Hepatocellular transport of cyclosomatostatins: evidence for a carrier system related to the multispecific bile acid transporter

Ziegler, K.; Lins, W.; Frimmer, M.

doi:10.1016/0005-2736(91)90294-i

Cited by 36 publications

(17 citation statements)

References 21 publications

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“…Somatostatin is a stimulant of multiple tyrosine and serine/threonine phosphatases [34,35,36]. Ziegler [37,38] demonstrated that certain cyclic analogs of somatostatin, as octreotide, are rapidly taken up by the rat liver and subsequently excreted intact in the bile. The ATP-dependent uptake of [ 14 C]octreotide by canalicular membrane vesicles was inhibited by verapamil in a concentration-dependent manner [39].…”

Section: Discussionmentioning

confidence: 99%

Effect of P-Glycoprotein Modulators on Alkaline Phosphatase Activity in Cultured Rat Hepatocytes

Calhau¹,

Martel²,

Hipólito-Reis³

et al. 2000

Cell Physiol Biochem

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Alkaline phosphatases (orthophosphoric-monoester phosphohydrolase, E.C. 3.1.3.1) are a group of nonspecific phosphomonoesterases located primarily in the plasma membrane of the cells in which they occur [1].It was recently demonstrated that alkaline phosphatase (ALP) concentration in different tissues is positively correlated with the extent of exchange surface per unit volume of the tissue, suggesting an association between ALP and transport systems [2]. Moreover, several groups [3,4,5] obtained evidence of an involvement of ALP in the modulation of P-glycoprotein activity in hepatocytes. The aim of the present study was to determine the putative influence of compounds known to modulate P-glycoprotein-mediated transport on hepatic ALP activity, by using primary cultured rat hepatocytes.The K_m and V_max values of ALP were determined (657.2 μM (306.8-933.1) and 32.0±1.5 nmol mg protein^–1 min^–1, respectively). Vanadate and corticosterone concentration-dependently reduced ALP activity, producing maximal reductions of 79% (100 μM) and 71% (100 μM), respectively. The IC50’s were found to be 7.9 μM (2.1-29.5 μM) and 2.4 μM (0.2-35.2 μM), respectively. Cyclosporin A, verapamil, octreotide, kaempferol, daunomycin and genistein produced a concentration-dependent increase in ALP activity. ALP activity was maximally increased to 253%, 390%, 180%, 487%, 449% and 193% of control in the presence of 100 μM cyclosporin A, 50 μM verapamil, 10 μM octreotide, 100 μM kaempferol, 100 μM daunomycin and 1 μM genistein, respectively.The results show that all P-glycoprotein modulators tested were able to significantly affect the activity of hepatic-ALP. These effects on ALP activity may contribute to the modulation of P-glycoprotein activity by these drugs.

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Section: Discussionmentioning

confidence: 99%

Effect of P-Glycoprotein Modulators on Alkaline Phosphatase Activity in Cultured Rat Hepatocytes

Calhau¹,

Martel²,

Hipólito-Reis³

et al. 2000

Cell Physiol Biochem

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“…For example, in rats, influx of bilirubin and BSP falls by approximately 50% within 6 h of liver regeneration resulting from two-thirds partial hepatectomy, returning to normal by 4 days (41, 135), and correlating with changes in oatp1a1 mRNA and protein levels (220). Transport is also modulated during development as seen by BSP uptake that is 70% lower in hepatocytes prepared from 3-week-old rats as compared to adults (2).…”

Section: Cellular Physiology Of Transporter Functionmentioning

confidence: 99%

Organic Anion Uptake by Hepatocytes

Wolkoff

2014

Comprehensive Physiology

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Many of the compounds taken up by the liver are organic anions that circulate tightly bound to protein carriers such as albumin. The fenestrated sinusoidal endothelium of the liver permits these compounds to have access to hepatocytes. Studies to characterize hepatic uptake of organic anions through kinetic analyses, suggested that it was carrier-mediated. Attempts to identify specific transporters by biochemical approaches were largely unsuccessful and were replaced by studies that utilized expression cloning. These studies led to identification of the organic anion transport proteins (oatps), a family of 12 transmembrane domain glycoproteins that have broad and often overlapping substrate specificities. The oatps mediate Na+-independent organic anion uptake. Other studies identified a seven transmembrane domain glycoprotein, Na+/taurocholate transporting protein (ntcp) as mediating Na+-dependent uptake of bile acids as well as other organic anions. Although mutations or deficiencies of specific members of the oatp family have been associated with transport abnormalities, there have been no such reports for ntcp, and its physiologic role remains to be determined, although expression of ntcp in vitro recapitulates the characteristics of Na+-dependent bile acid transport that is seen in vivo. Both ntcp and oatps traffic between the cell surface and intracellular vesicular pools. These vesicles move through the cell on microtubules, using the microtubule based motors dynein and kinesins. Factors that regulate this motility are under study and may provide a unique mechanism that can alter the plasma membrane content of these transporters and consequently their accessibility to circulating ligands.

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“…These results supported our proposition that the limit in the distribution process at the high dose was the factor responsible for the nonlinear pharmacokinetics of TAK-044. It has been already suggested that various kinds of small peptides are transported into liver cells by carrier-mediated active transport systems [11,13,14,[17][18][19][20][21][22]. Therefore, we also considered that a specific carrier-mediated system was associated with the distribution of TAK-044 from plasma to liver.…”

Section: Discussionmentioning

confidence: 95%

Nonlinear pharmacokinetics of TAK‐044, a new endothelin antagonist, in rats

Takeuchi

Tagawa

Hagihara

et al. 2001

Biopharm & Drug Disp

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The mechanism of the nonlinear pharmacokinetics of TAK-044 in rats was shown from in vivo and in vitro studies to be due to capacity-limited hepatic uptake. In the rats, which were given intravenous injections of (14)C-labeled TAK-044 ([(14)C]TAK-044) (1, 3, 10, 30 and 100 mg/kg), the AUC(inf) per unit dose of unchanged compound increased remarkably. An analysis model indicated that the CL(tot), V(1) and k(12) values of TAK-044 decreased significantly with increasing dose, whereas the k(el) values remained constant over the doses examined. The uptake clearance of [(14)C]TAK-044 by several tissues was investigated by an integration plot at doses from 0.3 to 60 mg/kg. This study showed that the liver played the principal role in the removal of TAK-044 from the plasma, while hepatic uptake was capacity-limited at doses greater than 30 mg/kg. The hepatic uptake study using rat hepatocytes indicated that a carrier-mediated transport system contributed to the hepatic uptake of TAK-044, and this system had high affinity (K(m,in vitro); 8.4 micromol/L) with low capacity (V(max,in vitro); 86.3 pmol/mg protein/min). These results show that the saturation of hepatic uptake by the carrier-mediated transport system could explain the nonlinear pharmacokinetics of TAK-044 in rats.

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Hepatocellular transport of cyclosomatostatins: evidence for a carrier system related to the multispecific bile acid transporter

Cited by 36 publications

References 21 publications

Effect of P-Glycoprotein Modulators on Alkaline Phosphatase Activity in Cultured Rat Hepatocytes

Effect of P-Glycoprotein Modulators on Alkaline Phosphatase Activity in Cultured Rat Hepatocytes

Organic Anion Uptake by Hepatocytes

Nonlinear pharmacokinetics of TAK‐044, a new endothelin antagonist, in rats

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