Hepatobiliary excretion transporters

MDCK II cells (Fig. 12.3) [93], Kinetic analysis revealed that the Km value for transcellular transport (24 pM) was similar to the Km for OATP2 (34 pM) [93], Moreover, the efflux across the bile canalicular membrane was not saturated under these experimental conditions. These in vitro observations are consistent with in vivo experimental results in rats which showed that the rate-determining process for the biliary excretion of pravastatin is uptake across the sinusoidal membrane. By normalizing the expression level between the double transfectant and human hepatocytes, it might be possible to predict in vivo hepatobiliary excretion. 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

There is evidence in literature that alkaloid biology is connected with regulation, stimulation and induction functions. Tsai et al. proved that caffeine levels in the blood, brain and bile of rats decreased when given a treatment of rutaecarpine, an alkaloid from Evodia rutaecarpa (Figure 78). It is known that caffeine has been found to enter the brain by both simple diffusion and saturable carrier-mediated transport . The hepatobiliary excretion of caffeine has also been reported in humans rabbits and rats. ... 

Kusuhara H, Suzuki H, Sugiyama Y. The role of P-glycoprotein and canalicular multi specific organic anion transporter in the hepatobiliary excretion of chugs. J Pharm Sci 1998 87 1025-1040. 

It has been suggested that multidrug resistance proteins (MRPs) play an important role in the transport and detoxification of a wide range of endogenous compounds and xenobiotics. They are predominantly expressed at the apical membrane of the small intestine, proximal tubules of the kidney and canalicular membrane of hepatocytes involved in intestinal, renal and hepatobiliary excretion of compounds. 

The information summarized in this chapter describes how transporters play an important role in the hepatobiliary excretion of drugs, which is also one of the... 

Chen, C., Hennig, G.E., and Manautou, J.E. (2003) Hepatobiliary excretion of acetaminophen glutathione conjugate and its derivatives in transport-deficient (TR ) hyperbilirubinemic rats. Drug Metabolism and Disposition, 31 (6), 798-804. 

Watanabe T, Miyauchi S, Sawada Y, et al. Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver. Possible roles of P-glycoprotein in biliary excretion of vincristine. J Hepatol 1992 16(l-2) 77-88. 

In an in vivo study in rats, endotoxin reduced the biliary excretion of sparfloxacin and its glucuronide, probably owing to impairment of hepatobiliary transport systems and renal handling (2). 

The SLC transporters mediate either drug uptake or efflux, whereas ABC transporters mediate only unidirectional efflux. Asymmetrical transport across a monolayer of polarized ceUs, such as the epithelial and endothelial cells of brain capillaries, is called vectorial transport (Figure 2-5). Vectorial transport is important in the efficient transfer of solutes across epithelial or endothelial barriers it plays a major role in hepatobiliary and urinary excretion of drugs from the blood to the lumen and in the intestinal absorption of drugs and nutrients. In addition, efflux of drugs from the brain via brain endothelial cells and brain choroid plexus epithelial cells involves vectorial transport. 

Cherian MG (1977) Biliary excretion of cadmium in rat. II. The role of metallothionein in the hepatobiliary transport of cadmium. J Toxicol Environ Health 2 955-961... 

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