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Coproporphyrins I and III As Functional Markers of OATP1B Activity: in Vitro and in Vivo Evaluation in Preclinical Species S

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Coproporphyrins I and III As Functional Markers of OATP1B Activity: in Vitro and in Vivo Evaluation in Preclinical Species S Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2016/02/23/jpet.116.232066.DC1 1521-0103/357/2/382–393$25.00 http://dx.doi.org/10.1124/jpet.116.232066 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:382–393, May 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species s Hong Shen, Jun Dai, Tongtong Liu, Yaofeng Cheng, Weiqi Chen, Chris Freeden, Yingru Zhang, W. Griffith Humphreys, Punit Marathe, and Yurong Lai Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey Received January 12, 2016; accepted February 12, 2016 ABSTRACT Inhibition of organic anion-transporting polypeptide (OATP)1B by 2.6- and 5.2-fold, while rifampicin (15 mg/kg, oral) in- Downloaded from function can lead to serious clinical drug-drug interactions, thus creased the AUCs by 2.7- and 3.6-fold, respectively. As the a thorough evaluation of the potential for this type of interaction systemic exposure increased, the excretion of both isomers must be completed during drug development. Therefore, sensitive in urine rose from 1.6- to 4.3-fold in monkeys. In agreement and specific biomarkers for OATP function that could be used with this finding, the AUC of rosuvastatin (RSV) in cynomolgus in conjunction with clinical studies are currently in demand. In monkeys increased when OATP1B inhibitors were coadminis- the present study, preclinical evaluations were conducted to tered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b2/2), characterize the suitability of coproporphyrins (CPs) I and III as CPs in plasma and urine were significantly increased compared jpet.aspetjournals.org markers of hepatic OATP functional activity. Active uptake of with wild-type animals (7.1- to 18.4-fold; P , 0.001), which CPsIandIIIwasobservedinhumanembryonickidney(HEK) were also in agreement with the changes in plasma RSV 293 cells singly expressing human OATP1B1 (hOATP1B1), exposure (14.6-fold increase). We conclude that CPs I and III hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or in plasma and urine are novel endogenous biomarkers reflect- cOATP1B3, as well as human and monkey hepatocytes. ing hepatic OATP function, and the measurements have the Cyclosporin A (100 mg/kg, oral) markedly increased the area potential to be incorporated into the design of early clinical under the curve (AUC) plasma concentrations of CPs I and III evaluation. at ASPET Journals on October 2, 2021 Introduction although ATV is mainly eliminated via metabolism mediated by cytochrome P450 enzymes (Neuvonen et al., 2006). Human organic anion-transporting polypeptide (OATP)1B1 Currently, both the Food and Drug Administration (http://www.fda. (SLCO1B1) and OATP1B3 (SLCO1B3) are expressed on the gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ basolateral membrane of hepatocytes and are responsible for Guidances/UCM292362.pdf) and the European Medicines Agency the hepatic uptake of numerous drugs and endogenous (http://www.ema.europa.eu/docs/en_GB/document_library/ compounds. Transporter-mediated hepatic uptake could be a Scientific_guideline/2012/07/WC500129606.pdf) require new rate-determining process in elimination of both metabolically chemical entities to be characterized for OATP1B inhibition stable and unstable drugs (Kalliokoski and Niemi, 2009; and propose decision trees for assessing OATP1B inhibitors. Niemi et al., 2011; Yoshida et al., 2012; Shitara et al., The Food and Drug Administration and European Medicines 2013a). Hepatic uptake has clearly been demonstrated to be Agency recommend using a static mathematical approach to a potential source of pharmacokinetic variability for drugs estimate the risk of clinically relevant OATP1B-mediated such as rosuvastatin (RSV) and atorvastatin (ATV). For drug-drug interactions (DDIs) by calculating the ratio of example, in 32 healthy volunteers with different SLCO1B1 unbound maximum portal vein drug concentration in vivo genotypes dosed with 20 mg ATV, the mean area under the against in vitro IC50. However, this approach is solely based curve (AUC) of ATV was 144% higher in subjects with the on in vitro-to-in vivo extrapolation without any in vivo 5 521CC genotype (n 4) than in subjects with the 521TT calibration. In addition, the use of this in vitro-to-in vivo 5 genotype (reference genotype; n 16) (Pasanen et al., 2007), extrapolation approach is challenged by the uncertain im- pact of protein binding–measured, drug absorption, and interlaboratory variability in IC50 assessment using different This study is supported by the Bristol-Myers