Transporter Database, TP-Search: A Web-Accessible Comprehensive Database for Research in Pharmacokinetics of Drugs

Ozawa, Naok̆i; Shimizu, Takako; Morita, Rika; Yokono, Yoshiya; Ochiai, Takumi; Munesada, K.; Ohashi, Akiyoshi; Aida, Yoshitaka; Hama, Yoshimasa; Taki, Katsuhiko; Maeda, Kazuya; Kusuhara, Hiroyuki; Sugiyama, Yuichi

doi:10.1023/b:pham.0000048207.11160.d0

Cited by 49 publications

(40 citation statements)

References 8 publications

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“…The only SLC transporter with significant expression was SLC16A1 (monocarboxylate transporter 1), which was equally expressed in both Saos-2/pcDNA3 and Saos-2/wtABCG2 cells at levels corresponding to one fifth of BCRP/ABCG2. Only one compound in the data set, quercetin, has been reported to interact with monocarboxylate transporter 1 (Ozawa et al, 2004). The results indicate that active efflux in the BCRPtransfected Saos-2 cells is not confounded by other transporters or by oxidative metabolism, and we conclude that Saos-2/wtABCG2 cells constitute a close to ideal model for studying the interplay between active efflux and passive membrane permeability in isolation from confounding factors.…”

Section: Resultsmentioning

confidence: 68%

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

Matsson

Englund²,

Ahlin³

et al. 2007

J Pharmacol Exp Ther

112

103

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In this article, we explore the entire structural space of registered drugs to obtain a global model for the inhibition of the drug efflux transporter breast cancer resistance protein (BCRP; ABCG2). For this purpose, the inhibitory effect of 123 structurally diverse drugs and drug-like compounds on mitoxantrone efflux was studied in Saos-2 cells transfected with human wild-type (Arg482) BCRP. The search for BCRP inhibitors throughout the drug-like chemical space resulted in the identification of 29 previously unknown inhibitors. The frequency of BCRP inhibition was 3 times higher for compounds reported to interact with other ATP-binding cassette (ABC) transporters than for compounds without reported ABC transporter affinity.An easily interpreted computational model capable of discriminating inhibitors from noninhibitors using only two molecular descriptors, octanol-water partition coefficient at pH 7.4 and molecular polarizability, was constructed. The discriminating power of this two-descriptor model was 93% for the training set and 79% for the test set, respectively. The results were supported by a global pharmacophore model and are in agreement with a two-step mechanism for the inhibition of BCRP, where both the drug's capacity to insert into the cell membrane and to interact with the inhibitory binding site of the transporter are important.The ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP; ABCG2) has received much attention for its role in resistance to various cytotoxic agents (Doyle et al., 1998;Krishnamurthy and Schuetz, 2006) and has recently been shown to also influence the disposition of structurally unrelated drugs from other therapeutic classes (Gupta et al., 2004;Jonker et al., 2005;Zhang et al., 2005). BCRP is expressed in many tissue barriers throughout the body, including the intestine, the blood-brain barrier, the blood-placenta barrier, and the liver canalicular membrane (Maliepaard et al., 2001;Fetsch et al., 2006). A picture is emerging that, similar to the most well studied ABC transporter, P-glycoprotein (ABCB1), BCRP interacts with a wide variety of compounds, and it is one of the major ABC transporters affecting drug disposition throughout the body. The key role of BCRP in drug disposition was recently exemplified by a 111 times higher systemic exposure to the antiinflammatory drug sulfasalazine after oral administration to Bcrp1-knockout mice compared with wild-type mice (Zaher et al., 2006). Furthermore, the human oral bioavailability of the BCRP substrate topotecan was more than doubled after coadministration with the potent inhibitor GF120918 (Elacridar) (Kruijtzer et al., 2002), highlighting the risk of significantly altered drug exposure due to inhibition of BCRP. It would therefore be of great interest to develop models that can predict drug-mediated BCRP inhibition, but so far, studies have been limited to structurally homologous series of compounds (Gupta et al., 2004), and the only published computational model was not validated with an ex...

