Organic anion transporters (OAT) 1 and 3 are important for renal drug elimination. Assessment of the potential to cause transporter-mediated drug-drug interactions (DDI) is required during drug development. Clinical readouts could be improved by using endogenous biomarkers for transporter-mediated DDI. There is still a need for well-characterized, sensitive and specific biomarkers. From previous metabolomic studies in healthy volunteers, seven sensitive and specific potential biomarkers for OAT1/OAT3-mediated renal DDI were selected, which remained insufficiently characterized as substrates of OAT1, OAT3 and other drug transporters in vitro: indolelactic acid, cinnamoylglycine, indoleacetyl glutamine, phenylacetylglutamine, 1,7-dimethyluric acid, 1-methyluric acid and 7-methyluric acid. Therefore, we used cell models to characterize transport properties regarding OAT1, OAT3, organic anion transporting polypeptides 1B1 and 1B3, organic cation transporter 2, multidrug and toxin extrusion protein 1 and P-glycoprotein, together with OAT1/OAT3 transport kinetics for two most promising candidates. All seven potential biomarkers were identified as substrates of OAT1 and OAT3 (Km of indolelactic acid and indoleacetyl glutamine for OAT1: 319.4 ± 31.9 µM and 609.8 ± 129.2 µM, respectively; and for OAT3: 290.1 ± 41.0 µM and 161.4 ± 20.3 µM, respectively), while transport by other transporters was completely absent or low compared to OAT1/OAT3-mediated uptake. Altogether, based on the consistency of present in vitro and previous in vivo results and the possible impact of diet on disposition of the investigated potential biomarkers, indolelactic acid and indoleacetyl glutamine emerge as the most promising candidates for further validation as biomarkers for OAT1/OAT3-mediated renal drug-drug interactions.

Activating PIK3CA mutations, present in up to 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (Her2−) breast cancer (BC) patients, can be effectively targeted with the alpha isoform-specific PI3K inhibitor Alpelisib. This treatment significantly improves outcomes for HR+, Her2−, and PIK3CA-mutated metastatic BC patients. However, acquired resistance, often due to aberrant activation of the mTOR complex 1 (mTORC1) pathway, remains a significant clinical challenge. Our study, using in vitro and orthotopic xenograft mouse models, demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism. Mechanistically, mTORC1 suppresses the induction of autophagy during metabolic perturbation, leading to energy stress, a critical depletion of aspartate, and ultimately cell death. Supporting this mechanism, BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metabolically active drugs. In BC patients, high mTORC1 activity, indicated by 4E-BP1T37/46 phosphorylation, correlated with p62 accumulation, a sign of impaired autophagy. Together, these markers predicted poor overall survival in multiple BC subgroups. Our findings reveal that aberrant mTORC1 signaling, a common cause of PI3K inhibitor resistance in BC, creates a druggable metabolic vulnerability by suppressing autophagy. Additionally, the combination of 4E-BP1T37/46 phosphorylation and p62 accumulation serves as a biomarker for poor overall survival, suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.

The inhibition of renally expressed transport proteins such as organic cation transporter (OCT) 2 or multidrug and toxin extrusion protein (MATE) 1 can cause clinically relevant drug-drug interactions (DDIs). Endogenous biomarkers have been proposed as tools to characterize the DDI risk of new molecules in drug development. Many previously proposed biomarkers for OCT2/MATE1-mediated DDIs lack specificity and/or sensitivity indicating a need for additional, well characterized biomarkers. Recently, we demonstrated that treatment with cimetidine, a classical OCT/MATE-inhibitor, decreased the renal excretion of serotonin, tyramine, 1-methylhistamine, 5-amino valeric acid betaine, and 4-guanidinobutanoic acid in humans. So far, these compounds are incompletely characterized as substrates of OCT2, MATE1, and other drug transporters. We therefore used established cell models overexpressing OCT2 and/or MATE1, and cell models for other clinically important drug transporters (organic anion transporters 1 and 3, organic anion transporting polypeptides 1B1 and 1B3, and P-glycoprotein) to investigate the cellular uptake and/or vectorial transport of these 5 putative biomarkers. The in vitro results show that serotonin, tyramine, 1-methylhistamine, 5-amino valeric acid betaine, and 4-guanidinobutanoic acid are substrates of OCT2 and/or MATE1, supporting that the in vivo effect of cimetidine is due to inhibition of these transporters. Based on their transport by OCT2 and/or MATE1 compared to the minimal transport by other drug transporters and the in vivo effects of classical transport protein inhibitors in healthy volunteers, serotonin and 1-methylhistamine appear to be the most promising candidates for further validation as endogenous biomarkers for the early detection of clinically relevant OCT2- and MATE1-mediated renal DDIs. SIGNIFICANCE STATEMENT: This study characterizes 5 endogenous metabolites as substrates of the renally expressed transport proteins organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and other important drug transporters. These transport proteins are known as important contributors to clinically observed drug-drug interactions. Of the respective 5 compounds, serotonin and 1-methylhistamine are the most promising candidates to be further investigated as biomarkers for interactions via OCT2/MATE1, which could improve drug-drug interaction assessment during clinical drug development.

