Influx transporters

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

DFinfiuxii) = Distribution factor for influx transporter in compartment i. 

Keywords Inner blood-retinal barrier Transporter Influx transport Efflux transport Microdialysis Cell line Drug delivery... 

Blood-to-retina influx transport GLUT1 D-Glucose/Dehydroascorbic acid + TR-iBRB Isolated retinal capillary [5, 13, 14, 43, 47]... 

Schiffer, R., Neis, M., Holler, D., et al. Active influx transport is mediated by members of the organic anion transporting polypeptide family in human epidermal ker-atinocytes. J. Invest. Dermatol. 120(2) 285-291, 2003. 

Holzer AK, Katano K, Klomp LWJ, Howell SB. Cisplatin rapidly down-regulates its own influx transporter hCTRl in cultured human ovarian carcinoma cells. Clin. Cancer Res. 2004 10 6744-6749. 

Using a similar approach to our studies of cisplatin-induced ototoxicity, we have identified a series of SNPs associated with anthrac-yline-induced cardiotoxicity in children with cancer in Canada, a finding that we have verified in a replication cohort from the Netherlands [69, 70]. We identified a series of risk and protective alleles that can be related at least in good part to the known pharmacology of the anthracyclines these variants include protective variants characterized by loss-of-function for influx transporters for anthracyclines as well as risk variants characterized by loss-of-function for efflux transporters for anthracyclines (Table 2, Fig. 5) [69],... 

The mechanism of action of cisplatin is relatively well understood. The dmg enters cells by passive diffusion, but also by an active transport mechanism. Ctrl, the major copper influx transporter, described in Chapter 8, has... 

Maeda, T., Takahashi, K., Ohtsu, N., Oguma, T., Ohnishi, T., Atsumi, R. and Tamai, I. (2007) Identification of influx transporter for the quinolone antibacterial agent levofloxadn. Molecular Pharmacology, 4, 85-94. 

Caco-2 Human colon adrenocarcinoma Most well-established cell model / Differentiates and expresses some relevant efflux transporters / Expression of influx transporters variable... 

For many years, the rate and extent of absorption in the small intestine were thought to be determined solely by the lipid/water solubility and membrane permeability characteristics of the drug. While this relatively simplistic model worked for many drugs, there are a number of exceptions to this rule, suggesting other forces are at work within the GI system to control the absorption of drugs. It is now known that a complex system of transporter proteins and metabolic enzymes is present within the GI system. Expression of influx transporters in the intestinal epithelial cells can increase absorption of drugs that are substrates for these transporters, whereas efflux transporters can reduce oral absorption of these drugs. In particular, the impact of the... 

Transporters expressed in tissues that may be targets for drug toxicity (e.g., brain) or in barriers to such tissues (e.g., the blood-brain barrier [BBB]) can tightly control local drug concentrations and thus control the drug exposure of these tissues (Figure 2-3, middle panel). Drug-induced toxicity sometimes is caused by the concentrative tissue distribution mediated by influx transporters. 

Microsomal Incubation Conditions Incubations in animal or human liver microsomes are the most common way to determine activity in the presence of added substrate, UDPGA, Mg, and a buffer. As there is no method available to directly determine enzyme concentration, the incubations are standardized by addition of the same amount of protein (typically 0.25-1.0 mg protein/ImL) after determination of linearity of product formation with respect to protein concentration and time. In general, the enzyme is stable up to 45 min to 1 h. Because of the location of the enzyme, a portion of the microsomal vesicle will be obtained in the normal configuration with the enzyme active site entrapped within the vesicle. Since UDPGA must have access to the active site, and the UDPGA influx transporter is not operative without ATP, it may be necessary to activate or remove latency of the enzyme. In the past this has been achieved by a variety of methods, but most commonly by addition of detergents such as Brij 58, Lubrol, or Triton X... 

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