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Objective: The uptake of drugs into hepatocytes is a key determinant for hepatic metabolism, intrahepatic action, their subsequent systemic plasma concentrations, and extrahepatic actions. In vitro and in vivo studies indicate that many drugs used for treatment of cardiovascular diseases (e.g., oral antidiabetic drugs, statins) are taken up into hepatocytes by distinct organic anion transporters (organic anion transporting polypeptides [OATPs]; gene symbol SLCO/SLC21) or organic cation transporters (OCTs; gene symbol SLC22). Because most patients with type 2 diabetes receive more than one drug and inhibition of drug transporters has been recognized as a new mechanism underlying drug-drug interactions, we tested the hypothesis of whether oral antidiabetic drugs can inhibit the transport mediated by hepatic uptake transporters. Research Design and Methods: Using stably transfected cell systems recombinantly expressing the uptake transporters OATP1B1, OATP1B3, OATP2B1, or OCT1, we analyzed whether the antidiabetic drugs repaglinide, rosiglitazone, or metformin influence the transport of substrates and drugs (for OATPs, sulfobromophthalein [BSP] and pravastatin; for OCT1, 1-methyl-4-phenylpyridinium [MPP(+)] and metformin). Results: Metformin did not inhibit the uptake of OATP and OCT1 substrates. However, OATP-mediated BSP and pravastatin uptake and OCT1-mediated MPP(+) and metformin uptake were significantly inhibited by repaglinide (half-maximal inhibitory concentration [IC(50)] 1.6-5.6 micromol/l) and rosiglitazone (IC(50) 5.2-30.4 micromol/l). Conclusions: These in vitro results demonstrate that alterations of uptake transporter function by oral antidiabetic drugs have to be considered as potential mechanisms underlying drug-drug interactions. [ABSTRACT FROM AUTHOR]

Background: Torasemide is frequently used for the treatment of hypertension and heart failure. However, the determinants of torasemide pharmacokinetics in patients during steady-state conditions are largely unknown. We therefore explored the impact of genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), gender, and the effects of losartan and irbesartan comedication on the interindividual variability of steady-state pharmacokinetics of torasemide.Patients and Methods: Twenty-four patients receiving stable medication with torasemide 10 mg once daily and with an indication for additional angiotensin II receptor blocker (ARB) treatment to control hypertension or to treat heart failure were selected. Blood samples were taken before torasemide administration and 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. After this first study period, patients received either irbesartan 150 mg (five female and seven male patients aged 69+/-8 years) or losartan 100 mg (two female and ten male patients aged 61+/-8 years) once daily. After 3 days of ARB medication, eight blood samples were again collected at the timepoints indicated above. The patients' long-term medications, which did not include known CYP2C9 inhibitors, were maintained at a constant dose during the study. All patients were genotyped for CYP2C9 (*1/*1 [n=15]; *1/*2 [n = 4]; *1/*3 [n=5]) as well as for SLCO1B1 (c.521TT [n=13]; c.521TC [n=11]).Results: Factorial ANOVA revealed an independent impact of the CYP2C9 genotype (dose-normalized area under the plasma concentration-time curve during the 24-hour dosing interval at steady state [AUC(24,ss)/D]: *1/*1 375.5+/-151.4 microg x h/L/mg vs *1/*3 548.5+/-271.6 microg x h/L/mg, p=0.001), the SLCO1B1 genotype (AUC(24,ss)/D: TT 352.3+/-114 microg x h/L/mg vs TC 487.6+/-218.4 microg x h/L/mg, p<0.05) and gender (AUC(24,ss)/D: males 359.5+/-72.2 microg x h/L/mg vs females 547.3+/-284 microg x h/L/mg, p<0.01) on disposition of torasemide. Coadministration of irbesartan caused a 13% increase in the AUC(24,ss)/D of torasemide (p=0.002), whereas losartan had no effect.Conclusion: This study shows that the CYP2C9*3 and SLCO1B1 c.521TC genotype and female gender are significant and independent predictors of the pharmacokinetics of torasemide. Coadministration of irbesartan yields moderate but significant increases in the torasemide plasma concentration and elimination half-life. [ABSTRACT FROM AUTHOR]

