Maria Karlgren

Uppsala University, Uppsala, Uppsala, Sweden

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Publications (24)59.46 Total impact

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    ABSTRACT: Freshly isolated human hepatocytes are considered the gold standard for in vitro studies of liver functions, including drug transport, metabolism, and toxicity. For accurate predictions of in vivo outcome, the isolated hepatocytes should reflect the phenotype of their in vivo counterpart, i.e., hepatocytes in human liver tissue. Here, we quantified and compared the membrane proteomes of freshly isolated hepatocytes and human liver tissue using a label-free shotgun proteomics approach. A total of 5144 unique proteins were identified, spanning over six orders of magnitude in abundance. There was a good global correlation in protein abundance. However, the expression of many plasma membrane proteins was lower in the isolated hepatocytes than in the liver tissue. This included transport proteins that determine hepatocyte exposure to many drugs and endogenous compounds. Pathway analysis of the differentially expressed proteins confirmed that hepatocytes are exposed to oxidative stress during isolation and suggested that plasma membrane proteins were degraded via the protein ubiquitination pathway. Finally, using pitavastatin as an example, we show how protein quantifications can improve in vitro predictions of in vivo liver clearance. We tentatively conclude that our data set will be a useful resource for improved hepatocyte predictions of in vivo outcome.
    Journal of Proteome Research 07/2015; DOI:10.1021/acs.jproteome.5b00334 · 5.00 Impact Factor
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    ABSTRACT: Differences in the expression and function of the organic anion transporting polypeptide (OATP) transporters contribute to inter-individual variability in atorvastatin clearance. However, the importance of the bile acid transporter NTCP (SLC10A1) in atorvastatin uptake clearance (CLupt) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CLupt in twelve human liver samples. The impact of inhibition on atorvastatin CLupt was also studied, using inhibitors of different isoform specificities. Expression levels of the four transport proteins were quantified by LC-MS/MS. These data, together with atorvastatin in vitro kinetics, were used to predict the maximal transport activity (MTA) and inter-individual differences in CLupt of each transporter in vivo. Subsequently, hepatic uptake impairment upon co-administration of five clinically interacting drugs was predicted using in vitro inhibitory potencies. NTCP and OATP protein expression varied 3.7- to 32-fold among the twelve sample donors. The rank order in expression was OATP1B1 > OATP1B3 ≈ NTCP ≈ OATP2B1. NTCP was found to be of minor importance in atorvastatin disposition. Instead, OATP1B1 and OATP1B3 were confirmed as the major atorvastatin uptake transporters. The average contribution to atorvastatin uptake was OATP1B1 > OATP1B3 > OATP2B1 > NTCP, although this rank order varied between individuals. The inter-individual differences in transporter expression and CLupt resulted in marked differences in drug-drug interactions due to isoform-specific inhibition. We conclude that this variation should be considered in in vitro to in vivo extrapolations.
    Drug metabolism and disposition: the biological fate of chemicals 05/2014; 42(7). DOI:10.1124/dmd.113.056309 · 3.33 Impact Factor
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    ABSTRACT: Two clinical trials and a large set of in vitro transporter experiments were performed to investigate if the hepatobiliary disposition of the direct thrombin inhibitor prodrug AZD0837 is the mechanism for the drug-drug interaction with ketoconazole observed in a previous clinical study. In Study 1, [(3)H]AZD0837 was administered to healthy male volunteers (n=8) to quantify and identify the metabolites excreted in bile. Bile was sampled directly from the jejunum by duodenal aspiration via an oro-enteric tube. In Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics of AZD0837, the intermediate metabolite (AR-H069927) and the active form (AR-H067637) was investigated (n=17). Co-administration with ketoconazole elevated the plasma exposure to AZD0837 and the active form approximately two-fold compared to placebo, which may be explained by inhibited CYP3A4 metabolism and reduced biliary clearance, respectively. High concentrations of the active form was measured in bile with a bile-to-plasma AUC ratio of approximately 75, indicating involvement of transporter-mediated excretion of the compound. AZD0837 and its metabolites were further investigated as substrates of hepatic uptake and efflux transporters in vitro. Studies in MDCK-MDR1 cell monolayers and P-glycoprotein (P-gp) expressing membrane vesicles identified AZD0837, the intermediate and the active form as substrates of P-gp. The active form was also identified as a substrate of the multidrug and toxin extrusion 1 (MATE1) transporter and the organic cation transporter 1 (OCT1), in HEK cells transfected with the respective transporter. Ketoconazole was shown to inhibit all of these three transporters; in particular, inhibition of P-gp and MATE1 occurred in a clinically relevant concentration range. In conclusion, the hepatobiliary transport pathways of AZD0837 and its metabolites were identified in vitro and in vivo. Inhibition of the canalicular transporters P-gp and MATE1 may lead to enhanced plasma exposure to the active form, which could, at least in part, explain the clinical interaction with ketoconazole.
