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In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Läkemedelsformulering)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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2012 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 2, 411-426 p.Article in journal (Other academic) Published
Abstract [en]

To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter. The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways. Sixty-five compounds were identified as OATP1B1 inhibitors at 20 mu M. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified. Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

Place, publisher, year, edition, pages
2012. Vol. 29, no 2, 411-426 p.
Keyword [en]
in silico, in vitro-in vivo extrapolation, inhibition, MRP2, OATP1B1
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics; Pharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-107573DOI: 10.1007/s11095-011-0564-9ISI: 000299506700007OAI: oai:DiVA.org:uu-107573DiVA: diva2:231774
Available from: 2009-08-17 Created: 2009-08-17 Last updated: 2017-12-13Bibliographically approved
In thesis
1. In vitro and in silico prediction of drug-drug interactions with transport proteins
Open this publication in new window or tab >>In vitro and in silico prediction of drug-drug interactions with transport proteins
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug transport across cells and cell membranes in the human body is crucial for the pharmacological effect of drugs. Active transport governed by transport proteins plays an important role in this process. A vast number of transport proteins with a wide tissue distribution have been identified during the last 15 years. Several important examples of their role in drug disposition and drug-drug interactions have been described to date. Investigation of drug-drug interactions at the transport protein level are therefore of increasing interest to the academic, industrial and regulatory research communities.

The gene expression of transport proteins involved in drug transport was investigated in the jejunum, liver, kidney and colon to better understand their influence on the ADMET properties of drugs. In addition, the gene and protein expression of transport proteins in cell lines, widely used for predictions of drug transport and metabolism, was examined.

The substrate and inhibitor heterogeneity of many transport proteins makes it difficult to foresee whether the transport proteins will cause drug-drug interactions. Therefore, in vitro assays for OCT1 and OATP1B1, among the highest expressed transport proteins in human liver, were developed to allow investigation of the inhibitory patterns of these proteins. These assays were used to investigate two data sets, consisting of 191 and 135 registered drugs and drug-like molecules for the inhibition of OCT1 and OATP1B1, respectively. Numerous new inhibitors of the transport proteins were identified in the data sets and the properties governing inhibition were determined. Further, antidepressant drugs and statins displayed strong inhibition of OCT1 and OATP1B1, respectively. The inhibition data was used to develop predictive in silico models for each of the two transport proteins.

The highly polymorphic nature of some transport proteins has been shown to affect drug response and may lead to an increased risk of drug-drug interactions, and therefore, the OCT1 in vitro assay was used to study the effect of common genetic variants of OCT1 on drug inhibition and drug-drug interactions. The results indicated that OCT1 variants with reduced function were more susceptible to inhibition. Further, a drug-drug interaction of potential clinical significance in the genetic OCT1 variant M420del was proposed.

In summary, gene expression of transport proteins was investigated in human tissues and cell lines. In vitro assays for two of the highest expressed liver transport proteins were used to identify previously unknown SLC transport protein inhibitors and to develop predictive in silico models, which may detect previously known drug-drug interactions and enable new ones to be identified at the transport protein level. In addition, the effect of genetic variation on inhibition of the OCT1 was investigated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 104
Keyword
Solute carrier, SLC transporter, OCT1, Organic cation transporter 1, SLC22A1, OATP1B1, SLCO1B1, Organic anion transporting peptide 1B1, Drug transport, Active transport, Genetic polymorphism, Cell lines, Gene expression, Multivariate data analysis, OPLS
National Category
Pharmaceutical Sciences Pharmaceutical Sciences
Research subject
Pharmaceutics; Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-107492 (URN)978-91-554-7589-5 (ISBN)
Public defence
2009-10-02, B21, Biomedical Center, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Supervisors
Available from: 2009-09-10 Created: 2009-08-13 Last updated: 2009-09-16Bibliographically approved

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Karlgren, MariaAhlin, GustavBergström, Christel A. SSvensson, RichardArtursson, Per

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