Renal Drug Research Articles

Nephrotoxicity of direct factor Xa inhibitors: a pharmacovigilance study using real-world data from the Federal Adverse Event Reporting System database.

Factor Xa inhibitors (FXaIs) may induce nephrotoxicity despite their FDA approval for thrombotic diseases, which has raised concerns due to its severe consequences. This study utilizes the FAERS database to assess the potential link between direct FXaIs and nephrotoxicity. Data from the FAERS database, spanning from the third quarter of 2011 to the fourth quarter of 2023, were used to perform a disproportionality analysis on Apixaban, Edoxaban, and Rivaroxaban. Disproportionality analysis and statistical processing were conducted using R software. Descriptive analysis revealed that males and individuals aged 65-85 are more susceptible to nephrotoxic adverse events. The disproportionality analysis indicated that all three drugs are associated with acute renal failure and renovascular disorders, with Edoxaban showing the strongest correlation. This study quantitatively analysed the relative risk of nephrotoxic adverse reactions associated with direct FXaIs, emphasizing the importance of renal function monitoring for these medications. The results indicate that Edoxaban has a significant association with nephrotoxicity, necessitating closer attention to its use and recommending additional renal function tests and drug concentration testing for high-risk patients.

Isolation of Primary Human Proximal Tubule Epithelial Cells and Their Use in Creating a Microphysiological Model of the Renal Proximal Tubule.

Kidney disease affects over 850 million people globally, including 37 million Americans. Risk factors forchronic kidney disease include environmental influences, genetic predispositions, co-existing medical conditions, and a history of acute kidney injury. These factors often take months or years to develop, complicating longitudinal studies of disease etiology and pathophysiology. Advanced kidney models are needed to improve our understanding of disease mechanisms and enhance nephrotoxicity prediction in drug development. Proximal tubule epithelial cells (PTECs) in the kidney play a critical role in xenobiotic and toxin clearance as well as the reabsorption of essential nutrients. We have previously demonstrated that three-dimensional (3D) microphysiological system (MPS) platforms, populated with isolated primary PTECs, can be used to investigate renal drug interactions, assess nephrotoxicity of compounds, and predict drug clearance. Here, we present protocols for isolating and culturing primary PTECs from whole human kidneys and for seeding them into a 3D MPS platform that mimics in vivo renal physiology. This protocol enables long-term studies supporting PTEC viability, physiological morphology, and functional polarization of key transporter proteins in MPS devices for up to 6 months.

A strategy for evaluating the impact of processing of Chinese meteria medica on meridian tropism: the influence of salt-water processing of phellodendri chinensis cortex on renal transport proteins.

This study elucidated the potential mechanisms by which Phellodendri Chinensis Cortex with salt-water processing (SPC) enhances renal targeting efficacy, through investigating the effects of Phellodendri Chinensis Cortex (PC) on renal uptake and efflux transport capabilities before and after salt-water processing. This study employed molecular docking, UPLC-TDQ-MS/MS, BCA, Western Blotting, and RT-PCR to assess the effects of raw Phellodendri Chinensis Cortex (RPC), SPC, berberine (BBR), and berberrubine (BBRR) on the transport capacity and expression of renal transport proteins OAT1, OAT3, OCT2, MATE1, MATE2K, P-gp, and MRP2 in HEK-293 cells. Analyses demonstrated that BBR and BBRR exhibited a strong affinity for OCT2, P-gp, MRP2. Compared to RPC, SPC can increase the uptake capacity and expression of OCT2, while it can decrease efflux capacity and expression of P-gp and MRP2. Simultaneously, BBRR showed similar effects on OCT2, P-gp, and MRP2, compared to BBR. Therefore, the enhanced renal targeting effect of SPC can be attributed to the differential impact of the partial conversion of BBR to BBRR on the transport capacity of the renal transporters OCT2, P-gp, and MRP2. This study investigated the interactions between renal transporter proteins and drugs, with the objective of elucidating the mechanism by which SPC enhances renal targeting efficacy. The findings of this study offer new insights and methodologies for exploring the effects of Processing of Chinese Materia Medica (PCMM) on the meridian tropism of other traditional Chinese medicines (TCMs).

A review of physiologically based pharmacokinetic modeling of renal drug disposition.

