Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport

Petzinger, Ernst

doi:10.1007/bfb0030903

Cited by 60 publications

(30 citation statements)

References 825 publications

(795 reference statements)

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“…Although it was suggested very early (Sperber 1959), it was later shown that drug excretion and absorption is strongly dominated by membrane carrier proteins, i.e. in liver (Petzinger et al 1989;Petzinger 1994), kidney (Greger et al 1981) and gut (Gilles-Baillieu and Gilles 1983). As with the detoxification enzymes of phase I and phase II, these carriers are subject to postnatal development in neonates (Gao et al 2004), and regulation and induction by diseases may occur (Trauner and Boyer 2003;Kullak-Ublick et al 2004).…”

Section: Functional Indications Of Drug Transportersmentioning

confidence: 99%

“…Later it was recognized that this protein was a glutathione-S-transferase (Habig et al 1974). Other travelling proteins considered were cytosolic fatty acid-binding proteins (cFABPs), ileal lipid-binding proteins (ILBP) and bile acid-binding proteins (for a review see Petzinger 1994;. They comprise intracellular steps of the enterohepatic circulation of bile acids and drugs.…”

Section: An Extended Phase Conceptmentioning

confidence: 99%

See 1 more Smart Citation

Drug transporters in pharmacokinetics

Petzinger¹,

Geyer²

2006

Naunyn Schmied Arch Pharmacol

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This review deals with the drug transporters allowing drugs to enter and leave cells by carrier-mediated pathways. Emphasis is put on liver transporters but systems in gut, kidney, and blood-brain barrier are mentioned as well. Drug-drug interactions on carriers may provoke significant modification in pharmacokinetics as do carrier gene polymorphisms yielding functional carrier protein mutations. An integrated phase concept should reflect the interplay between drug metabolism and drug transport.

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Section: Functional Indications Of Drug Transportersmentioning

confidence: 99%

Section: An Extended Phase Conceptmentioning

confidence: 99%

Drug transporters in pharmacokinetics

Petzinger¹,

Geyer²

2006

Naunyn Schmied Arch Pharmacol

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“…Sodium-independent bile salt uptake has been estimated to contribute only about 10% to 20% of total uptake. 27 Therefore, one might question if inhibition of sodium-independent uptake is sufficient to explain the previously reported substantial increase in serum bile acids. However, hepatic first-pass elimination of bile salts is very efficient, and thus under physiologic conditions, only 10% to 20% of bile acids present in portal blood reaches the systemic circulation.…”

Section: Fig 1 Inhibition Of Oatp1 Andmentioning

confidence: 99%

“…1 According to the K i estimates, the affinity of rifampicin to Oatp2 is even stronger than that of rifamycin SV. Because rifamycin SV is an anionic compound, whereas rifampicin in solution behaves as a zwitterion, 27 their differential affinity for Oatp1 and Oatp2 further supports the concept that Oatp1 mainly transports organic anions, whereas Oatp2 is less charge-selective and thus additionally exhibits high-affinity transport for some neutral (e.g., digoxin) or even cationic compounds (e.g., rocuronium and N-(4,4-azo-n-pentyl)-21-deoxyajmalinium). 29 Similarly, as reported above for negatively charged Oatp2-substrates, 10 µmol/L rifamycin SV did not inhibit Oatp2-mediated transport of the neutral substrate, digoxin (102% of control), whereas 10 µmol/L rifampicin reduced Oatp2-mediated digoxin transport to 15% of control (data not shown).…”

Section: Fig 1 Inhibition Of Oatp1 Andmentioning

confidence: 99%

Rifamycin SV and rifampicin exhibit differential inhibition of the hepatic rat organic anion transporting polypeptides, Oatp1 and Oatp2

