Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the Hepatic Uptake of Pitavastatin in Humans

Hirano, Masashi; Maeda, Kazuya; Shitara, Yoshihisa; Sugiyama, Yuichi

doi:10.1124/jpet.104.068056

Cited by 416 publications

(427 citation statements)

References 26 publications

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“…Therefore, in the current studies, regulation of OATP1B3 transport function by PKC activation was studied in primary human hepatocytes using CCK-8 as a probe substrate Kullak-Ublick et al, 2001;Hirano et al, 2004). We confirm in the current studies that [ 3 H]CCK-8 is transported by OATP1B3 but not by OATP1B1 and OATP2B1 in transporter-overexpressing HEK-293 cells (Supplemental Fig.…”

Section: Discussionsupporting

confidence: 64%

“…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%

“…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%

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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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Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…It shows active uptake into hepatocytes, mediated mainly by Organic Anion Transporting Polypeptide (OATP) 1B1 [1,2]. It is desired to investigate the nonlinear kinetics of in vitro hepatic uptake of the OATP substrate, Pitavastatin, and quantify the mechanisms present both structurally and numerically.…”

Section: Introductionmentioning

confidence: 99%

Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake

Grandjean¹,

Chappell²,

Yates³

et al. 2014

Computer Methods and Programs in Biomedicine

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a b s t r a c tIn this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available.

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“…OATP1B1 and OATP1B3 are the predominant OATP isoforms expressed in the liver, and they are involved in the uptake of multiple endogenous and exogenous compounds, including bilirubin [5] , bosentan [6,7] , and statins [8][9][10] . Additionally, OATP2B1-mediated selective scutellarin uptake plays a key role in the much lower exposure of scutellarin than that of isoscutellarin in humans [11] .…”

Section: Introductionmentioning

confidence: 99%

Potential role of organic anion transporting polypeptide 1B1 (OATP1B1) in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers

Guo

Wang

et al. 2014

Acta Pharmacol Sin

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Aim: Hematoporphyrin monomethyl ether (HMME), which consists of equal amounts of isomers HMME-1 and HMME-2, is a novel porphyrin-related drug for photodynamic therapy. This study was aimed to investigate the uptake transporter-mediated selective uptake of HMME into the liver and to identify the major uptake transporter isoforms involved. Methods: Adult SD rats were intravenously injected with a single dose of HMME (5 mg/kg) with or without rifampicin (an inhibitor of organic anion transporting polypeptides OATP1B1 and OATP1B3, 25 mg/kg). Blood samples were collected, and HMME concentrations were measured using LC-MS/MS. Rat hepatocytes, human hepatocytes and HEK293 cells expressing OATP1B1, OATP1B3, or OATP2B1 were used to investigate the uptake of HMME or individual isomers in vitro. Results: Co-administration of rifampicin significantly increased the exposure of HMME isomers, and decreased the AUC ratio of HMME-1 to HMME-2 from 1.98 to 1.56. The uptake of HMME-2 into human hepatocytes and the HEK293 cells expressing OATP1B1 or OATP2B1 in vitro was 2-7 times greater than that of HMME-1, whereas OATP1B3 mediated a higher HMME-1 uptake. OATP1B1 exhibited a higher affinity for HMME-2 than for HMME-1 (the K m values were 0.63 and 5.61 μmol/L, respectively), which were similar to those in human hepatocytes. By using telmisartan (a non-specific OATP inhibitor) and rifampicin, OATP2B1 was demonstrated to account for <20% of hepatic HMME uptake. Conclusion: OATP1B1 is the major transporter involved in the rapid hepatic uptake of HMME, and the greater uptake of HMME-2 by OATP1B1 may lead to a lower exposure of HMME-2 than HMME-1 in humans.

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Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the Hepatic Uptake of Pitavastatin in Humans

Cited by 416 publications

References 26 publications

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

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

Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake

Potential role of organic anion transporting polypeptide 1B1 (OATP1B1) in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers

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