The L-arginine derivative and uremic toxin symmetric dimethylarginine (SDMA) is an independent risk marker for total mortality and cardiovascular events. Interferences with L-arginine- or L-homoarginine-related signaling, metabolism, or transport have been proposed as underlying mechanisms. SDMA is endogenously formed and predominantly eliminated via the kidney. Whereas for L-arginine and other L-arginine derivatives such as L-homoarginine and asymmetric dimethylarginine (ADMA) key transport proteins involved in the cellular uptake and release have been characterized, comparable data for the transport of SDMA are lacking.Using HEK cell lines overexpressing the transport proteins OCT2, OATP4C1, MATE1, OAT4, and OAT10, which are all expressed in renal proximal tubule cells, and the ubiquitously-expressed transport protein CAT1 we performed uptake experiments demonstrating that SDMA is a substrate for CAT1, OATP4C1, OCT2, and MATE1 in physiological concentrations, but not of OAT4 and OAT10. Km values for OATP4C1-, CAT1-, and MATE1-mediated SDMA uptake were 70 µM, 246 µM, and 1 973 µM, respectively. For OCT2-mediated uptake, no saturation could be reached, precluding the determination of a Km value. Uptake of SDMA by these transporters could be inhibited by known substrates of the respective transport proteins. Furthermore, CAT1 and OATP4C1 also mediate the efflux of SDMA out of cells.These results show that SDMA is a substrate of renally-expressed transport proteins OATP4C1, OCT2, and MATE1 and of CAT1 demonstrating that these transporters are involved in the homeostasis of this uremic toxin and possible sites of interactions with related compounds.

Background: The orexin receptor (OXR) plays a role in drug addiction and appears as a tumor marker in colon carcinoma. Subtype-selective OXR PET ligands have not yet been reported. The present work deals with the development of 18F-labeled OXR ligands dervived from selective OX1R antagonist JH112. Methods: Applying computational analysis, medicinal chemistry, integrated OXR binding studies, Cu-mediated 18F-fluorination and initial small animal PET studies, we evaluated a series of OXR ligands (1a-1f), varying the heteroarene scaffold of FH112 by 5-fluorobenzoxazole, 5-/6-fluorobenzthiazole and 6-fluoroquinoxaline. Receptor binding studies were preformed on HEK293T cells transiently expressing the OX1R and OX2R. Cu-mediated 18F-fluorination was performed on BPin and boroxine precursors. In vitro assays for logD7.4, stability in plasma, plasma-protein binding and potential P-gp-mediated transport in the Caco-2 monolayer model were performed. The brain uptake of 18F-labeled ligands was studied by dynamic PET imaging in rats. Results: Computational analysis predicted that fluorine substitution (1e) and introduction of the fluorobenzothiazole scaffold (1f) would be suitable for maintaining high OX1R affinity. After multi-step synthesis of 1a-1f, in vitro OXR binding studies confirmed molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a-f, ranging from 0.69 nM-2.5 nM. The benzothiazole 1f showed high OX1R affinity (Ki = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18F-fluorination of the nonselective OXR ligands benzothiazole [18F]1c and quinoxaline [18F]1d yielded RCY of 44% and 56%, respectively, after 10 min, compared to low RCY for benzoxazole [18F]1a of 12% after 20 min. The nonselective OXR ligand [18F]1c and the selective OX1R ligand [18F]1f gave total activity yields of 14% and 22%, respectively, using boroxine precursors for Cu-mediated 18F-fluorination with 5 min reaction time and a total synthesis time of 50-60 min. [18F]1c and [18F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([18F]1c) and 2.37 ([18F]1f), and high plasma-protein binding of 66% and 77%, respectively, reflecting only marginal differences in brain uptake of [18F]1c (0.17 %ID/g) and [18F]1f (0.15 %ID/g). 1c showed higher passive permeability than 1f in vitro, which was consistent with the faster brain clearance of [18F]1c compared to [18F]1f. However, preinjection of the OXR antagonist suvorexant did not significantly block [18F]1c or [18F]1f uptake in the rat brain. Pretreatment with cyclosporin A to study the role of P-gp in limiting brain accumulation moderately increased brain uptake of [18F]1c and [18F]1f. Accordingly, in vitro experiments demonstrated that the P-gp inhibitor zosuquidar only moderately inhibited polarized, basal to apical transport of 1c (p<0.05) and had no influence on transport of 1f (n.s.), indicating that P-gp does not play a relevant role in brain accumulation of [18F]1c and [18F]1f in vivo. Conclusions: The in vitro and in vivo results of [18F]1c and [18F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging. This could be achieved through structural changes that would result in lower blood protein binding and 18F labeling methods that would allow for improved molar activities.