Objectives: We investigated whether the loss of function CYP2C19 681G>A *2 polymorphism is associated with high (>14%) residual platelet aggregation (RPA) on clopidogrel and whether high on-clopidogrel RPA impacts clinical outcome after elective coronary stent placement.Background: The cytochrome P450 (CYP)-dependent conversion of clopidogrel to its active metabolite may contribute to the variability in antiplatelet effect of clopidogrel.Methods: The study included 797 consecutive patients undergoing percutaneous coronary intervention, who were followed-up for 1 year. Adenosine-diphosphate-induced (5 mumol/l) RPA was assessed after a 600-mg loading dose and after the first 75-mg maintenance dose of clopidogrel before discharge. CYP2C19 genotype was analyzed by real-time polymerase chain reaction.Results: Of the patients included, 552 (69.3%) were CYP2C19 wild-type homozygotes (*1/*1) and 245 (30.7%) carried at least one *2 allele. Residual platelet aggregation at baseline did not differ significantly between genotypes. On clopidogrel, RPA was significantly (p < 0.001) higher in *2 carriers than in wild-type homozygotes (23.0% [interquartile range (IQR) 8.0% to 38.0%] vs. 11.0% [IQR 3.0% to 28.0%] after loading; 11.0% [IQR 5.0% to 22.0%] vs. 7.0% [IQR 3.0% to 14.0%] at pre-discharge). Between *2 carriers and wild-type homozygotes, we found significant (p < 0.001) differences in the proportion of patients with RPA >14%, both after loading (62.4% vs. 43.4%) and at pre-discharge (41.3% vs. 22.5%). Residual platelet aggregation >14% at pre-discharge incurred a 3.0-fold increase (95% confidence interval 1.4 to 6.8; p = 0.004) in the 1-year incidence of death and myocardial infarction.Conclusions: Patients carrying at least one CYP2C19*2 allele are more prone to high-on clopidogrel platelet reactivity, which is associated with poor clinical outcome after coronary stent placement (Effect of Clopidogrel Loading and Risk of PCI [EXCELSIOR]; NCT00457236). [ABSTRACT FROM AUTHOR]

Objectives: Urinary steroid profiling after hydrolysis of conjugates is an emerging tool to differentiate aggressive adrenocortical carcinomas (ACC) from benign adrenocortical adenomas (ACA). However, the shortcomings of deconjugation are the lack of standardized and fully validated hydrolysis protocols and the loss of information about the originally conjugated form of the steroids. This study aimed to evaluate the quality of the deconjugation process and investigate novel diagnostic biomarkers in urine without enzymatic hydrolysis., Methods: 24 h urine samples from 40 patients with ACC and 40 patients with ACA were analyzed by untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry both unmodified and after hydrolysis with arylsulfatase/glucuronidase from Helix pomatia. Both approaches were compared regarding the differentiation of ACC vs. ACA via ROC analyses and to evaluate the hydrolyzation efficiency of steroid conjugates., Results: Steroid glucuronides were fully deconjugated, while some disulfates and all monosulfates were still largely detectable after enzymatic hydrolysis, suggesting incomplete and variable deconjugation. In unhydrolyzed urine, steroid monosulfates showed the best differentiation between ACC and ACA (highest AUC=0.983 for C 21 H 32 O 6 S, followed by its isomer and two isomers with the molecular formula C 21 H 32 O 7 S). Moreover, several disulfates were highly abundant and increased in ACC compared to ACA., Conclusions: This work highlights the limitations of hydrolyzing steroid conjugates before analysis and shows a possible superiority of a direct analysis approach compared to a hydrolysis approach from a methodological point of view and regarding diagnostic accuracy. Several steroid conjugates were found as promising diagnostic biomarkers for differentiation between ACC and ACA., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

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 log 2 -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 log 2 -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., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Financial competing interests: KG has received lecture fees from AstraZeneca. MFF has received consultancy fees and lecture fees from Boehringer Ingelheim and third-party funds for research projects at his institution by Boehringer Ingelheim and Heidelberg Pharma Research GmbH. FD has received consultancy fees from Lilly Deutschland and SANDOZ AG and has received lecture fees from E. Lilly and Janssen. KG, MFF, and FD received an earmarked financial contribution for the first award of the MSD Germany Health Award 2021. PL, LC, and MM declared that no financial competing interests exist. Non-financial interests: The authors have declared that no non-financial competing interests exist., (Copyright: © 2024 Lensker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: Previous work has identified several limitations in "Summaries of Product Characteristics" (SmPCs), which are associated with risks for patients. The aim of this study was to evaluate pharmacists' and physicians' interpretation of contraindications in SmPCs and reasons for their nonadherence in clinical routine., Methods: For 20 commonly missed or ignored absolute contraindications, an anonymous online survey providing 24 clinical example cases (one or two per contraindication) for physicians and pharmacists was developed. Experts in medication safety were asked whether the respective case fulfilled the definition of the contraindication in the SmPC: (a) formally, irrespective of the clinical relevance of the contraindication (17 cases), and (b) whether the contraindication was deemed clinically relevant in each respective case (24 cases)., Results: Twenty-seven pharmacists and 27 physicians completed the survey. For only one case (1/17; 5.8%) did all experts agree on the same answer option regarding the formal fulfilment of a given contraindication statement. Experts gave heterogeneous answers regarding the interpretation of a contraindication. For instance, among 10 predefined answer options for the contraindication "active liver disease" in the SmPC of simvastatin, every option was selected by at least six experts. In 17/24 (70.8%) clinical example cases a majority of experts agreed on the clinical relevance of a given contraindication. Key reasons for nonadherence to contraindications were "patient monitoring possible", "lack of alternative treatment" and "acute/severe situations"., Conclusions: Experts' disagreement on the interpretation of contraindications in SmPCs using clinical example cases indicates that further efforts are needed to improve their usability in clinical routine., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