The human kidney is a critical organ for the elimination of numerous drugs and metabolites. The mechanisms of renal drug handling are manifold including unbound filtration, transporter-mediated active secretion, bidirectional passive diffusion, and occasionally active reabsorption and renal metabolism. These mechanisms collectively dictate the fate of drugs at various spatiotemporal points as drug molecules travel through the renal vasculature, tubules, and cells, posing a significant challenge in accurately describing and predicting renal drug disposition. Toward this end, a physiologically based kidney model serves as a promising tool to combine the anatomical and physiological features of the kidney (eg, tubular flow rate, pH, and transporter expression) with the unique properties of drugs (eg, protein binding, lipophilicity, ionization, and transporter substrate) to capture the dynamic system-drug interactions. Despite the exciting progress over the past several decades, physiologically based pharmacokinetic modeling has overall been predominantly used to predict intestinal absorption and hepatic drug-drug interaction. In comparison, pharmacokinetic modeling of renal drug handling has been underappreciated. In this review, we first provide an overview of kidney function and physiology, renal clearance mechanisms, and the evolutionary history of the physiologically based mechanistic kidney model. We then summarize the recent efforts spent in different areas of kidney model application, particularly: (1) renal transporter-mediated drug-drug interaction, (2) disease effect from both renal and hepatic impairment, and (3) model applications across the lifespan (eg, pediatrics and geriatrics). Finally, we identify remaining knowledge gaps, future directions, and potential model utilities. SIGNIFICANCE STATEMENT: This review summarizes pharmacokinetic model case studies that are related to renal drug disposition, illustrating the current framework of modeling renal drug handling, highlighting knowledge gaps in predicting renal transporter-mediated drug-drug interactions, and modeling the effects of disease and age on renal drug handling. A discussion on robust model validation and areas for future directions is also provided.

Robotic Totally Endoscopic Tricuspid Valve Surgery: Early Results and Midterm Outcomes.

Although robotic cardiac surgery is becoming more widely adopted for mitral valve procedures, robot-assisted tricuspid valve (TV) surgery is less common. We describe clinical and echocardiographic outcomes for 70 isolated and concomitant TV repair (TVr) cases. Patients who underwent robotic totally endoscopic TV surgery at our institution were retrospectively reviewed. The da Vinci Si or Xi robot (Intuitive Surgical, Sunnyvale, CA, USA) was used for all cases, employing an 8 to 10 mm working port and using cardiopulmonary bypass on a beating heart. Early and midterm outcomes were reviewed, along with echocardiogram results when available. Between 2014 and 2024, 70 patients underwent TVr. Fourteen cases were isolated TV procedures and 56 were concomitant with mitral surgery. The mean patient age was 67 ± 14.4 years, 57% were female, and 11 patients (16%) had previous heart surgery. TVr with an annuloplasty band occurred in 97% of patients, 1 patient had a tissue valve replacement, and there were no conversions to sternotomy. Early mortality occurred in 1 patient (1.4%) with an observed to expected ratio of 0.4. Early postoperative echocardiography revealed none to mild residual tricuspid regurgitation (TR) in 65 patients (93%). Clinical follow-up was completed in 97% of patients. All-cause mortality occurred in 14 patients (20%), 11 of which were noncardiac, including cancer, gastrointestinal bleed, end-stage renal disease, SARS-CoV-2 infection, and drug overdose. Follow-up echocardiography results were available for 46 patients (66%) at a mean of 45 months, showing moderate or more recurrent TR in 6 patients (9%). Robot-assisted totally endoscopic TV surgery, for both isolated and concomitant TV disease, is a safe and effective approach. The sternal-sparing nature allows for rapid recovery and positive midterm outcomes.

A kidney protection nanoparticle based on Alpinia oxyphylla fructus polysaccharide by modulating macrophage polarization.

A kidney protection nanoparticle based on Alpinia oxyphylla fructus polysaccharide by modulating macrophage polarization.

Contribution and expression of renal drug transporters in renal cell carcinoma.

Renal cell carcinoma (RCC) is a common substantive tumor. According to incomplete statistics, RCC incidence accounts for approximately 90% of renal malignant tumors, and is the second most prevalent major malignant tumor in the genitourinary system, following bladder cancer. Only 10%-15% of chemotherapy regimens for metastatic renal cell carcinoma (mRCC) are effective, and mRCC has a high mortality. Drug transporters are proteins located on the cell membrane that are responsible for the absorption, distribution, and excretion of drugs. Lots of drug transporters are expressed in the kidneys. Changes in carrier function weaken balance, cause disease, or modify the effectiveness of drug treatment. The changes in expression of these transporters during cancer pathology results in multi-drug resistance to cancer chemotherapy. In the treatment of RCC, the study of drug transporters helps to optimize treatment regimens, improve therapeutic effects, and reduce drug side effects. In this review, we summarize advances in the role of renal drug transporters in the genesis, progression, and treatment of RCC.