BACKGROUND AND OBJECTIVES:Dermatological oral antitumor therapeutics (OAT) are often interaction-prone and used in complex regimens. The pharmacological/pharmaceutical care program of the randomized AMBORA trial significantly improved medication safety with various OAT; however, dermato-oncological patients were not included. It was subsequently implemented into clinical routine, including dermato-oncology. We aimed to analyze medication errors and adherence in patients treated with any dermatological OAT. PATIENTS AND METHODS:Medication errors were characterized, for example, according to their cause (PCNE V9.1). Adherence was assessed using the Medication Event Monitoring System (MEMS® Button) and the MARS-D questionnaire. Primary outcomes were the percentage of resolved OAT-involving errors and Dosing Adherence (DA); proportion of days with correct OAT intake) over 12 weeks. RESULTS:In 92 patients (81.5% melanoma), we detected 1.6 medication errors per patient and 61.6% involved the OAT. Thereof, 89.2% were resolved. Of 52 patients participating in the additional adherence monitoring, 48 were evaluable and reached a median DA of 95.0% and MARS-D score of 25/25. DA was higher in once- vs. twice-daily regimens (p = 0.0127). CONCLUSIONS:The interprofessional AMBORA care program in dermato-oncology was associated with the resolution of a large proportion of medication errors and high adherence. Evidence-based medication management and patient counseling by clinical pharmacologists/pharmacists optimizes medication safety in dermato-oncological practice.

BackgroundClinical pharmacy services and clinical decision support systems (CDSSs) are increasingly implemented to optimize medication safety. However, risks as overalerting can limit these benefits. Therefore, the Meona medication CDSS was interprofessionally evaluated and locally configured prior to implementation at Erlangen University Hospital.AimWe aimed to analyze the displayed CDSS alerts and to evaluate the content appropriateness and patient relevance of CDSS alerts in a hospital with established clinical ward pharmacists. Furthermore, we characterized pharmaceutical interventions triggered by CDSS and CDSS-independent interventions.MethodsPseudonymized clinical data of 160 patients from four clinical departments were prospectively included once between days 1 and 3 after hospital admission to analyze the frequency, type, and severity of the displayed CDSS alerts. All severe and “duplicate prescription” CDSS alerts were evaluated regarding their content appropriateness and patient relevance by clinical pharmacists using the four-eyes principle. For patient-relevant CDSS alerts, clinical ward pharmacists intervened during weekly ward rounds. All pharmaceutical interventions, including CDSS-independent interventions, were documented in ADKA-DokuPIK by recording reason, acceptance rate, and severity.ResultsIn total, 1,799 CDSS alerts (median 9.0/patient) were displayed. Of those, 33.9% (609/1,799) were classified as severe by Meona. Clinical pharmacists validated 647 CDSS alerts (609 severe and 38 “duplicate prescriptions”). Only 82.7% (535/647) were rated as content appropriate, of which 19.6% (105/535) were classified as patient relevant. The clinical ward pharmacists recorded 244 interventions in 150 patients discussed during rounds (1.6/patient). CDSS-independent interventions by clinical ward pharmacists (158/244, 64.8%) were significantly more frequent compared to pharmaceutical interventions triggered by the CDSS (86/244, 35.2%). (p = 0.0002). The acceptance rate of interventions was 92.2% (225/244). The most common severity category was C (error occurred, no harm).ConclusionDespite the locally customized medication CDSS, a high number of CDSS alerts were displayed. Interestingly, we still observed content-inappropriate CDSS alerts defined by pharmaceutical validation. The majority of CDSS alerts with appropriate content were rated not patient relevant in clinical practice and could be considered as overalerting. Our results highlight that a CDSS can support healthcare professionals but underline (1) the continuing need for clinical pharmacists to improve medication safety by interpreting CDSS alerts and performing comprehensive medication reviews and (2) the further need for CDSS improvements.

