Biliary transport

Apart from excretion via saliva [55], mercury is excreted by the liver through the bile [56], Inorganic mercury is secreted into bile complexed with a low-molecular-weight substance which appears to be glutathione [57] and the mercury secretion is in large part dependent on the biliary transport of glutathione [58]. 

Since probenecid is used extensively as an inhibitor of the urinary and biliary excretion of carboxylic, phenolic and sulphonic acids in many other animals, it was of interest to determine if probenecid would inhibit the urinary and/or biliary transport of phenol red in the shark (Table IV). The plasma levels determined at 4 hrs. after administration of phenol red alone or in combination... 

Pharmacokinetics Unlike most of the alkylating agents, cyclophosphamide and ifosfamide are preferentially administered by the oral route. Minimal amounts of the parent drug are excreted into the feces (after biliary transport), or into the urine by glomerular filtration. 

In addition to changes in clearance, drug distribution may be altered in liver disease by the resulting low plasma protein concentrations and ascites. Intrahepatic and extrahepatic cholestasis are also likely to affect biliary transport of more drugs and studies in patients with these conditions may need to be considered for some drugs. Pharmacodynamic changes that are... 

The human genome contains nearly 900 genes that encode transporters, of which over 300 are intracellular transporters [1] responsible for transporting a wide range of molecules across the membrane [2]. Further classification of these transporters into families such as the solute carrier dass (SLC) [3] and ATP binding cassette (ABC) family 4, 5] is possible. Transporters play a major role in clinical pharmacology as their adequate bioavailability determines the successful oral delivery of many therapeutics. Membrane transporter proteins are associated with drug absorption (uptake), tissue distribution (efflux and uptake), metabolism (hepatic efflux and uptake), and elimination (renal, biliary transporters, and breast milk efflux and uptake) [6, 7]. 

Hypothermia reduces plasma BSP removal rate in rats (B47, V2, V4) and in dogs (B68). The biliary transport maximum (T ,) was found (R13) to be reduced by hypothermia induced by pentobarbital which on its own depresses BSP removal (see Section 7.11) so that the effect cannot be attributed unequivocally to cold. However, direct cooling of dogs to 27°-28°C by extracorporeal circulation through a cooling bath reduced bile flow and biliary excretion of BSP although the biliary BSP concentration was unchanged (S40). 

W13. Wheeler, H. O., Meltzer, J. I., and Bradley, S. E., Biliary transport and hepatic storage of sulfobromophthalein sodium in the unaenesthetized dog, in normal man and in patients with liver disease. J. Clin. Invest. 39, 1131-1144 (1960). 

Human Canalicular Transport Proteins (Biliary Transport)... 

Inhibition of biliary transporter proteins Reactive metabolites... 

In a phase I study in patients with refractory solid tumours or lymphomas, ciclosporin 5 to 10 mg/kg was given as a 6-hour infusion beginning 3 hours before administration of irinotecan (initial dose 25 mg/m increased to 72 mg/m weekly). Ciclosporin increased the AUC of SN-38 (the active metabolite of irinotecan) by 23 to 630% and reduced irinotecan clearance by 39 to 64%, when compared with historical controls. The effects of ciclosporin on irinotecan may be due to inhibition of irinotecan-and SN-38-related biliary transporters, and this suggestion is supported by a study in Further clinical studies are needed to assess the effects of ciclosporin on the antitumour response and toxicity of irinotecan. 

Cherian MG (1980) Biliary excretion of cadmium in rat. III. Effects of chelation agents and change in intracellular thiol content on biliary transport and tissue distribution of cadmium. J Toxicol Environ Health 6 379-391 Cherian MG, Chan HM (1993) Biological functions of metallothionein. In Suzuki KT, Imura N, Kimura K (eds) Metallothionein III. Birkhauser, Basel, pp 87-109... 

The rate of biliary excretion of Hg is very low in comparison with methylmercury excretion (Ballatori and Clarkson 1984b). The form of Hg2+ excreted into the bile has been identified as a complex with GSH (GSHgSG) (Ballatori and Clarkson 1984b). Inhibition of biliary secretion of GSH by administration of sulfobromophthalein (BSP) resulted in a parallel inhibition of Hg secretion (Ballatori and Clarkson 1984a). Thus, the biliary secretion of Hg may be in large part dependent on the biliary transport of GSH. The mechanism of urinary excretion of Hg has not yet been clarified. As described above, Hg is incorporated into the kidneys by a y-GTP-dependent system, and inhibition of y-GTP significantly increases urinary excretion of Hg (Tanaka et al. 1990). Therefore, GSHgSG which has escaped from the action of y-GTP may be excreted into the urine. 

Aschner M, Clarkson TW (1989) Methylmercury uptake across bovine brain capillary endothelial cells in vitro the role of amino acid. Pharmacol Toxicol 64 293-297 Atchison WD, Narahashi T (1982) Methylmercury-induced depression of neuromuscular transmission in the rat. Neurotoxicology 3 37-50 Atchison WD, Clark AW, Narahashi T (1984) Presynaptic effects of methylmercury at the mammalian neuromuscular junction. In Narahashi T (ed) Cell and mol neurotoxicol. Raven, New York, pp 23-43 Ballatori N, Clarkson TW (1983) Biliary transport of glutathione and methylmercury. Am J Physiol 244 G435-G441... 

Ballatori N, Clarkson TM (1984a) Dependence of biliary secretion of inorganic mercury on the biliary transport of glutathione. Biochem Pharmacol 33 1093-1098... 

A new intravenous cholangiographic agent, meglumine iodoxamate, is claimed to have only half the toxicity and twice the biliary transport maximum of iodipamide. In... 

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