Hepatobiliary excretion

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]. 

In contrast to P-gp and the MRP proteins, the breast cancer resistance protein (BCRP) contains six transmembrane domains and only one ATP-binding domain. It was first cloned from the breast cancer cell line MCF-7 selected in doxombicin, in the presence of the P-gp inhibitor verapamil. It is found in many human tissues, such as the placenta, small intestine, colon, and liver [133], It is localized to the apical membrane of epithelial cells of the small intestine and colon and to the bile canalicular membrane in the liver and is involved in reducing intestinal uptake, increasing hepatobiliary excretion, etc., leading to diminished oral bioavailability. cDNA sequences identical to BCRP and named MXR and ABCP, respectively, were independently isolated from human colon carcinoma cells and human placenta [134], BCRP requires... 

G. Merino, J. W. Jonker, E. Wagenaar, A. E. van Herwaarden, and A. H. Schinkel. The breast cancer resistance protein (BCRP/ABCG2) affects pharmacokinetics, hepatobiliary excretion, and milk secretion of the antibiotic nitrofurantoin. Mol Pharmacol 67 1758-1764 (2005). 

Relatively small lipophilic molecule to improve hepatobiliary excretion and avoid complement activation. 

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. 

E187 Arvan, D. and Shirey, T.L. (1985). Conjugated bilirubin A better indicator of impaired hepatobiliary excretion than direct bilirubin. Ann. Clin. Lab. Sci. 15, 252-259. 

The long terminal plasma half-life of daunorubidn results from extensive tissue binding. It is readily metabolized to daunorubicinol hy reduction of its l. -keto gniup. This metabolite is one-tenth ns active as daunorubicin. The drug and its metabolite are eliminated hy hepatobiliary excretion. 

Like benzo[r ]pyrene, benz[a]anthracene may cross the gastrointestinal lining, pulmonary endothelium, or percutaneous barriers. Benz[a]anthracene is biotransformed to five dihydrodiols and a number of phenolic metabolites by P450 mixed-function oxidases. Detectable levels of benz[a]anthracene can be observed in most internal organs from minutes to hours after administration. Regardless of route of administration, once metabolized, hepatobiliary excretion and elimination through feces is the major route. 

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. 

The most successful therapy for cholestasis of pregnancy has been ursodeoxycholic acid (Figure 33-1). Ursodeoxycholic acid is a naturally occurring bile acid, which, when administered, relieves both pruritus and liver function abnormalities. Experimental evidence suggests that it protects hepa-tocytes and cholangiocytes from bile acid-induced cytotoxicity and improves hepatobiliary excretion. Additionally, it decreases bile salt transfer to the fetus and improves the secretory function of placental trophoblast cells. Ursodeoxycholic acid is recycled through the enterohepatic circulation. 

The gastrointestinal toxicity observed in patients receiving pre-targeted RIT was speculated to be due to cross-reactivity of the NR-LU-10 mAb with normal bowel, and not because of hepatobiliary excretion of °Y-DOTA-biotin. Cross-reactivity of NR-LU-10 with renal tubules was similarly thought to explain the increase in serum creatinine in two patients. The authors of the study concluded that pre-targeted RIT of malignancies in patients was feasible, but that the NR-LU-10 mAh was not an appropriate pre-targeting vehicle, due to its unfavorable normal tissue cross-reactivity. 

Shattuck LA, Eshima D, Taylor AT, Anderson TL, Graham DL, Latino FA, Payne SE (1994) Evaluation of the hepatobiliary excretion of technetium-99m-MAG3 and reconstitution factors affecting radiochemical purity. J Nucl Med 35 349-355... 

Hepatic extraction efficiency decreases with increasing serum bilirubin levels. With impaired hepatocyte function, high plasma concentrations (>8 mg/100 ml) may inhibit uptake of Tc-IDA complexes. As hepatobiliary excretion decreases, renal accumulation of certain " Tc-IDA complexes is observed (Fink-Bennett 1995). 

Pharmacokinetic Primer 5 Characterization of Hepatobiliary Excretion—Cont d... 

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