYP2A6 activity or downregulate CYP2A6 expression in liver. Hepatic metabolism of several drugs is reduced in kidney failure, mainly via downregulation of CYP enzymes and/or inhibition of transporters (Nolin et al. 2003). 

Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y (2003) Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivas-tatin and cyclosporin A. / Pharmacol Exp Ther 304, 610-616. 

However, from animal studies it becomes evident that the changes in tissue (intracellular) concentrations of drugs caused by inhibition of transporters are... 

Increased competitive inhibition of transport of other amino acids required for protein synthesis in the brain... 

Increased production of metabolites of phenylalanine that inhibit synthesis of a variety of substances required for normal brain growth Inhibition of TV-methyl-D-aspartate receptors, which are involved in memory and learning Competitive inhibition of transport of other amino acids required for protein synthesis Impaired polyribosome formation or stabilization Reduced synthesis/increased degradation of myelin Decreased formation of norepinephrine and serotonin Altered myelin structure and function... 

In AQP1, C191 is responsible for mercury inhibition of transport (Prasad et al., 1998). It is positioned similarly to its homologous residue Phe-200 in GlpF at the narrowest position of the channel. Thus mercury inhibition in aquaporins is brought about by a chemical modification of the thiol in the selectivity filter. 

Cells carefully control the homeostasis of their ion concentrations by the action of ion channels (Na, K , Ca " channels) and throu Na, K -ATPase and Ca -ATPase. These channels and pumps are involved in signal transduction, active transport processes, and neuronal and neuromuscular signaling. Inhibition of transport processes (ion channels, carriers) is achieved by (Table IV) acronycine, ervatamine, harmaline, quinine, reserpine, colchicine, nitidine, salsolinol, sanguinarine, stepholidine, caffeine, sparteine, monocrotaline, steroidal alkaloids, aconitine, capsaicine, cassaine, maitoxin, ochratoxin, palytoxin, pumiliotoxin, saxitoxin, sole-nopsine, and tetrodotoxin. 

Excretion may be altered by the induction or inhibition of transport proteins, and by decreases in blood flow to the organs where excretion takes place (liver and kidney). 

The pyruvate transporter [201] and the carnitine translocase [202] have both been isolated but not characterized in any detail. The pyruvate transporter and the carnitine translocase, like the phosphate transporter, are inhibited by maleimide derivatives and mercurials, although at higher concentrations of the sulfhydryl reagents. The pyruvate transporter has been isolated in inactive form covalently linked to phenyl maleimide. Identification was based on the correlation of labelling of the protein with inhibition of transport, and by the fact that mercurials prevented the labelling. The molecular weight of the isolated monomeric protein is surprisingly low, approximately 15000. 

Inhibition of transport processes that carry substances across cells, e.g. blockade of anion transport in the renal tubule cell by probenecid can be used to delay excretion of penicillin, and to enhance elimination of mate... 

The primary sites and effects of drug-drug interactions involving other medications and MPA are likely to be decreased absorption in the gastrointestinal tract, inhibition of enterohepatic cycling, and inhibition of transport of the primary phenolic glucuronide metabolite. Meal consumption just before oral intake of MMF delays absorption, causing a reduction in the maximal concentration by about... 

Shitara, Y., Itoh, T., Sato, H., Li, A.P. and Sugiyama, Y. (2003) Inhibition of transporter-mediated hepatic uptake... 

Group IV Inhibition of transport process high renal clearance deieciion best in urt ne ... 

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