DRUG DEVELOPMENT AND EVALUATION: AGE, SEX, AND FRAILTY CONSIDERATIONS TO FACILITATE THE FORTITUDE FACTOR

Abstract Development and evaluation of drugs used by older adults must consider the effects of ageing, of lifelong factors including sex, and of other characteristics common in geriatric patients that affect pharmacokinetics and pharmacodynamics and outcomes, such as frailty. These factors interact within older people, resulting in major inter-individual variability. In some cases, the intersection of age, sex, frailty and other factors act in the same direction, e.g, age, female sex and frailty may all reduce renal drug clearance. In others they may act in opposite directions, e.g. age may decrease pharmacodynamic sensitivity to a drug, male sex may increase it, and frailty may reduce reserve to tolerate drug effects. Interactions with the older person’s other drugs in the presence of polypharmacy, their other diseases with multimorbidity, their genetics and environmental exposures further complicate prediction of drug effects in older adults. The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee’s position statement on ‘Measurement of Frailty in Drug Development and Evaluation’ outlines key principles relevant to all phases of translational research. These include measurement of frailty, testing drug exposures and outcomes that are clinically relevant for older adults, use of physiologically based pharmacokinetic-pharmacodynamic modelling and artificial intelligence. In all phases of drug development and evaluation, the pre-clinical models used and clinical trial populations studied should be representative of the people who will use the drugs in age, sex, frailty, and other determinants of drug response. This will inform drug use that facilitates the fortitude factor in older adults.

Caught in the Crossfire: Unmasking the Silent Renal Threats of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia.

Renal adverse drug reactions (ADRs) associated with tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) are relatively rare, and there is currently no standardized protocol for their management. Therefore, this study aimed to summarize renal ADRs related to TKIs use in CML and propose an evidence-based approach to monitor and manage these ADRs. A systematic literature review was performed to identify renal ADRs associated with TKIs in CML. Two authors screened the search results and extracted data from 37 eligible studies. These findings were then used to develop a scheme for clinicians to monitor and manage these ADRs. Overall, imatinib seemed to be significantly linked to renal adverse events compared to other TKIs, and switching to dasatinib or nilotinib significantly improved renal function. Similar events were reported with bosutinib, although they were not statistically significant. However, most of the renal events reported on dasatinib were described as nephrotic syndrome that resolved with switching to imatinib. Few cases were reported with nilotinib that described tumor lysis syndrome (TLS)-related kidney injury. Recommendations include monitoring for progressive decline in the estimated glomerular filtration rate with imatinib, nephrotic syndrome with dasatinib, and TLS with nilotinib. Additionally, holding the offending TKI and managing renal ADRs according to local guidelines were adopted more frequently than reducing the TKI dose.

A real-world pharmacovigilance analysis for agalsidase beta: findings from the FDA adverse event reporting database

ABSTRACT Background Fabry disease (FD), an X-linked lysosomal disorder, is marked by a lack of alpha-galactosidase A (α-Gal A). Agalsidase beta, a recombinant form of α-Gal A, is fundamental to enzyme replacement therapy for FD but requires close monitoring for adverse events (AEs). Research Design and Methods This study retrospectively analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) database for agalsidase beta-related AEs. Disproportionality analysis was used for data analysis. Results A total of 7,611 AE reports for agalsidase beta were analyzed. The most common AEs included pyrexia, pain, chills, malaise, and nausea. Several system organ classes including Cardiac Disorders, General Disorders and Administration Site Conditions, and Vascular Disorders, showed positive signals. Subgroup analysis by gender revealed differences in AE reporting, with males exhibiting a higher reporting odds ratio for certain preferred terms such as Renal Transplant and Drug Specific Antibody Present. Conclusion The FAERS database analysis of agalsidase beta AEs identified a significant number of cardiovascular, renal, and cerebrovascular system-related reports. While agalsidase beta is generally well-tolerated, the study underscores the necessity for gender-specific treatment approaches due to the higher incidence of certain AEs in males.

