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Comparative Evaluation of Dehydroepiandrosterone Sulfate

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Comparative Evaluation of Dehydroepiandrosterone Sulfate Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2016/12/01/dmd.116.072355.DC1 1521-009X/45/2/224–227$25.00 http://dx.doi.org/10.1124/dmd.116.072355 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 45:224–227, February 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Short Communication Comparative Evaluation of Dehydroepiandrosterone Sulfate Potential to Predict Hepatic Organic Anion Transporting Polypeptide Transporter-Based Drug-Drug Interactions s Received July 4, 2016; accepted November 30, 2016 ABSTRACT Pharmacokinetic drug-drug interactions (DDIs) on hepatic organic 59 ml/rat. Comparison of the in vitro IC50 of rifampicin for DHEAS anion transporting polypeptides (OATPs) are important clinical issues. uptake by isolated rat hepatocytes and in vivo plasma rifampicin Previously, we reported that plasma dehydroepiandrosterone sulfate concentration suggested that the effect of rifampicin on the plasma Downloaded from (DHEAS) could serve as an endogenous probe to predict OATP-based DHEAS concentration was explained mostly by the inhibition of DDIs in monkeys using rifampicin as an OATP inhibitor. Since the hepatic OATPs, demonstrating that DHEAS could be a biomarker of contribution of hepatic OATPs to the changes in plasma DHEAS by hepatic OATP activity. Next, previously reported rifampicin-induced rifampicin remains unclear, however, we performed an in vivo phar- changes in plasma concentrations evaluated as an AUC ratio (AUCR) macokinetic study to explore this issue. Since plasma DHEAS of possible probe compounds were compared on the basis of concentrations were low in our rat model, the disposition of externally rifampicin dose/body surface area. The AUCR values of endogenous dmd.aspetjournals.org administered DHEAS was evaluated. Intravenously administered compounds and i.v. administered statins, for which possible DDIs in DHEAS was recovered mainly in bile (29.1%) and less in urine the intestinal absorption process can be excluded, increased propor- (2.95%). The liver tissue-to-plasma concentration ratio (Kpliver)de- tionally to the rifampicin dose. Simultaneous measurement of these creased from 41.8 to 5.07 by rifampicin, and this decrement was endogenous compounds could be effective biomarkers for the pre- consistent with the decrease in distribution volume from 247 to diction of OATP-based DDIs. at ASPET Journals on October 1, 2021 Introduction et al., 2014). Although those probe drugs are useful, endogenous probe Membrane transporters are involved in the absorption and disposition of compounds might be advantageous since in vivo DDI could be examined at many drugs, and alterations in their functional activities may lead to an early stage of drug development without the need for additional studies decreased efficacy and/or adverse events. Such alterations can occur as a involving the administration of probe drugs. result of drug-drug interactions (DDIs) and drug-food interactions with Several endogenous compounds, including bilirubin, bile acids, and concurrently administered drugs or foods (Shitara et al., 2013; Nakanishi and coproporphyrins, have been proposed as biomarkers to monitor DDIs on Tamai, 2015). Regulatory agencies, such as the U.S. Food and Drug hepatic OATPs (Chu et al., 2015; Watanabe et al., 2015b; Shen et al., 2016, Administration, European Medicines Agency, and Japanese Pharmaceuticals Lai et al., 2016). In addition, we recently reported that dehydroepiandros- and Medical Devices Agency, have proposed that clinical DDI studies should terone sulfate (DHEAS) served as a biomarker to reflect the DDI on hepatic be required for drugs under development; thus, there is a need to develop OATPs when cynomolgus monkeys were administered an inhibitor of convenient ways to predict DDI and drug-food interaction potential. Organic OATPs (Watanabe et al., 2015a). Although the observed increase in the anion transporting polypeptides (OATPs) contribute to drug absorption and plasma concentration of DHEAS by rifampicin was less than that by statins, disposition (Tamai et al., 2000; Shitara et al., 2013). For example, OATPs plasma DHEAS was dose dependently increased by rifampicin. Despite the expressed in the liver take up various drugs into hepatocytes from the apparent differences in sensitivity for detecting the effect of rifampicin systemic circulation, thereby affecting systemic and liver exposures to these among these putative biomarkers, they might be broadly comparable when drugs (König, 2012; Shitara et al., 2013). OATP1B1 and OATP1B3 are key the dose of rifampicin in each study is taken into account, in spite of the