Objectives: Accumulating evidence argues for a more widespread use of therapeutic drug monitoring (TDM) to support individualized medicine, especially for therapies where toxicity and efficacy are critical issues, such as in oncology. However, development of TDM assays struggles to keep pace with the rapid introduction of new drugs. Therefore, novel approaches for faster assay development are needed that also allow effortless inclusion of newly approved drugs as well as customization to smaller subsets if scientific or clinical situations require. Methods: We applied and evaluated two machine-learning approaches i.e., a regression-based approach and an artificial neural network (ANN) to retention time (RT) prediction for efficient development of a liquid chromatography mass spectrometry (LC-MS) method quantifying 73 oral antitumor drugs (OADs) and five active metabolites. Individual steps included training, evaluation, comparison, and application of the superior approach to RT prediction, followed by stipulation of the optimal gradient. Results: Both approaches showed excellent results for RT prediction (mean difference +/- standard deviation: 2.08 % +/- 9.44 % ANN; 1.78 % +/- 1.93 % regression-based approach). Using the regression-based approach, the optimum gradient (4.91 % MeOH/min) was predicted with a total run time of 17.92 min. The associated method was fully validated following FDA and EMA guidelines. Exemplary modification and application of the regression-based approach to a subset of 14 uro-oncological agents resulted in a considerably shortened run time of 9.29 min. Conclusions: Using a regression-based approach, a multi drug LC-MS assay for RT prediction was efficiently developed, which can be easily expanded to newly approved OADs and customized to smaller subsets if required.

PURPOSE Implementation science endeavors to facilitate the translation of evidence-based research into clinical routine. The clinical pharmacological/pharmaceutical care program evaluated in the randomized AMBORA trial on medication safety with oral antitumor therapeutics (OAT) optimizes care delivery and provides significant benefits for patients, treatment teams, and health care systems. Thus, we aimed to investigate the implementation of this care program within the AMBORA Competence and Consultation Center (AMBORA Center). METHODS The AMBORA Center within a University Comprehensive Cancer Center offered several services (eg, patient consultations) and was evaluated according to the RE-AIM framework. This multicenter hybrid type III trial focused on implementation outcomes (eg, patient recruitment, referring units, evaluation of services) while concurrently investigating effectiveness (eg, side effects, medication errors). Quantitative and qualitative assessments were combined. RESULTS The AMBORA Center conducted over 800 consultations with 420 patients in seven institutions. The primary end point of counseling 70% of patients treated with OAT was not reached. Patients were referred by 15 treatment units compared with 11 units in the AMBORA trial. On the basis of heterogeneous referral rates and characteristics across the institutions, barriers and facilitators of the implementation process were derived. Several survey results (eg, stakeholder interviews, online/paper-based questionnaires) reflected a high appreciation of services by patients and health care professionals. The severity of 60.1% (178 of 296) of detected side effects improved, and 86.3% (297 of 344) of medication errors were resolved. CONCLUSION Despite not reaching the primary implementation outcome, the AMBORA Center included more treatment units and demonstrated patient benefit of the AMBORA care program by meeting all effectiveness outcomes. We outlined quantitative and qualitative implementation characteristics to enhance outreach and foster further dissemination of centers to optimize medication safety with OAT.