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., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Amino acids are important for cellular metabolism. Their uptake across the plasma membrane is mediated by transport proteins. Despite the fact that the organic anion transporting polypeptide 4C1 (OATP4C1, Uniprot: Q6ZQN7) mediates transport of l-arginine and l-arginine derivatives, other members of the OATP family have not been characterized as amino acid transporters. The OATP family member OATP3A1 (gene symbol SLCO3A1, Uniprot: Q9UIG8) is ubiquitously expressed in human cells and highly expressed in many cancer tissues and cell lines. However, only a few substrates are known for OATP3A1. Accordingly, knowledge about its biological relevance is restricted. Our aim was to identify new substrates of OATP3A1 to gain insights into its (patho-)physiological function. In an LC-MS-based untargeted metabolomics assay using untreated OATP3A1-overexpressing HEK293 cells and control cells, we identified several amino acids as potential substrates of OATP3A1. Subsequent uptake experiments using exogenously added substrates revealed OATP3A1-mediated transport of l-tryptophan, l-tyrosine, and l-phenylalanine with 194.8 ± 28.7% (P < 0.05), 226.2 ± 18.7% (P < 0.001), and 235.2 ± 13.5% (P < 0.001), respectively, in OATP3A1-overexpressing cells compared to control cells. Furthermore, kinetic transport parameters (K m values) were determined (Trp = 61.5 ± 14.2 μm, Tyr = 220.8 ± 54.5 μm, Phe = 234.7 ± 20.6 μm). In summary, we identified the amino acids l-tryptophan, l-tyrosine, and l-phenylalanine as new substrates of OATP3A1. These findings could be used for a better understanding of (patho-)physiological processes involving increased demand of amino acids, where OATP3A1 should be considered as an important uptake transporter of l-tryptophan, l-tyrosine, and l-phenylalanine., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

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., Competing Interests: Competing interests: FK is an employee of GSK, Wavre, Belgium., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed in colorectal tumors. Subtype-selective OXR PET ligands suitable for in vivo use have not yet been reported. This work reports the development of 18 F-labeled OXR PET ligand candidates derived from the OXR antagonist suvorexant and the OX1R-selective antagonist JH112., 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 the molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a-f, ranging from 0.69 to 2.5 nM. The benzothiazole 1f showed high OX1R affinity (K i  = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18 F-fluorination of boroxine precursors allowed for a shortened reaction time of 5 min to provide the non-selective OXR ligand [ 18 F]1c and its selective OX1R congener [ 18 F]1f in activity yields of 14% and 22%, respectively, within a total synthesis time of 52-76 min. [ 18 F]1c and [ 18 F]1f were stable in plasma and serum in vitro, with logD 7.4 of 2.28 ([ 18 F]1c) and 2.37 ([ 18 F]1f), and high plasma protein binding of 66% and 77%, respectively. Dynamic PET imaging in rats showed similar brain uptake of [ 18 F]1c (0.17%ID/g) and [ 18 F]1f (0.15%ID/g). However, preinjection of suvorexant did not significantly block [ 18 F]1c or [ 18 F]1f uptake in the rat brain. Pretreatment with cyclosporine A to study the role of P-glycoprotein (P-gp) in limiting brain accumulation moderately increased brain uptake of [ 18 F]1c and [ 18 F]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 effect on the transport of 1f, indicating that P-gp does not play a relevant role in brain accumulation of [ 18 F]1c and [ 18 F]1f in vivo., Conclusions: The in vitro and in vivo results of [ 18 F]1c and [ 18 F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging., (© 2024. The Author(s).)

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.