Effects of vitamin D3 supplementation on lipid profile and renal indices in rat model of drug induced renal injury

Introduction and aim. Renal injury is associated with decreased renal function, hypovitaminosis D, deranged calcium-phos phate metabolism and dyslipidemia, thus increasing risk for chronic kidney disease and cardiovascular diseases. However, re ports on the effects of vitamin D on drug induced renal injury are few. The aim was to investigate the possible role of vitamin D supplementation in reversing deranged lipid profile and renal function post drug induced renal injury. Material and methods. Wister male rats (36) were randomly divided into group 1, 2 and 3 (n=12). Single dose of Adriamycin was given to all except group 1(control) to induce renal injury. Group 2 left untreated, group 3 given vitamin D3 for 28 days. Serum urea, creatinine, total protein, total cholesterol (TC), triglycerides (TG), LDL-C, HDL, apolipoprotein (Apo) A and B were measured. C-reactive protein (CRP) and nitric oxide were assessed in kidney homogenate. Results. Vitamin D3 significantly brought down levels of serum creatinine, TC, LDL CRP, nitric oxide and increased the levels of Apo A, albumin, HDL. Serum urea, TG and Apo B in group 3 were not significantly different after vitamin D3 administration. His tological examination revealed improvement in glomerular messangialisation. Conclusion. Vitamin D3 may improve renal health, through its positive impact on dyslipidemia, inflammation, and oxidative stress in drug induced renal injury.

Obesity-related drug transporter expression alterations in human liver and kidneys

BackgroundPathophysiological changes associated with obesity might impact various drug pharmacokinetics (PK) parameters. The liver and kidneys are the primary organs involved in drug clearance, and the function of hepatic and renal transporters is critical to efficient drug elimination (or reabsorption). Considering the impact of an increased BMI on the drug’s PK is crucial in directing dosing decisions. Given the critical role of transporters in drug biodisposition, this study investigated how overweight and obesity affect the gene expression of renal and hepatic drug transporters.MethodsHuman liver and kidney samples were collected post-mortem from 32 to 28 individuals, respectively, which were divided into the control group (lean subjects; 18.5 ≤ BMI < 25 kg/m2) and the study group (overweight/obese subjects; BMI ≥ 25 kg/m2). Real-time quantitative PCR was performed for the analysis of 84 drug transporters.ResultsOur results show significant changes in the expression of genes involved in human transporters, both renal and hepatic. In liver tissue, we found that ABCC4 was up-regulated in overweight/obese subjects. In kidney tissue, up-regulation was only observed for ABCC10, while the other differentially expressed genes were down-regulated: ABCA1, ABCC3, and SLC15A1.ConclusionsThe observed alterations may be reflected by the differences in drug PK between lean and obese populations. However, these findings need further evaluation through the proteomic and functional study of these transporters in this patient population.

Modeling Metformin and Dapagliflozin Pharmacokinetics in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.

Three-dimensional culture of human proximal tubular epithelial cells for an in vitro evaluation of drug-induced kidney injury

Three-dimensional culture of human proximal tubular epithelial cells for an in vitro evaluation of drug-induced kidney injury

Loganin Ameliorates Acute Kidney Injury and Restores Tofacitinib Metabolism in Rats: Implications for Renal Protection and Drug Interaction.

Tofacitinib, a Janus kinase (JAK) inhibitor used to treat rheumatoid arthritis, is metabolized through hepatic cytochrome P450 (CYP), specifically CYP3A1/2 and CYP2C11. Prolonged administration of rheumatoid arthritis medications is generally associated with an increased risk of renal toxicity. Loganin (LGN), an iridoid glycoside, has hepatorenal regenerative properties. This study investigates the potential of LGN to mitigate acute kidney injury (AKI) and its effects on the pharmacokinetics of tofacitinib in rats with cisplatin-induced AKI. Both intravenous and oral administration of tofacitinib to AKI rats significantly increased the area under the plasma concentration-time curve from time 0 to infinity (AUC) compared with control (CON) rats, an increase attributed to the decelerated non-renal clearance (CLNR) and renal clearance (CLR) of tofacitinib. Administration of LGN to AKI rats, however, protected kidneys from severe impairment, restoring the pharmacokinetic parameters (AUC, CLNR, and CLR) of tofacitinib to those observed in untreated CON rats, with partial recovery of kidney function, as evidenced by an increase in creatinine clearance (CLCR). Possible interactions between drugs and natural components should be considered, especially when co-administering both a drug and a natural extract containing LGN or iridoid glycosides to patients with kidney injury.

