Absorption transporter proteins

Figure 50-4. Absorption of iron. is converted to Fe + by ferric reductase, and Fe " is transported into the enterocyte by the apicai membrane iron transporter DMTl. Fieme is transported into the enterocyte by a separate heme transporter (HT), and heme oxidase (FiO) reieases Fe from the heme. Some of the intraceiiuiar Fe + is converted to Fe + and bound by ferritin. The remainder binds to the basoiaterai Fe + transporter (FP) and is transported into the biood-stream, aided by hephaestin (FiP). in piasma, Fe + is bound to the iron transport protein transferrin (TF). (Reproduced, with permission, from Ganong WF Review of Medical Physiology, 21 st ed. McGraw-Hill, 2003.)...

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

P-glycoprotein, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys 42 This protein provides a biologic barrier by eliminating toxic substances and xenobiotics that may accumulate in these organs. P-glycoprotein plays an important role in the absorption and distribution of many medications. Medications that are CYP3A4 substrates, inhibitors, or inducers are also often affected by P-glycoprotein therefore, the potential for even more DDIs exists in transplant recipients.42... 

Gastrointestinal absorption of lead is influenced by dietary and nutritional calcium and iron status. An inverse relationship has been observed between dietary calcium intake and PbB concentration (Mahaffey et al. 1986 Ziegler et al. 1978). Complexation with calcium (and phosphate) in the gastrointestinal tract and competition for a common transport protein have been proposed as possible mechanisms for this interaction (Barton et al. 1978a Heard and Chamberlain 1982). Absorption of lead from the... 

We can speculate that in the absorptive zone of the villus, the enterocyte regulates its iron absorption as a function of the message that has been programmed into the IRP proteins (Figure 9.4b). In this context, we should note that both the putative apical transport (DCT1) and basolateral (IREG1) transport proteins have IREs, respectively in their 3 - and 5 -UTRs (as discussed in Chapter 9), but that to date their direct involvement with IRPs remains to be established. 

Fig. 7.1. The intestinal permeability of drugs in vivo is the total transport parameter that may be affected by several parallel transport mechanisms in both absorptive and secretory directions. Some of the most important transport proteins that may be involved in the intestinal transport of drugs and their metabolites across intestinal epithelial membrane barriers in humans are displayed.

From the above, it is clear that the gut wall represents more than just a physical barrier to oral drug absorption. In addition to the requirement to permeate the membrane of the enterocyte, the drug must avoid metabolism by the enzymes present in the gut wall cell as well as counter-absorptive efflux by transport proteins in the gut wall cell membrane. Metabolic enzymes expressed by the enterocyte include the cytochrome P450, glucuronyltransferases, sulfotransferases and esterases. The levels of expression of these enzymes in the small intestine can approach that of the liver. The most well-studied efflux transporter expressed by the enterocyte is P-gp. 

Ayrton, A., Morgan, P., Role of transport proteins in drug absorption, distribution and excretion, Xenobiotica 2001, 31, 469-497. 

Danzig, A. H., Oral absorption of (S-lactams by intestinal peptide transport proteins, Adv. Drug Ddiv. Rev. 1997,... 

The volume is divided into five sections. Part one looks at the experimental study of membrane permeability and oral absorption. In Part two, problems of measuring and prediction solubility, as one of the key determinants in the absorption process, will be discussed in detail. In the next part, progress in the science around transporter proteins and gut wall metabolism and their effect on the overall absorption process is presented. Part four looks at the in silico approaches and models to predict permeability, absorption and bioavailability. In the last part of the book, a number of drug development issues will be highlighted, which could have an important impact of the overall delivery strategies for oral pharmaceutical products. 

In addition to phase I and phase II enzymes, equally important is a group of transporter proteins expressed in various tissues, such as the liver, intestine, brain and kidney, which modulate the absorption, distribution and excretion of many drugs. 

Figure 15.2 Transport proteins involved in the intestinal absorption and the renal and hepatic excretion of drugs. In the intestine, drugs are taken up from the luminal side into enterocytes before the subsequent elimination into blood. In hepatocytes, drugs are taken up from the blood over the basolateral membrane and excreted over the canalicular membrane into bile. In the renal epithelium, drugs undergo secretion (drugs are taken up from the blood and excreted into the urine) or reabsorption (drugs are taken up from the urine and are excreted back into blood). Uptake transporters belonging to the SLC transporter superfamily are shown in red and export pumps...

Many drugs have been recognized to cross the intestinal epithelial cells via passive diffusion, thus their lipophilicity has been considered important. However, as described above, recent studies have demonstrated that a number of drug transporters including uptake and efflux systems determine the membrane transport process. In this chapter, we provide an overview of the basic characteristics of major drug transporters responsible not only for absorption but also for disposition and excretion in order to delineate the impact of drug transport proteins on pharmacokinetics. 

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