et al. 2000

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The antibiotics, rifamycin SV and rifampicin, are known to interfere with hepatic bile salt and organic anion uptake. The aim of this study was to explore which transport systems are affected. In short-term-cultured rat hepatocytes, low concentrations (10 mol/L) of both compounds inhibited mainly sodium-independent taurocholate uptake, whereas higher concentrations (100 mol/L) also inhibited sodium-dependent taurocholate uptake. In Xenopus laevis oocytes expressing the Na ؉ /taurocholate cotransporting polypeptide (Ntcp), high rifamycin SV and rifampicin concentrations were required for inhibition of taurocholate uptake. In contrast, sodiumindependent taurocholate uptake mediated by the organic anion transporting polypeptides, Oatp1 and Oatp2, was already substantially inhibited by 10 mol/L rifamycin SV. Rifampicin potently inhibited Oatp2-mediated taurocholate uptake, but did not interfere with Oatp1-mediated taurocholate uptake. Similar effects of rifamycin SV and rifampicin were found for Oatp1-and Oatp2-mediated estradiol-17␤-glucuronide transport. Dixon plot analysis yielded a pattern compatible with competitive inhibition of estradiol-17␤-glucuronide transport with K i estimates of 6.6 mol/L and 7.3 mol/L for rifamycin SV-induced inhibition of Oatp1 and Oatp2, respectively, and of 1.4 mol/L for rifampicin-induced inhibition of Oatp2. These results demonstrate that rifamycin SV and rifampicin exhibit differential inhibition on Oatp1 and Oatp2, and identify rifampicin as a selective Oatp2 inhibitor. The data indicate that these inhibitors can be used to determine the in vivo relevance of Oatp1 and Oatp2 for the overall bioavailability and disposition of drugs and other Oatp1/2 substrates. (HEPATOLOGY 2000;32:82-86.)The antibiotics, rifamycin SV and rifampicin, are mainly eliminated by hepatic uptake, metabolism, and excretion into bile. 1,2 For rifamycin SV, hepatic first-pass elimination is so efficient that oral administration is unfeasible. 3 Rifamycin SV interferes with the hepatic elimination of many compounds including bilirubin, bromosulfophtalein, and indocyanine green. 4,5 Rifampicin has been shown to increase serum bile salt concentrations in 72% of patients 6 after the first dose, suggesting acute inhibition of hepatocellular bile salt uptake. 7 In isolated rat hepatocytes, rifamycin SV and rifampicin inhibited cholate uptake, with K i values of 30 and 46 µmol/L in the absence and of 18 and 31 µmol/L in the presence of bovine serum albumin (3%). 8 The corresponding K i values for taurocholate were 60 and 122 µmol/L in the absence and 128 and 237 µmol/L in the presence of bovine serum albumin. 8 The values reported for cholate are close to the serum concentrations of 5 to 10 µmol/L measured after administration of therapeutic doses of rifamycin SV or rifampicin in humans. 1,9 Recently, several carrier proteins involved in the hepatic uptake of bile salts and other albumin-bound organic anions have been cloned from rat liver. 10 The Na ϩ /taurocholate cotransporting polypeptide, Ntcp, mediates sodiu...

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“…Current extensive molecular studies have identified several families of multispecific organic anion transporters that are involved in the elimination of various organic anions (Moller and Sheikh, 1983;Boyer et al, 1992;Pritchard and Miller, 1993;Ullrich and Rumrich, 1993;Petzinger, 1994;Meier, 1995;Muller and Jansen, 1997;Ullrich, 1997). In the liver and kidney, water-soluble metabolites and organic anions are actively eliminated from the body via transporters across their basolateral and/or luminal membranes (Moller and Sheikh, 1983;Boyer et al, 1992;Pritchard and Miller, 1993;Ullrich and Rumrich, 1993;Petzinger, 1994;Meier, 1995;Bossuyt et al, 1996;Muller and Jansen, 1997;Ullrich, 1997). The proximal tubular cells of the kidney take up organic anions from the blood stream via multispecific organic anion transport pathway(s) in the basolateral membranes (Moller and Sheikh, 1983;Ullrich and Rumrich, 1993;Pritchard and Miller, 1993;Ullrich, 1997).…”

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confidence: 99%

Isolation, Characterization and Differential Gene Expression of Multispecific Organic Anion Transporter 2 in Mice

et al. 2002

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We isolated cDNA encoding a multispecific organic anion transporter 2 (OAT2) from the mouse kidney cDNA library. Isolated mouse OAT2 (mOAT2) consisted of 1623 base pairs that encoded a 540-amino acid residue protein with 12 putative membrane-spanning domains, and the amino acid sequence was 87% identical to that of rat OAT2 (rOAT2). The gene coding for mOAT2, Slc22a7, is found on chromosome 17C. Northern blot analysis revealed that the mOAT2 mRNA is abundantly expressed in the male mouse kidney, whereas it was predominantly expressed in both the liver and kidney of female mice. When expressed in Xenopus laevis oocytes, mOAT2 mediated the high affinity transport of glutarate (K m ϭ 15.8 Ϯ 3.2 M) and prostaglandin E 2 (K m ϭ 5.2 Ϯ 0.5 nM) in a sodium-independent manner. mOAT2-expressing oocytes also mediated the uptake of ␣-ketoglutarate, glutarate, prostaglandin E 2 , p-aminohippuric acid, methotrexate, ochratoxin A, valproate, and allopurinol. However, we did not observe mOAT2-mediated uptake of salicylate. A wide range of structurally unrelated organic anions inhibited mOAT2-mediated glutarate uptake especially erythromycin, a potent inhibitor. These results indicate that isolated mOAT2 is a multispecific organic anion transporter having some differences in substrate specificity compared with rOAT2. In addition, we found that there exists a sex-and speciesrelated differential gene expression of the OAT2 isoform.Organic anion transporters play central roles in the elimination of a wide range of endogenous and exogenous anionic compounds including drugs, environmental toxicants, and their metabolites. Current extensive molecular studies have identified several families of multispecific organic anion transporters that are involved in the elimination of various organic anions (Moller and Sheikh, 1983;Boyer et al

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Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport

Cited by 60 publications

References 825 publications

Drug transporters in pharmacokinetics

Drug transporters in pharmacokinetics

Rifamycin SV and rifampicin exhibit differential inhibition of the hepatic rat organic anion transporting polypeptides, Oatp1 and Oatp2

Isolation, Characterization and Differential Gene Expression of Multispecific Organic Anion Transporter 2 in Mice

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