    Molecular Pharmaceutics 09/2013; 10(11). DOI:10.1021/mp400341t · 4.79 Impact Factor
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    ABSTRACT: The absorption, distribution, metabolism and excretion (ADME) of drugs in vivo are to a large extent dependent on different transport and metabolism routes. Elucidation of this complex transport-metabolism interplay is a major challenge in drug development and at present no in vitro models suitable for this purpose are at hand. The aim of this study was to develop flexible, well-controlled, easy-to-use, integrated cell models, where drug transport and drug metabolism processes could be studied simultaneously. HEK293 cells stably transfected with the organic anion transporting polypeptide 1B1 (OATP1B1) were subjected to either transient transfection or adenoviral infection to introduce the genes expressing cytochrome P450 3A4 (CYP3A4), NADPH cytochrome P450 oxidoreductase (POR), cytochrome b5 (CYB5A), and multidrug resistance protein 1 (MDR1), in different combinations. Thereafter, the time and concentration-dependent transport and metabolism of two well-characterized statins, atorvastatin (acid and lactone forms), and simvastatin (acid form) were determined in the different models. The results show that CYP3A4-dependent metabolism of the more hydrophilic atorvastatin acid was dependent on OATP1B1 uptake and influenced by MDR1 efflux. In contrast, metabolism of the more lipophilic atorvastatin lactone was not affected by active transport, whereas the metabolism of simvastatin acid was less influenced by active transport than atorvastatin acid. Our results, together with the models being applicative for any combination of drug transporters and CYP metabolizing enzymes of choice, provide proof-of-concept for the potential of the new integrated cell models presented as valuable screening tools in drug discovery and development.
    Molecular Pharmaceutics 07/2013; 10(8). DOI:10.1021/mp400202d · 4.79 Impact Factor
  • Pär Matsson, Per Artursson, Maria Karlgren
    Transporters in Drug Discovery, Development and Use, Edited by Bente Steffansen, Yuichi Sugiyama, 07/2013: chapter In vitro characterization of interactions with drug transporting proteins; Springer Verlag, Heidelberg, Germany.
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    ABSTRACT: The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
    Journal of Medicinal Chemistry 04/2012; 55(10):4740-63. DOI:10.1021/jm300212s · 5.48 Impact Factor
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    ABSTRACT: 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 μM. 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.
    Pharmaceutical Research 08/2011; 29(2):411-26. DOI:10.1007/s11095-011-0564-9 · 3.95 Impact Factor
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    ABSTRACT: The cytochromes P450 (CYPs) are very efficient catalysts of foreign compound metabolism and are responsible for the major part of metabolism of clinically important drugs. The enzymes are important in cancer since they (a) activate dietary and environmental components to ultimate carcinogens, (b) activate or inactivate drugs used for cancer treatment, and (c) are potential targets for anticancer therapy. The genes encoding the CYP enzymes active in drug metabolism are highly polymorphic, whereas those encoding metabolism of precarcinogens are relatively conserved. A vast amount of literature is present where investigators have tried to link genetic polymorphism in CYPs to cancer susceptibility, although not much conclusive data have hitherto been obtained, with exception of CYP2A6 polymorphism and tobacco induced cancer, to a great extent because of lack of important functional polymorphisms in the genes studied. With respect to anticancer treatment, the genetic CYP polymorphism is of greater importance, where treatment with tamoxifen, but also with cyclophosphamide and maybe thalidomide is influenced by CYP genetic variants. In the present review we present updates on CYP genetics, cancer risk and treatment and also epigenetic aspects of interindividual variability in CYP expression and the use of these enzymes as targets for cancer therapy. We conclude that the CYP polymorphism does not predict cancer susceptibility to any large extent but that this polymorphism might be an important factor for optimal cancer therapy using selected anticancer agents.