OBJECTIVE:Oral antitumour therapeutics (OAT) are increasingly used due to improvements in outcomes and their convenient application. However, complex intake regimens pose several challenges. The randomised AMBORA trial (Medication Safety With Oral Antitumour Drugs) demonstrated highly positive outcomes of a clinical pharmacological/pharmaceutical care program for adults treated with numerous OAT, but comparable concepts in paediatrics are lacking so far. METHODS:We used a parallel mixed-methods approach to develop a tailored pharmacological/pharmaceutical care program for OAT in paediatrics (youngAMBORA). We combined a quantitative analysis of tumour entities and used OAT in a paediatric cancer centre with a qualitative survey for patients, caregivers, and healthcare professionals to identify particular demands and educational needs (e.g., application problems, side effects). RESULTS:Leukaemia (77/315) and antimetabolites (95/151) were the most frequently observed entity and OAT, respectively. Of 22 surveyed patients, 81.8% wanted to be involved in oral medication education. Compared to caregivers, significantly more healthcare professionals graded the three most common application problems to be challenging ('Smell/taste': 32/36 vs. 23/42, p = 0.001; 'Refusal of intake': 31/36 vs. 16/42, p<0.001; 'Swallowing problems': 28/36 vs. 21/42, p = 0.011). We identified nine relevant side effects, of which two ('Skin dryness', 'Taste changes') were not included in 15 previously published core side effects of the Common Terminology Criteria of Adverse Events (CTCAE) item library. CONCLUSION:Based on the present findings, the tailored youngAMBORA care program will include: 1) counselling sessions for classic and targeted OAT, 2) child-friendly support with drug application, and 3) systematic evaluation of 17 relevant side effects from patients' and caregivers' points of view including age-appropriate information material.

OBJECTIVE:Mucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD. DESIGN:ACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models. RESULTS:ACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4+ and to a lesser extent in CD8+ T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4+ T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLYhigh CD4+ T cells and ameliorated chronic colitis. CONCLUSION:ACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.

BACKGROUND:Search engines often serve as a primary resource for patients to obtain drug information. However, the search engine market is rapidly changing due to the introduction of artificial intelligence (AI)-powered chatbots. The consequences for medication safety when patients interact with chatbots remain largely unexplored. OBJECTIVE:To explore the quality and potential safety concerns of answers provided by an AI-powered chatbot integrated within a search engine. METHODOLOGY:Bing copilot was queried on 10 frequently asked patient questions regarding the 50 most prescribed drugs in the US outpatient market. Patient questions covered drug indications, mechanisms of action, instructions for use, adverse drug reactions and contraindications. Readability of chatbot answers was assessed using the Flesch Reading Ease Score. Completeness and accuracy were evaluated based on corresponding patient drug information in the pharmaceutical encyclopaedia drugs.com. On a preselected subset of inaccurate chatbot answers, healthcare professionals evaluated likelihood and extent of possible harm if patients follow the chatbot's given recommendations. RESULTS:Of 500 generated chatbot answers, overall readability implied that responses were difficult to read according to the Flesch Reading Ease Score. Overall median completeness and accuracy of chatbot answers were 100.0% (IQR 50.0-100.0%) and 100.0% (IQR 88.1-100.0%), respectively. Of the subset of 20 chatbot answers, experts found 66% (95% CI 50% to 85%) to be potentially harmful. 42% (95% CI 25% to 60%) of these 20 chatbot answers were found to potentially cause moderate to mild harm, and 22% (95% CI 10% to 40%) to cause severe harm or even death if patients follow the chatbot's advice. CONCLUSIONS:AI-powered chatbots are capable of providing overall complete and accurate patient drug information. Yet, experts deemed a considerable number of answers incorrect or potentially harmful. Furthermore, complexity of chatbot answers may limit patient understanding. Hence, healthcare professionals should be cautious in recommending AI-powered search engines until more precise and reliable alternatives are available.