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Section: Resultsmentioning

confidence: 68%

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

Matsson

Englund²,

Ahlin³

et al. 2007

J Pharmacol Exp Ther

112

103

View full text Add to dashboard Cite

show abstract

“…At the concentrations of 0.5-2 mM used in the experiments, elacridar inhibition of BCRP is minor, less than 20% (Matsson et al, 2009). Fexofenadine and erythromycin were used in P-gp inhibition experiments using the inhibitor elacridar, as these two compounds do not seem to interact with BCRP (Ozawa et al, 2004;Morrissey et al, 2012). Rosuvastatin and fexofenadine efflux from plated hepatocytes was measured in the presence or absence of inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Functional ATP-Binding Cassette Drug Efflux Transporters in Isolated Human and Rat Hepatocytes Significantly Affect Assessment of Drug Disposition

et al. 2014

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Freshly isolated hepatocytes are considered the gold standard for in vitro studies of hepatic drug disposition. To ensure a reliable supply of cells, cryopreserved human hepatocytes are often used. ABC-superfamily drug efflux transporters are key elements in hepatic drug disposition. These transporters are often considered lost after isolation of hepatocytes. In the present study, the expression and activity of ABC transporters BCRP, BSEP, P-gp, MRP2, MRP3, and MRP4 in human and rat cryopreserved hepatocytes were investigated. In commercially available human cryopreserved hepatocytes, all drug efflux transporters except human BCRP (hBCRP) exhibited similar expression levels as in fresh liver biopsies. Expression levels of hBCRP were 60% lower in cryopreserved human hepatocytes than in liver tissue, which could lead to, at most, a 2.5-fold reduction in hBCRP-mediated efflux. Fresh rat hepatocytes showed significantly lower levels of rat BCRP compared with liver expression levels; expression levels of other ABC transporters were unchanged. ABC transporters in human cryopreserved cells were localized to the plasma membrane. Functional studies could demonstrate P-gp and BCRP activity in both human cryopreserved and fresh rat hepatocytes. Inhibiting P-gp-mediated efflux by elacridar in in vitro experiments significantly decreased fexofenadine efflux from hepatocytes, resulting in an increase in apparent fexofenadine uptake. The results from the present study clearly indicate that ABC transporter-mediated efflux in freshly isolated as well as cryopreserved rat and human hepatocytes should be taken into account in in vitro experiments used for modeling of drug metabolism and disposition.

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“…After washing and removal of unattached cells, leaving a semiconfluent cell monolayer (.90% confluent), uptakes were performed at 1 mM substrate concentration in KHL. The activities of uptake transporters were tested with several well characterized substrates: rosuvastatin (AstraZeneca), OATPs (Ho et al, 2006); fexofenadine, OATPs (Cvetkovic et al, 1999); ipratropium, OCTs (Nakanishi et al, 2011); and taurocholate, NTCP (Ozawa et al, 2004). Rosuvastatin is also an NTCP substrate in human but not rat cells (Ho et al, 2006).…”

Section: Methodsmentioning

confidence: 99%

The Impact of Solute Carrier (SLC) Drug Uptake Transporter Loss in Human and Rat Cryopreserved Hepatocytes on Clearance Predictions

et al. 2014

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Cryopreserved hepatocytes are often used as a convenient tool in studies of hepatic drug metabolism and disposition. In this study, the expression and activity of drug transporters in human and rat fresh and cryopreserved hepatocytes was investigated. In human cryopreserved hepatocytes, Western blot analysis indicated that protein expression of the drug uptake transporters [human Na + -taurocholate cotransporting polypeptide (NTCP), human organic anion transporting polypeptides (OATPs), human organic anion transporters, and human organic cation transporters (OCTs)] was considerably reduced compared with liver tissue. In rat cryopreserved cells, the same trend was observed but to a lesser extent. Several rat transporters were reduced as a result of both isolation and cryopreservation procedures. Immunofluorescence showed that a large portion of remaining human OATP1B1 and OATP1B3 transporters were internalized in human cryopreserved hepatocytes. Measuring uptake activity using known substrates of OATPs, OCTs, and NTCP showed decreased activity in cryopreserved as compared with fresh hepatocytes in both species. The reduced uptake in cryopreserved hepatocytes limited the in vitro metabolism of several AstraZeneca compounds. A retrospective analysis of clearance predictions of AstraZeneca compounds suggested systematic lower clearance predicted using metabolic stability data from human cryopreserved hepatocytes compared with human liver microsomes. This observation is consistent with a loss of drug uptake transporters in cryopreserved hepatocytes. In contrast, the predicted metabolic clearance from fresh rat hepatocytes was consistently higher than those predicted from liver microsomes, consistent with retention of uptake transporters. The uptake transporters, which are decreased in cryopreserved hepatocytes, may be rate-limiting for the metabolism of the compounds and thus be one explanation for underpredictions of in vivo metabolic clearance from cryopreserved hepatocytes.

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Transporter Database, TP-Search: A Web-Accessible Comprehensive Database for Research in Pharmacokinetics of Drugs

Cited by 49 publications

References 8 publications

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)

Functional ATP-Binding Cassette Drug Efflux Transporters in Isolated Human and Rat Hepatocytes Significantly Affect Assessment of Drug Disposition

The Impact of Solute Carrier (SLC) Drug Uptake Transporter Loss in Human and Rat Cryopreserved Hepatocytes on Clearance Predictions

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