    Human Genetics 10/2009; 127(1):1-17. DOI:10.1007/s00439-009-0748-0 · 4.52 Impact Factor
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    ABSTRACT: Cytochrome P450 (CYP) enzymes are important for drug metabolism. A novel cytochrome P450 enzyme, CYP2W1, has recently been identified. This enzyme is mainly found in foetal colon tissue and in tumour tissue. In this pilot study, we have investigated the expression of CYP2W1 in 162 tumours from patients with stages II and III colorectal cancer. The expression of CYP2W1 enzyme was immunohistochemically detected using a polyclonal antibody. Staining intensity was defined using a visual grading scale from 0 to 3. Grades 0-2 were classified as low, and grade 3 was classified as high expression of CYP2W1. About 64% of the tumours expressed a low level of CYP2W1-expression, and 36% expressed a high level. CYP2W1-expression was an independent prognostic factor for overall survival (p=0.007), where a high expression was associated with a worse clinical outcome. Immunohistochemically assessed expression of CYP2W1 is an independent prognostic factor in patients with stages II and III colorectal cancer.
    European journal of cancer (Oxford, England: 1990) 03/2009; 45(4):705-12. DOI:10.1016/j.ejca.2008.11.031 · 4.82 Impact Factor
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    ABSTRACT: CYP2W1 is a novel enzyme shown to be selectively expressed in rat fetal colon and in human colon cancer and has previously been suggested as a potential drug target for cancer therapy. Here, the expression and gene methylation of CYP2W1 were analyzed in human colon carcinoma cell lines, colon tumors and in corresponding normal colon tissue. CYP2W1 mRNA and protein expression in HepG2 and Caco-2TC7 cells and normal colon and colon tumor tissue samples were analyzed using real-time PCR and Western blotting. CYP2W1 gene methylation status in the same samples was analyzed using the sodium bisulfite sequencing method. CYP2W1 mRNA was detected in all (n = 39) tumor samples analyzed. Moreover, in 60% (12/20) of the colon tumors, CYP2W1 mRNA levels were substantially higher than in corresponding normal tissues. CYP2W1 protein was detected in most of the colon tumor samples analyzed (n = 16), which appeared to be of two apparent phenotypes: those with five- to ten-fold induced CYP2W1 (approximately 50% of the tumors), and those with low expression, harboring similar or only slightly higher amounts of CYP2W1 as compared with surrounding control tissue. Methylation analysis of the CpG island in the exon 1-intron 1 junction of the CYP2W1 gene from both cell lines, tumors and normal tissues revealed that demethylated CpG dinucleotides appeared as a requirement for high CYP2W1 gene expression. The expression of CYP2W1 is colon tumor-specific and is associated with methylation status of the CYP2W1 gene, suggesting a potential causal link between the gene hypomethylation and its enhanced expression.
    Pharmacogenomics 10/2007; 8(10):1315-25. DOI:10.2217/14622416.8.10.1315 · 3.43 Impact Factor
  • Maria Karlgren, Magnus Ingelman-Sundberg
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    ABSTRACT: Recently, a new cytochrome P450, designated CYP2W1, was identified. This enzyme is expressed in transformed tissues and during fetal life, whereas in human adult tissues only low levels of expression have been detected. CYP2W1 has been shown to metabolise arachidonic acid and benzfetamine, as well as being able to metabolically activate several procarcinogens, including polycyclic aromatic hydrocarbon dihydrodiols, aflatoxin B1 and sterigmatocystin. The gene expression is governed by gene methylation. The selective expression in some forms of cancers and the low expression in normal tissues render CYP2W1 as a possible drug target during cancer therapy. Here, the authors review the data currently available for this enzyme and discuss its potential as a drug target.