The randomized AMBORA trial showed that medication errors are frequent in patients treated with oral antitumor therapeutics and that they can be substantially reduced by an intensified clinical pharmacological/pharmaceutical care program. While randomized controlled trials are essential to generate clinical evidence, their generalizability in real-world is not always given. The AMBORA care program was implemented in clinical routine within the AMBORA Competence and Consultation Center (AMBORA Center) at the Comprehensive Cancer Center Erlangen-EMN, allowing a thorough comparison of medication error frequencies and characteristics. Our primary analysis compared data at therapy initiation of new oral antitumor therapeutics from the AMBORA trial intervention group (n = 98) and the AMBORA Center (n = 142). Medication errors involving the oral antitumor therapeutics were twofold higher in real-world compared to the randomized controlled trial (mean 0.83 ± 0.80 per patient vs. 0.41 ± 0.53, P < 0.001). We observed more complex oral antitumor therapeutic regimens, a higher median number of medications, and a higher ECOG status in clinical routine vs. the randomized trial. A high percentage of medication errors was completely solved in both groups (85.7% vs. 88.3%, ns). Medication error characteristics within the complete medication (oral antitumor therapeutics and concomitant medication) were similar in both groups (e.g., patient-related causes, drug-drug/drug-food interactions). Taken together, medication errors were even more frequent in clinical routine than in the randomized controlled trial and a high rate was solved in clinical routine by a clinical pharmacological/pharmaceutical care program., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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., Competing Interests: M.F.F.: consulting or advisory roles (Boehringer Ingelheim); research funding (Boehringer Ingelheim, Heidelberg Pharma Research GmbH); other relationship (earmarked financial contribution for the first award of the MSD Germany Health Award 2021).F.D.: honoraria (lecture fees from E. Lilly); consulting or advisory roles (Boehringer Ingelheim, Lilly Deutschland, Pfizer Pharma GmbH, SANDOZ AG); other relationship (earmarked financial contribution for the first award of the MSD Germany Health Award 2021).All other authors declare no competing interests. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

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 ACLY high 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., Competing Interests: Competing interests: MFN has served as an advisor for Pentax, Giuliani, MSD, Abbvie, Janssen, Takeda and Boehringer. Moreover, MFN serves as an associated editor of the journal Gut. The remaining authors disclose no conflicts., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Endogenous biomarkers are discussed as tools for detection of drug-drug interactions (DDIs) mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2-K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intra-study comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of 10 previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with 4 inhibitors of transport proteins [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N-oxide were both sensitive and specific (median log2-fold changes -1.18 in estimated renal elimination and -0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2-fold changes -3.77 and -2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid, and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE- and OAT-mediated DDIs., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Solute carrier (SLC) transport proteins are fundamental for the translocation of endogenous compounds and drugs across membranes, thus playing a critical role in disease susceptibility and drug response. Because only a limited number of transporter substrates are currently known, the function of a large number of SLC transporters is elusive. Here, we describe the proof-of-concept of a novel strategy to identify SLC transporter substrates exemplarily for the proton-coupled peptide transporter (PEPT) 2 (SLC15A2) and multidrug and toxin extrusion (MATE) 1 transporter (SLC47A1), which are important renal transporters of drug reabsorption and excretion, respectively. By combining metabolomic profiling of mice with genetically-disrupted transporters, in silico ligand screening and in vitro transport studies for experimental validation, we identified nucleobases and nucleoside-derived anticancer and antiviral agents (flucytosine, cytarabine, gemcitabine, capecitabine) as novel drug substrates of the MATE1 transporter. Our data confirms the successful applicability of this new approach for the identification of transporter substrates in general, which may prove particularly relevant in drug research., Competing Interests: Declaration of Competing Interest Independently from this work, M.S. received support by Green Cross WellBeing Co. Ltd., Gilead Sciences Inc., Robert Bosch GmbH, CORAT Therapeutics GmbH, and Agena Bioscience. All other authors declare they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Aims: Prescribing information should follow a defined structure to help prescribers easily find required information. Often information appears in different sections of Summaries of Product Characteristics (SmPCs) in an inconsistent way. Still unknown is how this inconsistency affects absolute contraindications and how it can be improved. Thisstudy aimed to evaluate the structure of absolute contraindications in SmPCs based on absolute drug-drug contraindications (DDCI) in the section 'contraindications' and references to sections 'special warnings and precautions for use' (here as 'warnings') and 'interaction with other medicinal products and other forms of interaction' (here as 'interactions')., Methods: SmPCs of 693 commonly prescribed drugs were analysed regarding absolute DDCI in 'contraindications' sections. References to sections on 'warnings' and 'interactions' were evaluated to characterize information provided about DDCI., Results: Of 693 analysed SmPCs, 138 (19.9%) contained ≥1 absolute DDCI. Of 178 SmPCs that referred to sections on 'warnings' or 'interactions', 131 (73.6%) did not contain further information on absolute DDCI, whereas 47 (26.4%) did. Such additional information was found in sections on 'interactions' and 'warnings' in 41 (87.2%) and 9 (19.1%) SmPCs, respectively., Conclusions: Information regarding absolute DDCI was found not only in sections on 'contraindications' but also in sections on 'warnings' and 'interactions'. Information was not given with consistently straightforward phrasing and structure and so can leave uncertainty for prescribers. To improve drug safety, clear definitions and wording for absolute and relative contraindications should be provided, ideally in tables., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The high affinity dopamine D 4 receptor ligand APH199 and derivatives thereof exhibit bias toward the G i signaling pathway over β-arrestin recruitment compared to quinpirole. Based on APH199, two novel groups of D 4 subtype selective ligands were designed and evaluated, in which the original benzyl phenylsemicarbazide substructure was replaced by either a biphenylmethyl urea or a biphenyl urea moiety. Functional assays revealed a range of different bias profiles among the newly synthesized compounds, namely, with regard to efficacy, potency, and GRK2 dependency, in which bias factors range from 1 to over 300 and activation from 15% to over 98% compared to quinpirole. These observations demonstrate that within bias, an even more precise tuning toward a particular profile is possible, which─in a general sense─could become an important aspect in future drug development. Docking studies enabled further insight into the role of the ECL2 and the EPB in the emergence of bias, thereby taking advantage of the diversity of functionally selective D 4 agonists now available.

