Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver

Vavricka, Stephan R.; Montfoort, Jessica van; Ha, Huy Riêm; Meier, Peter J.; Fattinger, Karin

doi:10.1053/jhep.2002.34133

Cited by 336 publications

(268 citation statements)

References 29 publications

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“…Previous in vitro studies have shown that rifampicin is an inhibitor of Oatp1a4, Oatp1b2, OATP1B1, and OATP1B3 (44)(45)(46). Rifampicin, an antibiotic mainly used in the treatment of tuberculosis, has been shown to reduce the elimination of BSP and to increase serum-conjugated bilirubin and UCB levels (30,47).…”

Section: Figurementioning

confidence: 99%

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Steeg

Wagenaar²,

Kruijssen³

et al. 2010

J. Clin. Invest.

198

196

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Organic anion transporting polypeptides (OATPs) are uptake transporters for a broad range of endogenous compounds and xenobiotics. To investigate the physiologic and pharmacologic roles of OATPs of the 1A and 1B subfamilies, we generated mice lacking all established and predicted mouse Oatp1a/1b transporters (referred to as Slco1a/1b -/-mice, as SLCO genes encode OATPs). Slco1a/1b -/-mice were viable and fertile but exhibited markedly increased plasma levels of bilirubin conjugated to glucuronide and increased plasma levels of unconjugated bile acids. The unexpected conjugated hyperbilirubinemia indicates that Oatp1a/ 1b transporters normally mediate extensive hepatic reuptake of glucuronidated bilirubin. We therefore hypothesized that substantial sinusoidal secretion and subsequent Oatp1a/1b-mediated reuptake of glucuronidated compounds can occur in hepatocytes under physiologic conditions. This alters our perspective on normal liver functioning. Slco1a/1b -/-mice also showed drastically decreased hepatic uptake and consequently increased systemic exposure following i.v. or oral administration of the OATP substrate drugs methotrexate and fexofenadine. Importantly, intestinal absorption of oral methotrexate or fexofenadine was not affected in Slco1a/1b -/-mice. Further analysis showed that rifampicin was an effective and specific Oatp1a/1b inhibitor in controlling methotrexate pharmacokinetics. These data indicate that Oatp1a/1b transporters play an essential role in hepatic reuptake of conjugated bilirubin and uptake of unconjugated bile acids and drugs. Slco1a/1b -/-mice will provide excellent tools to study further the role of Oatp1a/1b transporters in physiology and drug disposition.

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Section: Figurementioning

confidence: 99%

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Steeg

Wagenaar²,

Kruijssen³

et al. 2010

J. Clin. Invest.

198

196

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“…For example, uptake of ICG is inhibited by rifamycin (Paumgartner, 1975), which is a potent liver OATP inhibitor (Fattinger et al, 2000;Vavricka et al, 2002). In contrast, coadministration of erythromycin and gadoxetic acid was recently found to have no effect on liver imaging (Huppertz et al, 2011).…”

Section: Interaction Of Drugs With Transport Systemsmentioning

confidence: 99%

“…In both scores, plasma bilirubin is a parameter that monitors, among others, transport capacity of hepatocytes and biotransformation, i.e., the detoxifying capacity of the liver. Hepatocyte-mediated detoxification involves four phases: phase 0 represents the uptake of substances into hepatocytes, phase I metabolism of substances, phase II, conjugation and phase III export of substances and/or metabolites from hepatocytes (Petzinger and Geyer, 2006;Vavricka et al, 2002). Hence, transport proteins are key molecular components of the hepatocellular detoxification system (phase 0 and phase III) and consequently of liver function tests.…”

Section: Introductionmentioning

confidence: 99%

The emerging role of transport systems in liver function tests

Stieger

Heger

Graaf

et al. 2012

European Journal of Pharmacology

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Liver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients' liver function over the course of their disease with liver function tests are needed to firmly establish and validate recently introduced and novel liver function markers. The emerging role of transport systems in liver function tests Bruno Stieger is supported by grant # 31003A_124652 from the Swiss National Science foundation. AbstractLiver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified, that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients liver function over the course of their disease with liver function testes are needed to firmly establish and validate recently introduced and novel liver function markers.

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“…Many drugs that are potent OATP inhibitors in vitro [e.g., cyclosporine (Letschert et al, 2006) and ritonavir (Annaert et al, 2010)] may cause clinically significant DDIs in vivo; for example, significant increases in the systemic exposure of statins have been reported when these OATP inhibitors are coadministered with statins, which are OATP substrates (Shitara et al, 2003;Kiser et al, 2008). OATP1B3 shares a variety of common substrates with OATP1B1, such as statins (Hirano et al, 2004;Kitamura et al, 2008), rifampicin (Vavricka et al, 2002), and bromosulfophthalein (BSP) (Cui et al, 2001). However, some OATP1B3-specific substrates have been identified, including the octapeptide cholecystokinin 8 (CCK-8) Kullak-Ublick et al, 2001;Hirano et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

et al. 2014

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The organic anion-transporting polypeptide (OATP) 1B3 is a membrane transport protein that mediates hepatic uptake of many drugs and endogenous compounds. Currently, determination of OATP-mediated drug-drug interactions in vitro is focused primarily on direct substrate inhibition. Indirect inhibition of OATP1B3 activity is under-appreciated. OATP1B3 has putative protein kinase C (PKC) phosphorylation sites. Studies were designed to determine the effect of PKC activation on OATP1B3-mediated transport in human hepatocytes using cholecystokinin-8 (CCK-8), a specific OATP1B3 substrate, as the probe. A PKC activator, phorbol-12-myristate-13-acetate (PMA), did not directly inhibit [ 3 H]CCK-8 accumulation in human sandwich-cultured hepatocytes (SCH). However, pretreatment with PMA for as little as 10 minutes rapidly decreased [ 3 H]CCK-8 accumulation. Treatment with a PKC inhibitor bisindolylmaleimide (BIM) I prior to PMA treatment blocked the inhibitory effect of PMA, indicating PKC activation is essential for downregulating OATP1B3 activity. PMA pretreatment did not affect OATP1B3 mRNA or total protein levels. To determine the mechanism(s) underlying the indirect inhibition of OATP1B3 activity upon PKC activation, adenoviral vectors expressing FLAG-Myc-tagged OATP1B3 (Ad-OATP1B3) were transduced into human hepatocytes; surface expression and phosphorylation of OATP1B3 were determined by biotinylation and by an anti-phosphor-Ser/Thr/Tyr antibody, respectively. PMA pretreatment markedly increased OATP1B3 phosphorylation without affecting surface or total OATP1B3 protein levels. In conclusion, PKC activation rapidly decreases OATP1B3 transport activity by posttranslational regulation of OATP1B3. These studies elucidate a novel indirect inhibitory mechanism affecting hepatic uptake mediated by OATP1B3, and provide new insights into predicting OATP-mediated drug interactions between OATP substrates and kinase modulator drugs/endogenous compounds.

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Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver

Cited by 336 publications

References 29 publications

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

The emerging role of transport systems in liver function tests

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

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