    Expert Opinion on Therapeutic Targets 02/2007; 11(1):61-7. DOI:10.1517/14728222.11.1.61 · 4.90 Impact Factor
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    ABSTRACT: The 16th International Symposium on Microsomes and Drug Oxidations (MDO2006) in Budapest, Hungary, had almost 400 attendees and was nicely organized by Laszlo Vereczkey and colleagues. The meeting had a very high standard in the field of drug metabolism, drug transport and related areas and in addition, the social events were much appreciated. At the meeting 70 invited lectures were presented in plenary sessions and in three parallel symposia sessions, and about 178 posters were shown, among them 26 posters in the young investigators workshop. The review herein is given of a majority (57) of the lectures presented at the Symposium.
    Drug News & Perspectives 01/2007; 19(10):637-51. · 3.13 Impact Factor
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    ABSTRACT: A novel human cytochrome P450, CYP2W1, was cloned and expressed heterologously. No or very low CYP2W1 mRNA levels were detected in fetal and adult human tissues, expression was however seen in 54% of human tumor samples investigated (n=37), in particular colon and adrenal tumors. Western blotting also revealed high expression of CYP2W1 in some human colon tumors. In rat tissues, CYP2W1 mRNA was expressed preferentially in fetal but also in adult colon. The CYP2W1 gene was shown to encompass one functional CpG island in the exon 1-intron 1 region which was methylated in cell lines lacking CYP2W1 expression, but unmethylated in cells expressing CYP2W1. Re-expression of CYP2W1 was seen following demethylation by 5-Aza-2'-deoxycytidine. Transfection of HEK293 cells with CYP2W1 caused the formation of a properly folded enzyme, which was catalytically active with arachidonic acid as a substrate. It is concluded that CYP2W1 represents a tumor-specific P450 isoform with potential importance as a drug target in cancer therapy.
    Biochemical and Biophysical Research Communications 04/2006; 341(2):451-8. DOI:10.1016/j.bbrc.2005.12.200 · 2.28 Impact Factor
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    ABSTRACT: The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human Genome Project, a great progress has recently been seen in the identification and characterization of novel extrahepatic P450s, including CYP2S1, CYP2R1, CYP2U1 and CYP2W1. Like the hepatic enzymes, these P450s may play a role in the tissue-specific metabolism of foreign compounds, but they may also have important endogenous functions. CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase. Regarding their metabolism of xenobiotics, much remains to be established, but CYP2S1 metabolizes naphthalene and it is likely that these P450s are responsible for metabolic activation of several different kinds of xenobiotic chemicals and contribute to extrahepatic toxicity and carcinogenesis.
    Toxicology and Applied Pharmacology 10/2005; 207(2 Suppl):57-61. DOI:10.1016/j.taap.2004.12.022 · 3.63 Impact Factor
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    ABSTRACT: The 15th International Symposium on Microsomes and Drug Oxidations: Chemical Biology in the Postgenomic Era--New Approaches and Applications in Mainz, Germany, July 4-9, 2004, had 570 attendees and was nicely organized by Franz and Barbara Oesch and colleagues. At the meeting, 73 different lectures were presented and about 240 posters were shown. This review discusses most of the lectures presented at the Symposium.
    Drug News & Perspectives 12/2004; 17(9):594-605. · 3.13 Impact Factor
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    ABSTRACT: A novel human cytochrome P450 cDNA designated CYP2U1 was identified using homology searches, and the corresponding gene is located on chromosome 4. The deduced 544 amino acid sequence displays up to 39% identity to other CYP2 family members, with closest resemblance to CYP2R1 and is highly conserved between species. CYP2U1 shows some structural differences compared to other CYP2 family members. The gene has only five exons and the enzyme harbors two insertions in the N-terminal region. Northern blot analysis revealed high mRNA expression in human thymus, with weaker expression in heart and brain, whereas in the rat similar mRNA levels were detected in thymus and brain. Western blot analysis revealed much higher CYP2U1 protein expression in rat brain than in thymus, particularly in limbic structures and in cortex. The physiological and toxicological role of this novel P450 is still unknown, but the selective tissue distribution suggests an important endogenous function.