Squibb Company. dx.doi.org/10.1124/jpet.116.232066. probe substrate and incubation conditions (Amundsen et al., 2010; s This article has supplemental material available at jpet.aspetjournals.org. Izumi et al., 2013, 2015; Shitara et al., 2013b). Therefore, the ABBREVIATIONS: ATV, atorvastatin; AUC, area under the curve; CCK-8, cholecystokinin octapeptide; CLR, renal clearance; cOATP, cynomolgus organic anion-transporting polypeptide; CP, coproporphyrin; CsA, cyclosporin A; DDI, drug-drug interaction; ERR, renal extraction ratio; E17bG, estradiol-17b-D-glucuronide; FLD, fluorescence detection; GFR, glomerular filtration rate; HEK, human embryonic kidney; hOATP, human organic anion-transporting polypeptide; HPLC, high-performance liquid chromatography; KO, knockout; OATP, organic anion-transporting polypeptide; RIF, rifampicin; RSV, rosuvastatin; WT, wild type; Xe, amount of compound excreted into urine. 382 Coproporphyrin as Endogenous In Vivo Probe for OATP1B 383 availability of endogenous biomarkers to assess transporter Waltham, MA). Formic acid and concentrated hydrochloric acid (12 N) activities during early drug development would have sub- were obtained from EMD Chemicals Inc. (Gibbstown, NJ). [3H]E17bG 3 stantial benefits for the pharmaceutical industry in order to (34.3 Ci/mmol) and [ H]CCK-8 (97.5 mCi/mmol) were purchased avoid expensive clinical trials and also minimize the risk of from Perkin Elmer Life and Analytical Sciences (Waltham, MA). All $ late-stage failures and even drug withdrawal. In this regard, compounds were of analytical grade ( 95% purity). Stock solutions of CPs and RIF were prepared in dimethylsulfoxide and stored at 270°C. many attempts have been made to identify endogenous Cell Culture and Reagents. Hygromycin and penicillin- compounds that could reflect the activities of enzymes streptomycin were purchased from Invitrogen (Carlsbad, CA). Other and transporters, such as CYP3A4 (Kanebratt et al., 2008; cell culture media and reagents including Dulbecco’s modified Eagle’s Diczfalusy et al., 2011; Shin et al., 2013; Kasichayanula et al., growth medium, fetal bovine serum, nonessential amino acid, 2014), CYP2D6 (Tay-Sontheimer et al., 2014), MATEs (Ito L-glutamine, N-2-hydroxyethylpiperazine-N9-2-ethanesulphonic acid, et al., 2012; Kato et al., 2014; Müller et al., 2015), and OAT3 phosphate-buffered saline, and Hanks’ balanced salt solution were (Imamura et al., 2014) to improve prediction of DDI. However, purchased from Corning (Manassas, VA). Biocoat poly-D-lysine as far as we know, no validated in vivo clinical endogenous 24-well plates were purchased from BD Biosciences (San Jose, probe of OATP1B has been identified. CA). Cryopreserved mouse, cynomolgus monkey, and human Coproporphyrin (CP) is one of the by-products of heme hepatocytes were purchased from BioreclamationIVT (Baltimore, MD). Pierce BCA protein assay kit was purchased from Thermo synthesis, and its physiologic role is unclear. CPs I and III are Scientific (Rockford, IL). not enzymatically altered in the liver (Kaplowitz et al., 1972), but instead are removed from the body via the bile and urine Downloaded from as intact molecules, albeit unequally. While CP III predomi- In vitro Studies nates over CP I in urine, the reverse is encountered in bile CP Uptake and Inhibition Studies in Cynomolgus Organic (Aziz et al., 1964a,b; French and Thonger, 1966; Koskelo et al., Anion-Transporting Polypeptide (cOATP)1B1, cOATP1B3, 1966; Koskelo and Toivonen, 1966; Koskelo et al., 1967; Human Organic Anion-Transporting Polypeptide (hOATP)1B1, Aziz and Watson, 1969; Ben-Ezzer et al., 1971). There are and hOATP1B3 Transfected Human Embryonic Kidney (HEK) relatively limited data available in the literature regarding 293 Cells. Recombinant cells expressing human and cynomolgus jpet.aspetjournals.org CP plasma concentrations and how they change in response to monkey OATP1B transporters were cultured as described previously physiologic alterations because of limited sensitivity of the (Shen et al., 2013). Uptake was initiated by the addition of transport buffer containing 3 mMCPisomerand100mM RIF or dimethylsulfoxide common assays (Table 4). Abnormal distribution of CP vehicle after washing cells with transport buffer. In control reactions, CP isomers was reported in the urine of patients with Rotor isomer was replaced with 1 mM[3H]E17bGand0.1mM[3H]CCK-8 for syndrome, i.e., a marked preponderance of CP I over CP III OATP1B1 and OATP1B3, respectively, to confirm activity of the trans- (Ben-Ezzer et al., 1971; Wolkoff et al., 1976). In addition, porter. The final concentration of dimethylsulfoxide was 0.5% (v/v) in administration of ethinylestradiol and phenodibromophthalein all incubations. Each test condition was assessed in triplicate. After at ASPET
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