Navigating allergies safely: tailored solutions in special circumstances – a comprehensive review of antihistamines

Personalised medicine is critical in managing allergic diseases, with the variety of second-generation antihistamines necessitating tailored approaches to individual patient needs. This encompasses considerations of age, pregnancy, breastfeeding, hepatic and renal failure, drug interactions, and aging. This paper synthesises current research and guidelines on the use of antihistamines across diverse clinical scenarios, paying special attention to paediatric allergy treatment, including safety profiles of first- and second-generation antihistamines, their use during pregnancy, breastfeeding, and interactions with other drugs, as well as considerations for elderly patients. Second-generation antihistamines are preferred for allergy treatment due to their safety, minimal adverse effects, and efficacy, with a strong recommendation against the use of first-generation antihistamines due to their potential to induce severe adverse reactions. Cetirizine, levocetirizine, and desloratadine are favoured in infants; whereas loratadine, rupatadine, and bilastine are recommended for preschoolers and older children. The safety of selected second-generation antihistamines during pregnancy (notably cetirizine, levocetirizine, desloratadine) and breastfeeding (notably loratadine, desloratadine, fexofenadine), in patients with renal failure and elderly patients (bilastine, desloratadine, fexofenadine), and patients with hepatic failure (bilastine, fexofenadine) is highlighted. The choice of second-generation antihistamines should be based on the patients’ individual needs and conditions to achieve optimal therapeutic outcomes and ensure safety, emphasising the importance of drug selection in varying clinical contexts.

Pharmacokinetics and pharmacological target attainment of standard temocillin dosing in non-critically ill patients with complicated urinary tract infections.

Temocillin, a carbapenem-sparing β-lactam antibiotic, is commonly used at the standard 4 g/day dosage for treating complicated urinary tract infections (cUTIs). However, pharmacokinetic/pharmacodynamic (PK/PD) data supporting this regimen is limited. This study evaluated the plasma pharmacokinetics (PK) and PTA of temocillin in non-critically ill cUTI patients with varying degrees of renal insufficiency (RI). In this single-centre clinical study, 22 cUTI patients received a fixed 4 g/day (2 g q12h, intravenously) temocillin dose, irrespective of renal function (no RI: n = 5, mild RI: n = 8, moderate RI: n = 9). Plasma samples were collected post-dosing for LC-MS analysis of total and unbound temocillin levels. Monte Carlo simulations were performed based on the established PK/PD target of ≥35% fT > MIC (minimal inhibitory concentration). Among patients, the highest plasma drug exposure and PK/PD target attainment were observed in those with moderate RI (median AUC0-12h = 1143 h.mg/L and %fT > MIC = 68%), followed by mild RI patients (median AUC0-12h = 918 h.mg/L and %fT > MIC = 34%), and the lowest in those with healthy kidney function (median AUC0-12h = 692 h.mg/L and %fT > MIC = 26%). Simulations indicated that the 4 g/day temocillin dose achieves 90% PTA only for glomerular filtration rate < 60 mL/min and MIC ≤ 8 mg/L. The standard temocillin dose may need to be increased from 4 to 6 g/day to treat non-critically ill cUTI patients, in line with recent EUCAST recommendations. For patients with moderate RI, who experience higher exposure due to reduced renal drug clearance, 4 g/day temocillin remains appropriate.

Drug-induced acute kidney injury in patients of the Military University Regional Hospital of Constantine

Introduction. Renal drug toxicity is the most frequent aspect of drug-induced acute kidney injury (Drug-induced AKI). This study aims to determine the incidence of drug induced AKI, and to study the clinical, biological and evolutionary characteristics of adult patients with AKI at Regional Military Hospital of Constantine (RMHC). Methods. this is prospective study, over a period of two years, from January 2017 to December 2018, interesting patients with drug-induced AKI hospitalized or seen at the outpatient clinic at RMHC. Variables were collected in a pre-established data collection form. Data entry and analysis were carried out using SPSS software version 20.0. Results. A total of 104 cases of drug-induced AKI were included in the study out of 636 AKI diagnosed from all causes, an incidence of 16.35%. Mean age was 60.48 ± 16.59 years, with a sex ratio M/F of 1.21. Drugs altering renal autoregulation were responsible for 51% of drug-induced AKI; followed by combinations of several nephrotoxic drugs in 15.4% of cases; chemotherapy products in 11.5%; contrast products in 9.6%; and antibiotics in 5.8%. At 6 months of the AKI episode, 20% of our patients recovered a GFR&gt; 60 ml / min, 55.8% presented a chronic kidney disease (CKD) stage 3, 15.8% CKD stage 4 and 8.4% CKD stage 5. Our study identified some factors of poor prognosis for progression to CKD, such as advanced age, history of diabetes and cancer, significant proteinuria, drug-related factors represented by chemotherapy products, concomitant intravenous and enteral route of administration as well as prolonged exposure to the drug, hypertensive patients under chemotherapy or Drugs altering renal autoregulation, and diabetic under chemotherapy or non steroidal anti-inflammatory drugs (NSAID). Conclusions. Subjects with drug AKI are at risk of developing CKD. Preventive measures should be taken by carefully prescribing the drugs identified in this study.