    Biochemical and Biophysical Research Communications 04/2004; 315(3):679-85. DOI:10.1016/j.bbrc.2004.01.110 · 2.28 Impact Factor
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    ABSTRACT: The hepatic organic anion transporting polypeptides (OATP) 1B1, 1B3 and 2B1 influence the pharmacokinetics of drug classes like statins and angiotensin II receptor antagonists and are involved in many clinical drug-drug interactions (DDIs). Predicting potential interactions with OATPs during drug discovery is, therefore, of value. Here, we developed in vitro and in silico models for the identification and prediction of specific and general inhibitors of the OATPs. The maximal transport activity (MTA) of each transporter in the human liver was predicted from transport kinetics and protein quantification in vitro and in vivo. We used this in vitro to in vivo extrapolation to quantify the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a dataset of 225 drug-like compounds, 91 OATP inhibitors were identified, of which 38 were novel inhibitors. The in silico model identified lipophilicity and polar surface area as key molecular features of OATP inhibition. Predictions of MTA of each OATP identified OATP1B1 and OATP1B3 as the major contributors to atorvastatin uptake in vivo. The relative contributions of OATPs to overall hepatic uptake were, however, changed when inhibitors with different isoform specificities were used in the DDI predictions.
    19th MDO and 12th European Regional International society for the study of xenobiotics Meeting;
  • Ge Gao, Maria Karlgren, Per Artursson
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    ABSTRACT: Purpose: Liver is one of the most important organs for accumulation and elimination of toxins. However, the transport mechanisms through human liver for ochratoxin A and citrinin are still little known. The aim of this study was to screen out effective uptake transporters that are highly expressed on liver membrane for ochratoxin A and citrinin uptake, and also figure out ochratoxin A and citrinin’s inhibition or stimulation effects on these transporters. Methods: Uptake 1μM ochratoxin A or citrinin by HEK 293 cells stably transfected with human OATP1B1, OATP1B3, OATP2B1 and NTCP to identify effective transporters. With different toxin incubation time, time dependant curve was plotted. Finally, transporters uptake their specific substrates inhibited by ochratoxin A or citrinin was studied to see the inhibition effect. Results: All the transporters studied are active uptake transporters for ochratoxin A but none of them is effective in citrinin uptake. With assistance of modeling, OATP1B1 is shown to be the most efficient for ochratoxin A uptake. Besides, ochratoxin A showed big inhibition effect on OATP1B1, OATP1B3, and OATP2B1 but stimulation effect on NTCP. Citrinin only has inhibition effect for OATP1B1. Conclusion: In conclusion, this study showed that ochratoxin A uptake was more than citrinin by human liver under the same condition, which may present more toxicity. OATP1B1 was proved to be the main transporter during uptake. Moreover, both ochratoxin A and citrinin are inhibitors for OATP1B1, and ochratoxin A has more interactions with other transporters.