Generating evidence for the efficacy of an intervention is not sufficient to guarantee its implementation in real-world settings. The randomized AMBORA trial (Medication Safety with Oral Antitumor Therapy) demonstrated that an intensified clinical pharmacological/pharmaceutical care program has substantial benefits for patients, treatment teams, and the healthcare system. Thus, we are now investigating its implementation into routine care within the AMBORA Competence and Consultation Center (AMBORA Center). We perform a multicenter type III hybrid trial following the RE-AIM framework to assess the clinical effectiveness of this care program under real-world conditions, while evaluating the implementation outcomes. Semi-structured stakeholder interviews based on the Consolidated Framework for Implementation Research (CFIR) have been conducted to identify barriers and facilitators. So far, 332 patients treated with oral antitumor drugs have been referred to the AMBORA Center by 66 physicians from 13 independent clinical units. In 20 stakeholder interviews (e.g., with clinic directors), 30% (6/20) of the interviewees anticipated possible barriers which may partly hinder sustainable implementation (e.g., unavailable consultation rooms). Furthermore, important facilitators (e.g., operational processes) were identified. This methodological description adds knowledge on how to structure a hybrid effectiveness-implementation trial and proposes multilevel implementation strategies to improve the medication safety of oral antitumor therapy.

N 1 -methylnicotinamide (NMN) has been proposed as endogenous biomarker for drug-drug interactions mediated by inhibition of multidrug and toxin extrusion proteins (MATEs) at the renal proximal tubule. We analyzed NMN in plasma and urine samples of two clinical trials investigating a new probe drug cocktail (consisting of digoxin, metformin, furosemide, and rosuvastatin) dedicated to clinically relevant drug transporters. In trial 1, NMN was investigated after single-dose treatment with individual cocktail components or after cocktail treatment. In trial 2, NMN was investigated after treatment with cocktail alone or with cocktail + inhibitor (cimetidine, a MATE inhibitor; or rifampin, verapamil, or probenecid, inhibitors of other transporters). In trial 1, NMN kinetics in plasma and urine were essentially not affected by individual cocktail components or after cocktail treatment. In trial 2, NMN renal clearance from 0 to 12 hours (CL R,0-12 ) geometric mean ratio (GMR) after cocktail + cimetidine vs. cocktail alone was 75% (90% confidence interval (CI): 65-87%). NMN CL R GMR after cocktail + verapamil, + rifampin, or + probenecid vs. cocktail alone was 99% (90% CI: 81-121%), 91% (90% CI: 75-111%), and 107% (90% CI: 91-126%), respectively. Compared with creatinine CL R and creatinine area under the plasma-concentration time curve, NMN CL R was more specific and more sensitive for renal MATE inhibition. Absence of impact of the cocktail on NMN in trial 1 allows for utilization of NMN in studies using this transporter cocktail. Trial 2 data support that NMN CL R is a specific and sensitive marker for MATE-mediated renal drug-drug interactions., (© 2023 Boehringer Ingelheim Pharma GmbH & Co. KG and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Due to alternative splicing, the SLCO1B3 gene encodes two protein variants; the hepatic uptake transporter liver-type OATP1B3 (Lt-OATP1B3) and the cancer-type OATP1B3 (Ct-OATP1B3) expressed in several cancerous tissues. There is limited information about the cell type-specific transcriptional regulation of both variants and about transcription factors regulating this differential expression. Therefore, we cloned DNA fragments from the promoter regions of the Lt-SLCO1B3 and the Ct-SLCO1B3 gene and investigated their luciferase activity in hepatocellular and colorectal cancer cell lines. Both promoters showed differences in their luciferase activity depending on the used cell lines. We identified the first 100 bp upstream of the transcriptional start site as the core promoter region of the Ct-SLCO1B3 gene. In silico predicted binding sites for the transcription factors ZKSCAN3, SOX9 and HNF1α localized within these fragments were further analyzed. The mutagenesis of the ZKSCAN3 binding site reduced the luciferase activity of the Ct-SLCO1B3 reporter gene construct in the colorectal cancer cell lines DLD1 and T84 to 29.9% and 14.3%, respectively. In contrast, using the liver-derived Hep3B cells, 71.6% residual activity could be measured. This indicates that the transcription factors ZKSCAN3 and SOX9 are important for the cell type-specific transcriptional regulation of the Ct-SLCO1B3 gene.

