Hepatic drug transporters

Chandra P, Brouwer KL. The complexities of hepatic drug transport current knowledge and emerging concepts. Pharm Res 2004 21(5) 719-735. 

K. L. R. Integration of hepatic drug transporters and phase II metabolizing enzymes Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur. J. Pharm. Sci. 27, 447-486, 2006. 

Le Vee M, Jigorel E, Glaise D et al (2006) Functional expression of sinusoidal and canalicular hepatic drug transporters in the differentiated human hepatoma HepaRG cell line. Eur J Pharm Sci 28 109-117... 

Figure 15.5 Hepatic drug transporter expression changes due to alcoholic hepatitis or idiosyncratic drug reactions. Drug- or ethanol-induced inflammation ofthe liver results in downregulation of NTCP, OATP2, BSEP, and MRP . MRP3 levels remain unchanged, whereas M DRl levels either remain constant or increase.

Figure 9.9 Human hepatic canalicular transport proteins. Important canalicular transport proteins are depicted with arrows denoting the direction of transport and ATP-dependent transporters designated by . Typical substrates are listed (OA , organic anions OC", organic cations TC, taurocholate MX, mitoxantrone). With kind permission from Springer Science +Business Media Pharmaceutical Research, The complexities of hepatic drug transport Current knowledge and emerging concepts, volume 21, 2004, pp.719-735, P. Chandra and K.L.R. Brouwer, Figure 2.

FIGURE 2-2 Hepatic drug transporters. Membrane transporters, shown as hexagons with arrows, work in concert with phase 1 and phase 2 drug-metabolizing enzymes in the hepatocyte to mediate the uptake and efflux of drugs and their metabolites. 

Inhibition of Hepatic Drug Transporters by Troglitazone Metabolites. 425... 

The liver plays an important role in determining the oral bioavailability of drags. Drag molecules absorbed into the portal vein are taken up by hepatocytes, and then metabolized and/or excreted into the bile. For hydrophilic drugs, transporters located on the sinusoidal membrane are responsible for the hepatic uptake [1, 2]. Biliary excretion of many drags is also mediated by the primary active transporters, referred to as ATP-binding cassette transmembrane (ABC) transporters, located on the bile canalicular membrane [1, 3-5], Recently, many molecular biological... 

Recently, molecular biology studies have been carried out on hepatic uptake transporters. With regard to the Na+-dependent hepatic uptake of bile acids, Na+-taurocholate cotransporting polypeptide (Ntcp/NTCP) has been cloned from both rodents and humans [14-17]. Ntcp/NTCP accepts bile salts, such as taurocholate and glycocholate, as well as some anionic compounds such as dehydroepian-drosterone sulfate and bromosulfophthalein [16, 18]. However, the presence of unidentified Na+-dependent transporters for anionic drugs (e.g., bumetanide) has also been suggested [19, 20]. 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

Nolin TD, Erye RF, Matzke GR (2003) Hepatic drug metabolism and transport in patients with kidney disease. Am J Kidney Dis 42(5) 906-925... 

Age In newborn infants, the glomerular filtration rate and tubular transport is immature, which takes 5 to 7 months to mature. Also, the hepatic drug metabolism capacity is also inadequate (that is why chloramphenicol can produce grey baby syndrome ), and due to the higher permeability of blood brain barrier, certain drugs attain high concentration in the CNS. 

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