    9th International International society for the study of xenobiotics Meeting;
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    ABSTRACT: Global proteomic analysis of human liver with focus on ADMET protein expression ADMET-proteins play an important role in the absorption, distribution, metabolism, excretion and sometimes also in the toxicity of xenobiotic and endogenous compounds. Quantitative information on the expression levels of these proteins can help to improve the understanding and prediction of the pharmacokinetics and safety profiles of new drugs. Here, we determined the global protein expression levels in membrane fractions of human liver (n=12) and isolated human hepatocytes (n=8) using a filter-aided sample preparation (FASP) based proteomics approach.1 Out of more than 4000 proteins detected in the mass spectrometric analysis of the liver samples, 173 ADMET proteins were identified, including 37 cytochrome P450 (CYP) enzymes and 30 transport proteins. As expected, there was a good correlation between the expression levels of ADMET proteins in human liver and in human hepatocytes (r2= 0.86). Cell specific markers (CD68 for Kuppfer cells, von Willebrand factor for endothelial cells, and CK19 for cholangiocytes) indicated a proper isolation of hepatocytes without contamination of other cell types. The expression levels of important phase I metabolizing enzymes were compared and CYP2C9 was identified as the most highly expressed CYP enzyme in the liver samples, which is in line with a recent publication. For CYP2C9 and CYP2C8, six individuals had much higher expression levels of both these enzymes than the other group of individuals. This could be a result of polymorphisms in these genes or, more likely, induction by e.g., medication or food since their gene expressions are regulated by the same nuclear receptors. CYP2D6 also displayed a high (n=4) and low expressing group of individuals (n=8). This is consistent with the fact that CYP2D6 is known to be highly polymorphic resulting in variations in the metabolic capacity of the enzyme. Among the transporters that are important for drug uptake and efflux, organic anion transporting polypeptide (OATP) 1B1 and bile salt export pump (BSEP) were identified as the most highly expressed uptake and efflux transporter, respectively. The inter-individual variability in OATP1B1 expression, displayed a four-fold difference. Interestingly, OATP1B3 was identified as one of the transporters with the largest inter-individual variation in abundance, revealing a 30-fold difference between the lowest and the highest expression level. The data obtained in this project is currently used to quantify and improve predictions of drug transport processes and drug-drug interactions in the human liver. In our first study, the contribution of three OATPs (OATP1B1, OATP1B3 and OATP2B1) to atorvastatin uptake and inhibition in the human liver was predicted.2 1 Wisniewski, J. R., Zougman, A., Nagaraj, N., Mann, M. Universal sample preparation method for proteome analysis. Nat Methods2009, 6 (5), 359-62. 2 Karlgren, M., Vildhede, A., Norinder, U., Wisniewski, J. R., Kimoto, E., Lai, Y., Haglund, U., Artursson, P. Classification of inhibitors of liver specific OATPs – influence of protein expression on drug-drug interactions. J Med Chem2012, accepted.
    19th MDO and 12th European Regional International society for the study of xenobiotics Meeting;
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    ABSTRACT: In the liver organic anion transporting polypeptides (OATP) 1B1, 1B3 and 2B1 are expressed in the sinusoidal membrane of the hepatocyte mediating uptake of drugs from the blood into the cells. These transport proteins are also known to be involved in many clinical drug-drug interactions. In general, OATP1B1 is considered as the major OATP transporter expressed in the liver and as the major OATP of clinical significance. In a previous study we have shown that there are large interindividual differences in the membrane protein expression levels of these transporters in human liver. Here we have, together with transport kinetics and protein quantification in vitro, utilized the quantitative expression levels of OATP1B1, OATP1B3 and OATP2B1 in twelve human livers for prediction of maximal transport activity (MTA) of each transporter and for each individual donor. Together with IC50 determinations of 15 potential OATP inhibitors, the predicted MTAs were subsequently used for extrapolation of the inhibitory effect on the OATP-mediated uptake of atorvastatin in vivo. Indeed, the results showed that both the relative and absolute contribution of each OATP transporter to atorvastatin uptake differed between the individuals, in some cases as much as 30-fold. In addition, the predictions showed that if atorvastatin mediated uptake was greatly dependent on one transporter the effects of DDIs can be further enlarged in presence of an inhibitor. These results show that even if OATP1B1 in most cases is the major atorvastatin OATP uptake transporter, for some individuals the contribution of OATP1B3 is greatly increased. Hence, the clinical significance of especially OATP1B3 but also OATP2B1 might need to be reconsidered. Further studies are needed to elucidate how these differences in protein expression levels affect the uptake of other substrates than atorvastatin and if these differences are connected to OATP polymorphisms.
    19th MDO and 12th European Regional International society for the study of xenobiotics Meeting;

Publication Stats

376 Citations
59.46 Total Impact Points

Institutions

  • 2009–2014
    • Uppsala University
      • Department of Pharmacy
      Uppsala, Uppsala, Sweden
  • 2005–2009
    • Karolinska Institutet
      • • Department of Physiology and Pharmacology
      • • Institute of Environmental Medicine - IMM
      Solna, Stockholm, Sweden