Cold atmospheric plasma (CAP) describes a partially ionized gas carrying large amounts of reactive oxygen (ROS) and nitrogen species (RNS). Numerous studies reported strong antitumor activity of CAP, thus rendering it a promising approach for tumor therapy. Although several cellular mechanisms of its cytotoxicity were identified in recent years, the exact molecular effects and contributing signaling pathways are yet to be discovered. We discovered a strong activation of unfolded protein response (UPR) after CAP treatment with increased C/EBP homologous protein (CHOP) expression, which was mainly caused by protein misfolding and calcium loss in the endoplasmic reticulum. In addition, both ceramide level and ceramide metabolism were reduced after CAP treatment, which was then linked to the UPR activation. Pharmacological inhibition of ceramide metabolism resulted in sensitization of melanoma cells for CAP both in vitro and ex vivo. This study identified a novel mechanism of CAP-induced apoptosis in melanoma cells and thereby contributes to its potential application in tumor therapy.

Regulatory authorities put major emphasis on QT (interval)-prolonging properties of new molecular entities. Product information/Summaries of Product Characteristics (SmPCs) of multiple drugs contain warnings or contraindications regarding QT prolongation, e.g., on coadministration of QT-prolonging drugs (QT drugs). To characterize the development of the QT drug burden, we performed a trend analysis of prescriptions and co-prescriptions of QT drugs in a large geriatric inpatient cohort. The German SmPCs (status of 2014 and of 2021) and the year-wise listings in the CredibleMeds ® database from 2011 to 2021 were used as sources. There were 402,631 geriatric cases included. The group of QT drugs according to SmPCs in 2014, which must not be combined with other QT drugs, was less frequently involved in contraindicated co-prescriptions in 2021 compared with 2015 (3.0% (2.5-3.7%) of cases with at least one of those drugs in 2021 vs. 4.0% (3.5-4.5%) in 2015), with citalopram, escitalopram, and amiodarone involved in nearly 90% of the co-prescriptions. The number of CredibleMeds-QT-drugs per patient increased from 0.4 (SD=1.1) in 2011 to 1.8 (SD=3.9) in 2021. The percentage of contraindicated co-prescriptions of drugs with known risk for torsade de pointes according to CredibleMeds ® listings at the beginning of the respective years increased from 1.7% in 2011 to 6.1% in 2021. Considering the regularly updated CredibleMeds ® QT drugs list, the contraindicated co-prescriptions of QT drugs markedly increased in the last decade. If prescribers considered only the few most frequently (co-) prescribed QT drugs, then most of the medication errors regarding QT drugs could be prevented., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Drug-related problems (DRPs), i.e., adverse drug reactions (ADRs) and medication errors (MEs), constitute a serious threat to the patient's safety. DRPs are often insufficiently captured by clinical routine documentation, and thus, they frequently remain unaddressed. The aim of this study was to assess the coverage and usability of the new 11th revision of the WHO International Classification of Diseases (ICD-11) to document DRPs. We refined the 'Quality and Safety Algorithm' from the ICD-11 Reference Guide and used it for DRP reporting to code 100 different anonymized DRPs (50 ADRs and 50 MEs) in a German hospital. The ICD-11 three-part model consisting of harm, cause, and mode was used whenever they were applicable. Of 50 ADRs, 15 (30.0%), such as drug-induced osteoporosis, were fully classifiable and codable by the ICD-11, whereas 35 (70.0%), such as drug-induced hypokalaemia, could not be fully classified due to sanctioning rules preventing the postcoordination (i.e., a combination of specific codes, such as drug and diagnosis). However, coding without the loss of information was possible in the 35 of these 35 (100.0%) ADR cases when we were deviating from the cluster code order of the Reference Guide. In all 50 MEs, the mode could be encoded, but for none of the MEs, postcoordination, i.e., the assignment of the ME to a specific drug, was allowed. In conclusion, the ICD-11 three-part model enables us to acquire more detailed documentation of DRPs than the previous ICD versions did. However, the codability, documentation, and reporting of DRPs could be significantly improved by simple modifications of the current ICD-11 sanctioning rules and by the addition of new ICD-11 codes.

