Targeted Disruption of Murine Organic Anion-Transporting Polypeptide 1b2 (oatp1b2/<i>Slco1b2</i>) Significantly Alters Disposition of Prototypical Drug Substrates Pravastatin and Rifampin

Zaher, Hani; Schwabedissen, Henriette E. Meyer zu; Tirona, Rommel G.; Cox, Melissa L.; Obert, Leslie; Agrawal, Nidhi; Palandra, Joe; Stock, Jeffrey L.; Kim, Richard B.; Ware, Joseph A.

doi:10.1124/mol.108.046458

Cited by 106 publications

(125 citation statements)

References 24 publications

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“…While the cause of the conjugated bilirubin elevation has not been determined, the increase in unconjugated bilirubin supports a role of Oatps in hepatocellular uptake of bilirubin. Mild elevation of mainly conjugated bilirubin is also observed in mice with inactivated Slco1b2 (Zaher et al, 2008), which was recently confirmed (Csanaky et al, 2011). Taken together, these human and animal data strongly support a physiological involvement of hepatocellular OATPs in the hepatic uptake of unconjugated and conjugated bilirubin.…”

Section: Bilirubinsupporting

confidence: 64%

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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Section: Bilirubinsupporting

confidence: 64%

The emerging role of transport systems in liver function tests

Stieger

Heger

Graaf

et al. 2012

European Journal of Pharmacology

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“…Although Slco1b2 -/-mice have already shown the impact of hepatic Oatp1b2 on liver uptake of some toxins, statins, and antibiotics (2,9,10), in this study we demonstrated that Oatp1a/1b effects an even more profound impact on drug pharmacokinetics by mediating (for some drugs, virtually all) hepatic uptake of drugs. This might have sweeping consequences for drug pharmacokinetics in patients, since many SNPs have been identified in the SLCO1B1, SLCO1B3, and SLCO1A2 genes, some of which are responsible for markedly reduced transport capacities (reviewed in ref.…”

Section: Figurementioning

confidence: 70%

“…For example, single Slco1b2 -/-mice have been generated and used to study the role of Oatp1b2 in plasma and liver distribution of toxins (phalloidin, microcystin-LR), statins (cerivastatin, lovastatin acid, pravastatin, and simvastatin acid) and antibiotics (rifampicin and rifamycin SV) (2,9,10). Furthermore, our group recently generated and characterized OATP1B1 transgenic mice, in which OATP1B1-mediated hepatic uptake of methotrexate (MTX) was demonstrated in vivo (11).…”

Section: Introductionmentioning

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.

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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“…The detailed information regarding the generation of Oatp1b2 KO mice was described recently (Zaher et al, 2008). Briefly, a targeting vector to disrupt the Oatp1b2 murine gene was constructed using 4.1 kilobase (kb) of 5Ј homology and 5.0 kb of 3Ј homology.…”

Section: Materials Cerivastatin Was Purchased From Sequoia Research mentioning

confidence: 99%

Utility of a Novel Oatp1b2 Knockout Mouse Model for Evaluating the Role of Oatp1b2 in the Hepatic Uptake of Model Compounds

Chen¹,

Stock²,

Liu³

et al. 2008

Drug Metab Dispos

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ABSTRACT:We generated the organic anion transporting polypeptide (Oatp) 1b2 knockout (KO) mouse model and assessed its utility to study hepatic uptake using model compounds: cerivastatin, lovastatin acid, pravastatin, simvastatin acid, rifampicin, and rifamycin SV. A selective panel of liver cytochromes P450 (P450s) (Cyp3a11, Cyp3a13, Cyp3a16, Cyp2c29, and Cyp2c39) and transporters [Oatp1b2, Oatp1a1, Oatp1a4, Oatp1a5; organic anion transporter (Oat) 1, Oat2, Oat3; multidrug resistance gene 1 (Mdr1) a, Mdr1b; bile salt export pump, multidrug resistance associated protein (Mrp) 2, Mrp3; breast cancer resistance protein] were measured by reverse transcription-polymerase chain reaction in both KO and wild-type (WT) male mice. Male KO and WT mice received each model compound s.c. at 3 mg/kg. Blood and liver samples were obtained at 0, 0.5, and 2 h postdose and analyzed using liquid chromatography/tandem mass spectrometry. Liver/plasma concentration ratio (K p,liver ) was calculated. Student's t test was used to compare the mRNA and K p,liver between the KO and WT mice. A similar mRNA expression was observed between the KO and WT for the selected P450s and transporters except for Oatp1b2, for which the level was negligible in the KO but prominent in the WT mice with P < 0.0001. The in vivo results showed a differential effect of Oatp1b2 on hepatic uptake of the model compounds, indicating that Oatp1b2 plays a more significant role in the hepatobiliary disposition of rifampicin and lovastatin than the other compounds tested. This study suggests the Oatp1b2 mouse as a useful in vivo tool to understand drug targeting and disposition in the liver.

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Targeted Disruption of Murine Organic Anion-Transporting Polypeptide 1b2 (oatp1b2/Slco1b2) Significantly Alters Disposition of Prototypical Drug Substrates Pravastatin and Rifampin

Cited by 106 publications

References 24 publications

The emerging role of transport systems in liver function tests

The emerging role of transport systems in liver function tests

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

Utility of a Novel Oatp1b2 Knockout Mouse Model for Evaluating the Role of Oatp1b2 in the Hepatic Uptake of Model Compounds

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