BACKGROUND:Computerized physician order entry (CPOE) and clinical decision support systems (CDSS) are widespread due to increasing digitalization of hospitals. They can be associated with reduced medication errors and improved patient safety, but also with well-known risks (e.g., overalerting, nonadoption). OBJECTIVES:Therefore, we aimed to evaluate a commonly used CDSS containing Medication-Safety-Validators (e.g., drug-drug interactions), which can be locally activated or deactivated, to identify limitations and thereby potentially optimize the use of the CDSS in clinical routine. METHODS:Within the implementation process of Meona (commercial CPOE/CDSS) at a German University hospital, we conducted an interprofessional evaluation of the CDSS and its included Medication-Safety-Validators following a defined algorithm: (1) general evaluation, (2) systematic technical and content-related validation, (3) decision of activation or deactivation, and possibly (4) choosing the activation mode (interruptive or passive). We completed the in-depth evaluation for exemplarily chosen Medication-Safety-Validators. Moreover, we performed a survey among 12 German University hospitals using Meona to compare their configurations. RESULTS:Based on the evaluation, we deactivated 3 of 10 Medication-Safety-Validators due to technical or content-related limitations. For the seven activated Medication-Safety-Validators, we chose the interruptive option ["PUSH-(&PULL)-modus"] four times (4/7), and a new, on-demand option ["only-PULL-modus"] three times (3/7). The site-specific configuration (activation or deactivation) differed across all participating hospitals in the survey and led to varying medication safety alerts for identical patient cases. CONCLUSION:An interprofessional evaluation of CPOE and CDSS prior to implementation in clinical routine is crucial to detect limitations. This can contribute to a sustainable utilization and thereby possibly increase medication safety.

The inhibition of renal transport proteins organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and organic anion transporters (OAT1, OAT3) causes clinically relevant drug-drug interactions (DDI). Endogenous biomarkers could be used to improve risk prediction of such renal DDIs. While a number of biomarkers for renal DDIs have been described so far, multiple criteria for valid biomarkers have frequently not been investigated, for example, specificity, metabolism, or food effects. Therefore, there is a need for novel biomarkers of renal DDIs. Here, we investigated the global metabolomic effects following the administration of two classical inhibitors of renal transport proteins [cimetidine (OCT2/MATEs), probenecid (OATs)] in human plasma and urine of healthy volunteers. Additionally, we investigated metabolomic effects of two inhibitors of other transporters [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides)] as controls. This analysis shows that both cimetidine and probenecid affect compounds involved in caffeine metabolism, carnitines, and sulfates. Hierarchical cluster analysis of the effects of all four inhibitors on endogenous compounds identified multiple promising new sensitive and specific biomarker candidates for OCT2/MATE- or OAT-mediated DDIs. For OCT2/MATEs, 5-amino valeric acid betaine (median log2-fold change of estimated renal elimination: -3.62) presented itself as a promising candidate. For OATs, estimated renal elimination of 7-methyluric acid and cinnamoylglycine (median log2-fold changes -3.10 and -1.92, respectively) was both sensitive and specific. This study provides comprehensive information on metabolomic effects of transport protein inhibition in humans and identifies putative new sensitive and specific biomarkers for renal transporter-mediated DDIs.

Determination of serum creatinine concentrations and subsequent calculation of estimated glomerular filtration rates (eGFR) is a cornerstone of clinical medicine. Crucial clinical decisions such as drug treatment discontinuations are based on eGFR calculated from serum creatinine measurements. However, creatinine is not only filtered in the kidneys, but also actively secreted into urine. Creatinine transporters such as OCT2, OCT3, MATE1, MATE2-K, and OAT2 expressed in proximal tubular cells are responsible for active renal secretion of creatinine. Multiple drugs (e.g., oral antitumor drugs) inhibit these transporters thereby causing a pseudo-worsening of kidney function with an increase in serum creatinine concentrations and a decrease in eGFR while other methods for eGFR determination (e.g., by cystatin C) reveal normal kidney function. Since US Prescribing Information (PI) and European Summaries of Product Characteristics (SmPCs) are the most relevant source of information for physicians, we investigated the quality of information in US PI/German SmPCs of drugs with clear evidence for pseudo-worsening of kidney function. 514 drugs putatively interacting with creatinine transporters were identified. For 149 of those drugs, an increase in serum creatinine concentrations has been described. Available data confirmed the existence of pseudo-worsening of kidney function for 30 of those drugs, for the remaining 119 drugs existing data are insufficient. Only 23.5% (12/51) of the 30 drugs' PI/SmPCs contained unambiguous statements on this proven pseudo-worsening of kidney function and gave clear recommendations for clinical management. Taken together, inadequate information provided in PI or SmPCs on the pseudo-worsening of kidney function poses patients at unnecessary risks.