molecules in the hepatic handling of drugs, and accurate predictions of difference in species (Nakakariya et al., 2008); however, it is not yet clear clinically significant DDIs on those OATPs are essential. Several probe drugs whether rifampicin affects only hepatic OATPs or whether other trans- to evaluate possible inhibitors of hepatic OATPs have been suggested, for porters and metabolic enzymes might contribute to the observed alterations. example, with statins as the “victims” (Yoshida et al., 2012; Prueksaritanont DHEAS is present in plasma at relatively high concentration, which makes it easy to analyze, and it has been proposed as a biomarker for aging- or disease-related physiologic changes (Stanczyk, 2006; Urbanski This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science [Grant 16H50111]. et al., 2013; Goodarzi et al., 2015). Since several factors other than dx.doi.org/10.1124/dmd.116.072355. OATPs may affect plasma DHEAS, as well as other potential biomarkers, s This article has supplemental material available at dmd.aspetjournals.org. it is essential to establish that the rifampicin-induced increase in plasma ABBREVIATIONS: AUC, area under the plasma concentration curve; AUCR, AUC ratio; CL, clearance; DDI, drug-drug interaction; DHEAS, dehydroepiandrosterone sulfate; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-tandem mass spectrometry; Kp, tissue-to-plasma concentration ratio; OATP, organic anion transporting polypeptide; Vdss, steady-state volume of distribution. 224 DHEAS as a Biomarker for OATP-based DDI 225 DHEAS is at least predominantly due to the interaction on hepatic uptake system was used to obtain the isocratic flow of the mobile phase at a rate of transporters, OATPs, to confirm the suitability of DHEAS as a possible 1.0 ml/min. biomarker. In the present study, therefore, we evaluated the in vivo Pharmacokinetic Analysis. Theplasmaconcentration-timedatawereanalyzed contribution of hepatic OATPs to the rifampicin-induced increase in the by noncompartmental analysis. The area under the plasma concentration time curve plasma concentration of DHEAS by measuring biliary and urinary (AUC0–4) was obtained by the trapezoidal rule from time 0 to 4 hours; AUC from 0toinfinity(AUC ) was estimated by extrapolation to infinity. Total clearance excretions, tissue concentrations, and pharmacokinetic parameters with inf (CL ) was estimated as dose (D)overAUC (D/AUC ), and renal clearance and without rifampicin. Since the endogenous plasma concentration of tot inf inf (CLurine) and biliary excretion clearance (CLbile) were estimated as Xurine,0-4/AUC0–4 DHEAS in the present rat model was unexpectedly low, to detect it by our and Xbile,0–4/AUC0–4,whereXurine,0–4 and Xbile,0–4 represent cumulative amounts of liquid chromatography-tandem mass spectrometry (LC-MS/MS) method DHEAS recovered in urine and bile, respectively. Biliary excretion clearance based (limit of detection: 0.5 nM), we evaluated the contribution of hepatic on liver tissue concentration (CLbile,liver) was estimated as Xbile,0–4/(Kpliver  AUC0–4). OATPS to the changes in DHEAS disposition by rifampicin by externally The apparent volume of distribution (Vdss)wasestimatedasVdss = CLtot  MRT, administering DHEAS. Furthermore, the usefulness of DHEAS as a where MRT is the mean residence time. The apparent tissue-to-plasma concentration biomarker was compared with that of other proposed markers reported in ratio (Kpliver and Kpkidney) was estimated as the ratio of liver or kidney concentration the literature. divided by the plasma concentration at 4 hours. Statistical Analysis. Student’s t test was used to analyze differences between groups. P , 0.05 was considered statistically significant. Materials and Methods Chemicals. Rifampicin, DHEAS, and dehydroepiandrosterone-d5-3-sulfate Downloaded from sodium salt were purchased from Wako Pure Chemical Industries (Osaka, Japan), Results and Discussion Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), and Sigma-Aldrich (St. Louis, MO), respectively. [3H]Dehydroepiandrosterone sulfate (2.22–3.70 Effect of Rifampicin on Pharmacokinetics of DHEAS. Endoge- TBq/mmol) sodium salt was purchased from PerkinElmer (Boston, MA). Other nous plasma concentration of DHEAS in rats was under the detection limit reagents and solvents were of analytical grade. of our LC-MS/MS method. Accordingly, in the present study, DHEAS Animals. Seven-week-old female Wistar rats (170–190 g) were purchased disposition was evaluated after i.v. administration of DHEAS. The plasma from Sankyo Labo Service (Tokyo, Japan). All animal studies were approved by concentration-time curves of DHEAS with and without i.v. rifampicin dmd.aspetjournals.org the Committee of Kanazawa University for the Care and Use of Laboratory (30 mg/kg)
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