Aims: Automated checks for medication-related problems have become a cornerstone of medication safety. In many clinical settings medication checks remain confined to drug-drug interactions because only medication data are available in an adequately coded form, leaving possible contraindicated drug-disease combinations unaccounted for. Therefore, we devised algorithms that identify frequently contraindicated diagnoses based on medication patterns related to these diagnoses., Methods: We identified drugs that are associated with diseases constituting common contraindications based on their exclusive use for these conditions (such as allopurinol for gout or salbutamol for bronchial obstruction). Expert-based and machine learning algorithms were developed to identify diagnoses based on highly specific medication patterns. The applicability, sensitivity and specificity of the approach were assessed by using an anonymized real-life sample of medication and diagnosis data excerpts from 3506 discharge records of geriatric patients., Results: Depending on the algorithm, the desired focus (i.e., sensitivity vs. specificity) and the disease, we were able to identify the diagnoses gout, epilepsy, coronary artery disease, congestive heart failure and bronchial obstruction with a specificity of 44.0-99.8% (95% CI 41.7-100.0%) and a sensitivity of 3.8-83.1% (95% CI 1.0-86.1%). Using only medication data, we were able to identify 123 (51.3%) of 240 contraindications identified by experts with access to medication data and diagnoses., Conclusion: This study provides a proof of principle that some key diagnosis-related contraindications can be identified based on a patient's medication data alone, while others cannot be identified. This approach offers new opportunities to analyse drug-disease contraindications in community pharmacy or clinical routine data., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Drug-related problems (e.g., adverse drug reactions, ADR) are serious safety issues in patients treated with oral anticancer therapeutics (OAT). The previously published randomized AMBORA trial showed that an intensified clinical pharmacological/pharmaceutical care program within the first 12 weeks of treatment reduces the number and severity of ADR as well as hospitalization rates in 202 patients. The present investigation focused on unscheduled hospitalizations detected within AMBORA and analyzed the characteristics (e.g., frequency, involved OAT) and cost of each hospital stay. To estimate the potential savings of an intensified care program in a larger group, the absolute risk for OAT-related hospitalizations was extrapolated to all insureds of a leading German statutory health insurance company (AOK Bayern). Within 12 weeks, 45 of 202 patients were hospitalized. 50% of all unscheduled hospital admissions were OAT-related (20 of 40) and occurred in 18 patients. The mean cost per inpatient stay was EUR 5873. The intensified AMBORA care program reduced the patients' absolute risk for OAT-related hospitalization by 11.36%. If this care program would have been implemented in the AOK Bayern collective (3,862,017 insureds) it has the potential to reduce hospitalization rates and thereby cost by a maximum of EUR 4.745 million within 12 weeks after therapy initiation.

Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3), a splice variant of the hepatic uptake transporter OATP1B3 (liver-type; Lt-OATP1B3), is expressed in several tumor entities including colorectal carcinoma (CRC) and breast cancer. In CRC, high OATP1B3 expression has been associated with reduced progression-free and overall survival. Several kinase inhibitors used for antitumor treatment are substrates and/or inhibitors of OATP1B3 (e.g. encorafenib, vemurafenib). The functional importance of Ct-OATP1B3 has not been elucidated so far. HEK293 cells stably overexpressing Ct-OATP1B3 protein were established and compared with control cells. Confocal laser scanning microscopy, immunoblot, and proteomics-based expression analysis demonstrated that Ct-OATP1B3 protein is intracellularly localized in lysosomes of stably-transfetced cells. Cytotoxicity experiments showed that cells recombinantly expressing the Ct-OATP1B3 protein were more resistant against the kinase inhibitor encorafenib compared to control cells [e.g. encorafenib (100 µM) survival rates: 89.5% vs. 52.8%]. In line with these findings, colorectal cancer DLD1 cells endogenously expressing Ct-OATP1B3 protein had poorer survival rates when the OATP1B3 substrate bromosulfophthalein (BSP) was coincubated with encorafenib or vemurafenib compared to the incubation with the kinase inhibitor alone. This indicates a competitive inhibition of Ct-OATP1B3-mediated uptake into lysosomes by BSP. Accordingly, mass spectrometry-based drug analysis of lysosomes showed a reduced lysosomal accumulation of encorafenib in DLD1 cells additionally exposed to BSP. These results demonstrate that Ct-OATP1B3 protein is localized in the lysosomal membrane and can mediate transport of certain kinase inhibitors into lysosomes revealing a new mechanism of resistance. Significance Statement We describe the characterization of a splice variant of the liver-type uptake transporter OATP1B3 expressed in several tumor entities. This variant is localized in lysosomes mediating resistance against kinase inhibitors which are substrates of this transport protein by transporting them into lysosomes and thereby reducing the cytoplasmic concentration of these antitumor agents. Therefore, the expression of the Ct-OATP1B3 protein is associated with a better survival of cells revealing a new mechanism of drug resistance., (Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics.)