Cytochrome P450 and UDP-Glucuronosyltransferase Expressions, Activities, and Induction Abilities in 3D-Cultured Human Renal Proximal Tubule Epithelial Cells.

The role of the kidney as an excretory organ for exogenous and endogenous compounds is well recognized, but there is a wealth of data demonstrating that the kidney has significant metabolizing capacity for a variety of exogenous and endogenous compounds that in some cases surpass the liver. The induction of drug-metabolizing enzymes by some chemicals can cause drug-drug interactions and intraindividual variability in drug clearance. In this study, we evaluated the expression and induction of cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) isoforms in 3D-cultured primary human renal proximal tubule epithelial cells (RPTEC) to elucidate their utility as models of renal drug metabolism. CYP2B6, CYP2E1, CYP3A4, CYP3A5, and all detected UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7) mRNA levels in 3D-RPTEC were significantly higher than those in 2D-RPTEC and HK-2 cells and were close to the levels in the human kidney cortex. CYP1B1 and CYP2J2 mRNA levels in 3D-RPTEC were comparable to those in 2D-RPTEC, HK-2 cells, and the human kidney cortex. Midazolam 1'-hydroxylation, trifluoperazine N-glucuronidation, serotonin O-glucuronidation, propofol O-glucuronidation, and morphine 3-glucuronidation in the 3D-RPTEC were significantly higher than the 2D-RPTEC and comparable to those in the HepaRG cells, although bupropion, ebastine, and calcitriol hydroxylations were not different between the 2D- and 3D-RPTEC. Treatment with ligands of the aryl hydrocarbon receptor and farnesoid X receptor induced CYP1A1 and UGT2B4 expression, respectively, in 3D-RPTEC compared with 2D-RPTEC. We provided information on the expression, activity, and induction abilities of P450s and UGTs in 3D-RPTEC as an in vitro human renal metabolism model. SIGNIFICANCE STATEMENT: This study demonstrated that the expression of cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) in 3D-cultured primary human renal proximal tubule epithelial cells (3D-RPTEC) was higher than those in 2D-cultured primary human renal proximal tubule epithelial cells and HK-2 cells. The results were comparable to that in the human kidney cortex. 3D-RPTEC are useful for evaluating the induction of kidney P450s, UDP-glucuronosyltransferases, and human renal drug metabolism in cellulo.

Interaction of the Atypical Tetracyclines Chelocardin and Amidochelocardin with Renal Drug Transporters.

Antimicrobial resistance is expected to increase mortality rates by up to several million deaths per year by 2050 without new treatment options at hand. Recently, we characterized the pharmacokinetic (PK) and pharmacodynamic properties of two atypical tetracyclines, chelocardin (CHD) and amidochelocardin (CDCHD) that exhibit no cross-resistance with clinically used antibacterials. Both compounds were preferentially renally cleared and demonstrated pronounced effects in an ascending urinary tract infection model against E. coli. Renal drug transporters are known to influence clearance into the urine. In particular, inhibition of apical transporters in renal tubular epithelial cells can lead to intracellular accumulation and potential cell toxicity, whereas inhibition of basolateral transporters can cause a higher systemic exposure. Here, selected murine and human organic cation (Oct), organic anion (Oat), and efflux transporters were studied to elucidate interactions with CHD and CDCHD underlying their PK behavior. CHD exhibited stronger inhibitory effects on mOat1 and mOat3 and their human homologues hOAT1 and hOAT3 compared to CDCHD. While CHD was a substrate of mOat3 and mOct1, CDCHD was not. By contrast, no inhibitory effect was observed on Octs. CDCHD rather appeared to foster enhanced substrate transport on mOct1. CHD and CDCHD inhibited the efflux transporter hMRP2 on the apical side. In summary, the substrate nature of CHD in conjunction with its autoinhibition toward mOat3 rationalizes the distinct urine concentration profile compared to CDCHD that was previously observed in vivo. Further studies are needed to investigate the accumulation in renal tubular cells and the nephrotoxicity risk.