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Polymorphic OCT1: a valid biomarker, but for which drugs? “[The] combined frequency of 9% of Caucasian individuals lacking OCT1 activity is comparable to the 10% rate of CYP2D6 inactivity in Caucasian individuals.” KEYWORDS: biomarker n knockout n membrane transport n metformin n morphine n OCT1 n organic cation transporter n sorafenib

At the end of each year, it is traditional to ask what we have learned in the past year and how we will we proceed. Although we may have slightly different answers, most of us will probably agree that the increasing availability of whole-genome resequencing has changed our view of genomic diversity and will significantly change research into, and probably the clinical application of, the field of pharmacogenomics. The utilization of individual phenotypes or genotypes to improve individual healthcare is the most immediate and convincing promise since the beginning of pharmacogenetics. To achieve this aim, the most convincing concept for therapy individualization is still that of single genotypes with a valid biomarker status. Single genotypes that are functionally well understood on the molecular and cellular level and that reproducibly modulate pharmaco­ kinetics or pharmacodynamics, as well as the efficacy and side effects of drugs, can be used as valid biomarkers to individualize drug therapy. Out of thousands of pharmacogenomics research publications, only a few new valid biomarkers are emerging. Indeed, the US FDA lists only 18 pharmacogenetically valid pharmacogenetic biomarkers (inherited genetic polymorphisms) and 14 tumor genomic biomarkers [101]. Probably every human gene carries some polymorphisms, but the number of genes carrying loss-of-function or knockout polymorphisms is small. According to a recent deep-sequencing analysis, each Caucasian individual may carry nearly 200 heterozygous knockout genes and 50 homozygous functional knockouts [1]. Already decades before hundreds of human genomes were decoded by deep sequencing and other technologies, we realized a particular enrichment of functional knockouts in genes coding for drug-metabolizing enzymes. There are frequent knockouts of CYP2C19, CYP2D6, CYP3A5, GSTM1, GSTT1 and UGT2B17 and nearly knockouts (negligible

activity) of NAT2, CYP2C9 and OATP1B1. Such knockout polymorphisms have exciting potential in terms of studying the functional roles of these genes directly in humans, and – if relevant in drug therapies – such polymorphisms are quasi automatically valid biomarkers. The gene coding for the organic cation transporter 1 (OCT1; alternative name SLC22A1) carries such knockout polymorphisms [2]. Owing to a few polymorphisms, approximately 2% of Caucasian individuals completely lack OCT1 activity, and another 7% lack OCT1 activity for various substrates. This combined frequency of 9% of Caucasian individuals lacking OCT1 activity is comparable to the 10% rate of CYP2D6 inactivity in Caucasian individuals. Indeed, many cationic drugs that are positively charged at physiological pH values are substrates of both OCT1 and CYP2D6 [3]. Both OCT1 and CYP2D6 may be required for the coordinated removal of some xenobiotics, such as the prototypic CYP2D6 substrate debrisoquine. The antihypertensive drug debrisoquine is no longer medically relevant. However, regarding the still poorly understood association between the debrisoquine hydroxylation phenotype and cancer risk [4], the fact that this phenotype may not only depend on CYP2D6 metabolism, but also on OCT1 transport, may be an important clue. Approximately 30% of all drugs may be organic cations and hundreds of drugs may exhibit some OCT1 inhibitory potential [5]. But in this context, a frequent misconception is to mix up the status of an inhibitor with the status of a substrate. OCT1 polymorphisms have thus far been shown to determine the pharmaco­ kinetics and clinical effects of only a very limited number of drugs. The antidiabetic drug metformin was considered to be a prototypic drug substrate of OCT1. Metformin is a hydrophilic drug that enters cells

10.2217/PGS.13.189 © 2013 Future Medicine Ltd

Pharmacogenomics (2013) 14(16), 1933–1936

Jürgen Brockmöller Author for correspondence: Institute of Clinical Pharmacology, University Medical Center, Georg-August-University Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany Tel.: +49 551 39 5770 Fax: +49 551 39 12767 [email protected]

Mladen V Tzvetkov Institute of Clinical Pharmacology, University Medical Center, Georg-August-University Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany

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poorly by diffusion alone, but its uptake into the liver may be facilitated by OCT1. However, the liver is not the eliminating organ for metformin, which may explain why the metformin pharmacokinetics showed only a minor dependence on OCT1 polymorphisms [6,7]. Nevertheless, metformin is presumed to act in the liver, and thus OCT1 may modulate efficacy. However, after great enthusiasm regarding data in knockout mice appearing to confirm this hypothesis [8], a large cohort study did not show any effects of OCT1 polymorphisms on glycemic response as a valid surrogate marker of clinical outcomes [9]. Perhaps even the common conception that metformin acts mostly in the liver may have to be revised, but it is more likely that OCT1 is not as important a metformin transporter as was assumed previously [10]. Indeed, OCT1 genotype may play a bigger role in lactate acidosis after phenformin than after metformin [10], but since no DNA was sampled in cases of phenformin lactate acidosis, this hypothesis will probably remain unproven forever. This year, morphine was identified as a substrate of OCT1, and lack of OCT1 activity was shown to affect morphine pharmacokinetics in both healthy volunteers and patients [11,12]. Pharmacokinetic differences were approximately twofold at maximum, but we must remember that, in this situation, we are dealing with narrow therapeutic index substances, and thus OCT1 polymorphisms may be relevant predictors of tramadol, codeine or morphine intoxication. However, this has not yet been shown in clinical data. The pharmacokinetics and consequent effects and side effects of another opioid, tramadol, were also shown to differ between OCT1 genotypes [13]. In the treatment of cancer and after surgery, not only the opioids, but also antiemetic drugs, are important, and again, OCT1 polymorphisms may be relevant, as shown for ondansetron and tropisetron [14]. The antiherpetic antiviral drugs acyclovir and ganciclovir and the antiretroviral drugs lamivudine and zalcitabine [15] were shown to be transported by OCT1, but, as with metformin, the major route of elimination is via the kidneys, where there is quite low expression of OCT1. Thus, OCT1 polymorphisms may not be relevant, with the possibly important exception of the treatment of hepatitis. Organic cation transporterdependent uptake of antivirals into white blood cells has been shown [15], but the expression of OCT1 in these cells is so low that only with convincing clinical study data could we conclude that OCT1 polymorphisms play a role in this scenario. 1934

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Another highlight of 2013 was the discovery of sorafenib as a possible OCT1 substrate [16,17]. Thus, together with imatinib [18], there are at least two kinase inhibitors for which efficacy may be modulated by OCT1. However, the transport of imatinib and sorafenib appears to be only marginally accelerated by OCT1, and further research is needed in order to understand how such a minor increase in membrane transport may be relevant for cytotoxicity.

“…lack of OCT1 activity was shown to affect morphine pharmacokinetics in both healthy volunteers and patients.”

One of the most exciting mysteries in this area is why we have these knockout polymorphisms and why they are enriched in genes controlling xenobiotic metabolism and transport. Broad hypotheses include: the advantage of genomic diversity and heterozygosity; protection from toxic plants ingested as food; and an effect of drug transporters or metabolizing enzymes on endogenous gene regulation, among others. However, this overarching question needs to be experimentally elucidated for each specific polymorphism. Numerous biogenic amines, such as tyramine, are substrates of OCT1, and such substances stem from traditional human foodstuffs, such as plants or bacterially contaminated meat or milk products. Before the invention of refrigerators, significant levels of these amines may have been in food, and indeed some level is still found in certain gourmet foods. Without efficient detoxification systems, an overload with biogenic amines, including several neurotransmitters or plant alkaloids, might result in potentially life-threatening neurotoxicity, as we see in encephalopathy occurring in global liver failure. Numerous plant alkaloids beyond morphine are organic cations and may also require carrier-mediated cellular uptake in order to protect humans from intoxication with such substances. However, as with the CYP450 enzymes, the role of OCT1 may be Janus-like: some plant alkaloids, such as monocrotaline, are rendered toxic by OCT1 [19]. Last but not least, one other role of OCT1 may be the removal of neuro­ transmitters released as spillover from tissues into the bloodstream. In vitro to in vivo extrapolation (IVIVE) may significantly increase the efficacy of drug development. In the transporter context, extensive amounts of data demonstrate inhibition of a prototypic substrate [5], but an inhibitor is not necessarily a substrate. As a first step in IVIVE, one future science group

Polymorphic OCT1: a valid biomarker, but for which drugs?

does not need a deep understanding of medicinal chemistry in order to guess the drugs for which OCT1 variation may be relevant – all of those drugs that are relatively hydrophilic and positively charged at approximately pH 7.4 may belong to the small but ‘exclusive club’ of drugs in which the OCT1 genotype may play a role. Furthermore – as we learned from the metformin story – the liver must play a rate-limiting role in elimination, either via biliary secretion or via catalyzing a ratelimiting metabolic step. If a drug is predicted to be affected by polymorphic OCT1 using IVIVE, in vivo transport measurements are mandatory in order to show relevant increases in uptake by OCT1. Using this approach, many more drugs than those discussed here have been identified as substrates of OCT1 [10], but whether or not OCT1 genotype is a relevant biomarker now requires new human studies in order to prove how significant the effect of OCT1 polymorphisms in humans may be.

“In the transporter context, extensive

amounts of data demonstrate inhibition of a prototypic substrate, but an inhibitor is not necessarily a substrate.” So in conclusion, for what drug therapies is OCT1 genotype a valid biomarker? Being a major hepatic drug uptake transporter, OCT1

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Shen H, Li J, Zhang J et al. Comprehensive characterization of human genome variation by high coverage whole-genome sequencing of forty four Caucasians. PLoS ONE 8(4), e59494 (2013).