Green tea (GT) alters the disposition of a number of drugs, such as nadolol and lisinopril. However, it is unknown whether GT affects disposition of hydrophilic anti-allergic drugs. The purpose of this study was to investigate whether pharmacokinetics of fexofenadine and pseudoephedrine are affected by catechins, major GT components. A randomized, open, 2-phase crossover study was conducted in 10 healthy Japanese volunteers. After overnight fasting, subjects were simultaneously administered fexofenadine (60 mg) and pseudoephedrine (120 mg) with an aqueous solution of green tea extract (GTE) containing (-)-epigallocatechin gallate (EGCG) of ~ 300 mg or water (control). In vitro transport assays were performed using HEK293 cells stably expressing organic anion transporting polypeptide (OATP)1A2 to evaluate the inhibitory effect of EGCG on OATP1A2-mediated fexofenadine transport. In the GTE phase, the area under the plasma concentration-time curve and the amount excreted unchanged into urine for 24 hours of fexofenadine were significantly decreased by 70% (P < 0.001) and 67% (P < 0.001), respectively, compared with control. There were no differences in time to maximum plasma concentration and the elimination half-life of fexofenadine between phases. Fexofenadine was confirmed to be a substrate of OATP1A2, and EGCG (100 and 1,000 μM) and GTE (0.1 and 1 mg/mL) inhibited OATP1A2-mediated uptake of fexofenadine. On the contrary, the concomitant administration of GTE did not influence the pharmacokinetics of pseudoephedrine. These results suggest that intake of GT may result in a markedly reduced exposure of fexofenadine, but not of pseudoephedrine, putatively by inhibiting OATP1A2-mediated intestinal absorption., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Endogenous biomarkers for transporter-mediated drug-drug interaction (DDI) predictions represent a promising approach to facilitate and improve conventional DDI investigations in clinical studies. This approach requires high sensitivity and specificity of biomarkers for the targets of interest (e.g., transport proteins), as well as rigorous characterization of their kinetics, which can be accomplished utilizing physiologically-based pharmacokinetic (PBPK) modeling. Therefore, the objective of this study was to develop PBPK models of the endogenous organic cation transporter (OCT)2 and multidrug and toxin extrusion protein (MATE)1 substrates creatinine and N 1 -methylnicotinamide (NMN). Additionally, this study aimed to predict kinetic changes of the biomarkers during administration of the OCT2 and MATE1 perpetrator drugs trimethoprim, pyrimethamine, and cimetidine. Whole-body PBPK models of creatinine and NMN were developed utilizing studies investigating creatinine or NMN exogenous administration and endogenous synthesis. The newly developed models accurately describe and predict observed plasma concentration-time profiles and urinary excretion of both biomarkers. Subsequently, models were coupled to the previously built and evaluated perpetrator models of trimethoprim, pyrimethamine, and cimetidine for interaction predictions. Increased creatinine plasma concentrations and decreased urinary excretion during the drug-biomarker interactions with trimethoprim, pyrimethamine, and cimetidine were well-described. An additional inhibition of NMN synthesis by trimethoprim and pyrimethamine was hypothesized, improving NMN plasma and urine interaction predictions. To summarize, whole-body PBPK models of creatinine and NMN were built and evaluated to better assess creatinine and NMN kinetics while uncovering knowledge gaps for future research. The models can support investigations of renal transporter-mediated DDIs during drug development., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Oral antitumor therapeutics (OAT) bear a high risk for medication errors, e.g., due to drug-drug or drug-food interactions or incorrect drug intake. Advanced age, organ insufficiencies, and polymedication are putting uro-oncological patients at an even larger risk. This analysis sets out to (1) investigate the frequency and relevance of medication errors in patients with prostate cancer or renal cell carcinoma treated with OAT and (2) compile recommendations for clinical practice. This post-hoc subgroup analysis used data collected in the randomized AMBORA trial (2017-2020; DRKS00013271). Clinical pharmacologists/pharmacists conducted advanced medication reviews over 12 weeks after initiation of a new oral regimen and assessed the complete medication process for drug-related problems. Medication errors related to either the OAT, prescribed or prescription-free concomitant medication, or food were classified regarding cause and severity. We identified 67 medication errors in 38 patients within the complete medication within 12 weeks. Thereof, 55% were detected at therapy initiation, 27% were caused by the patients, and 25% were drug-drug or drug-food interactions. Problem-prone issues are summarized in a 'medication safety table' to provide recommendations for clinical practice in uro-oncology. Tailored strategies including intensified care by clinical pharmacologists/pharmacists should be implemented in clinical practice to improve medication safety.

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 ( SLC47A1 ) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.