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Kerb R, Brinkmann U, Chatskaia N et al. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12(8), 591–595 (2002).

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Saadatmand AR, Tadjerpisheh S, Brockmöller J, Tzvetkov MV. The prototypic pharmacogenetic drug debrisoquine is a substrate of the genetically polymorphic organic cation transporter OCT1. Biochem. Pharmacol. 83(10), 1427–1434 (2012). Ayesh R, Idle JR, Ritchie JC, Crothers MJ, Hetzel MR. Metabolic oxidation phenotypes as markers for susceptibility to lung cancer. Nature 312(5990), 169–170 (1984). Ahlin G, Karlsson J, Pedersen JM et al. Structural requirements for drug inhibition of the liver specific human organic cation

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may be relevant for all positively charged drugs that undergo hepatic biotransformation or biliary elimination. This year, reports suggested OCT1 to be an important biomarker in terms of interindividually variable codeine and morphine toxicities [11,12]. We also learned this year that OCT1 may modulate the efficacy of the tyrosine kinase inhibitor sorafenib, despite only small OCT1-medicated increases in membrane transport [15]. The prediction of possible substrate status from physicochemical data and pharmacokinetic pathways is quite reliable, but ultimately we need in vitro transport measurements and adequate clinical studies [20] in humans in order to confirm these as valid biomarkers. Acknowledgements The authors thank VP O’Brien and J Pereira for their valuable suggestions contributing to the manuscript.

Financial & competing interests disclosure The authors gratefully acknowledge support of their OCT1related research from DFG grants TZ 74/1-1 and GRK1034. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. transport protein 1. J. Med. Chem. 51(19), 5932–5942 (2008).

References 6

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Tzvetkov MV, Vormfelde SV, Balen D et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin. Pharmacol. Ther. 86(3), 299–306 (2009). Christensen MM, Brasch-Andersen C, Green H et al. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet. Genomics 21(12), 837–850 (2011).

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Shu Y, Sheardown SA, Brown C et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest. 117(5), 1422–1431 (2007).

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GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, Wellcome Trust Case Control Consortium 2, Zhou K et al. Common variants near ATM are associated with glycemic response to metformin in Type 2 diabetes. Nat. Genet. 43(2), 117–120 (2011).

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10 Hendrickx R, Johannsson JG, Lohmann C

et al. Identification of novel substrates and structure–activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J. Med. Chem. 56(18), 7232–7242 (2013). 11 Fukuda T, Chidambaran V, Mizuno T et al.

OCT1 genetic variants influence the pharmacokinetics of morphine in children. Pharmacogenomics 14(10), 1141–1151 (2013). 12 Tzvetkov MV, Dos Santos Pereira JN,

Meineke I, Saadatmand AR, Stingl JC, Brockmöller J. Morphine is a substrate of the organic cation transporter OCT1 and polymorphisms in OCT1 gene affect morphine pharmacokinetics after codeine administration. Biochem. Pharmacol. 86(5), 666–678 (2013). 13 Tzvetkov MV, Saadatmand AR, Lötsch J,

Tegeder I, Stingl JC, Brockmöller J. Genetically polymorphic OCT1: another piece in the puzzle of the variable pharmacokinetics and pharmacodynamics of the opioidergic drug tramadol. Clin. Pharmacol. Ther. 90(1), 143–150 (2011).

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14 Tzvetkov MV, Saadatmand AR, Bokelmann

K, Meineke I, Kaiser R, Brockmöller J. Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT (3) antagonists tropisetron and ondansetron. Pharmacogenomics J. 12(1), 22–29 (2012). 15 Jung N, Lehmann C, Rubbert A et al.

Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab. Dispos. 36(8), 1616–1623 (2008). 16 Swift B, Nebot N, Lee JK et al. Sorafenib

hepatobiliary disposition: mechanisms of hepatic uptake and disposition of generated metabolites. Drug Metab. Dispos. 41(6), 1179–1186 (2013).

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17 Herraez E, Lozano E, Macias RI et al.

Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology 58(3), 1065–1073 (2013).

20 Stingl Kirchheiner JC, Brockmöller J. Why,

when, and how should pharmacogenetics be applied in clinical studies?: current and future approaches to study designs. Clin. Pharmacol. Ther. 89(2), 198–209 (2011).

18 White DL, Saunders VA, Dang P et al.

OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood 108(2), 697–704 (2006). 19 Tu M, Sun S, Wang K et al. Organic cation

transporter 1 mediates the uptake of monocrotaline and plays an important role in its hepatotoxicity. Toxicology 311(3), 225–230 (2013).

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„„ Website 101 US FDA. Table of pharmacogenomic

biomarkers in drug labels (2013). www.fda.gov/drugs/scienceresearch/ researchareas/pharmacogenetics/ucm083378. htm

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Polymorphic OCT1: a valid biomarker, but for which drugs?

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