Browsing by Author "Gisch, Debora L."

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    A Phase I Trial of the Pharmacokinetic Interaction Between Cannabidiol and Tacrolimus
    (Wiley, 2025) So, Gerald C.; Lu, Jessica Bo Li; Koyama, Sachiko; Cheng, Ying-Hua; Gisch, Debora L.; McClara, Kelsey; Dexter, Paul R.; Sharfuddin, Asif A.; Etkins, Jumar; Tillman, Emma M.; Beamon, Travis R.; Cowsert, Zachary; Stuart, Jennifer S.; Desta, Zeruesenay; Eadon, Michael T.; Medicine, School of Medicine
    One in six Americans uses cannabidiol-based or cannabis-derived products. Cannabidiol is a substrate of CYP3A, but its role as a potential CYP3A inhibitor remains unclear. We hypothesized that cannabidiol would inhibit CYP3A-mediated metabolism of tacrolimus. This report is an interim analysis of an open-label, three-period, fixed-sequence, crossover study in healthy participants. Participants first received a single dose of tacrolimus 5 mg orally. After washout, participants later received cannabidiol titrated to 5 mg/kg twice daily for 14 days to reach a steady state, followed by a second single dose of tacrolimus 5 mg orally. Tacrolimus concentrations in whole blood were measured by UHPLC-MS/MS method. Pharmacokinetic parameters were calculated by noncompartmental analysis. Twelve participants completed all periods of the study. The maximum concentration (Cmax) of tacrolimus increased 4.2-fold (P < 0.0001) with cannabidiol (40.2 ± 13.5 ng/mL) compared with without cannabidiol (9.85 ± 4.63 ng/mL). The area under the concentration-vs.-time curve (AUC0-∞) increased 3.1-fold (P < 0.0001). No change in half-life (t1/2) was observed. This study demonstrates that cannabidiol increases tacrolimus exposure. Our data suggest the need for dose reduction in tacrolimus and frequent therapeutic dose monitoring in transplant patients taking cannabidiol concomitantly. Whether this observed interaction occurred due to the inhibition of CYP3A4 and/or CYP3A5 in the liver, intestine, or both, or intestinal drug transporters (e.g., p-glycoprotein) during the first-pass elimination remains to be elucidated.
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    Inhibition of Tacrolimus Metabolism by Cannabidiol and Its Metabolites In Vitro
    (Wiley, 2025) So, Gerald C.; Lu, Jessica Bo Li; Cheng, Ying-Hua; Gisch, Debora L.; Koyama, Sachiko; Ferreira, Ricardo Melo; Beamon, Travis R.; Desta, Zeruesenay; Eadon, Michael T.; Medicine, School of Medicine
    Drug interactions are major causes of interindividual variability in tacrolimus exposure and effect. Tacrolimus, a widely used drug in transplant patients, is metabolized by CYP3A4 and CYP3A5. Cannabidiol (CBD) use after transplant is common. Clinical cases suggest CBD may alter tacrolimus exposure, but the mechanism of this interaction is unknown. We hypothesize that cannabidiol will inhibit tacrolimus metabolism in vitro mainly through CYP3A5 inhibition. In pooled human liver microsomes (HLMs) and recombinant (r) CYP3A4 and CYP3A5 enzymes, tacrolimus (1 μM) metabolism was determined using substrate depletion method in the absence (control) and the presence of 10 μM CBD, 7-hydroxyCBD, and 7-carboxyCBD. Ketoconazole (1 μM) served as a positive control for the inhibition of CYP3A. Linear regression analyses were performed to obtain kinetic parameters of the depletion. Tacrolimus depletion half-life was 2.54, 0.922, and 0.351 min with pooled HLMs, rCYP3A4, and rCYP3A5, respectively. In pooled HLMs, CBD and 7-hydroxyCBD increased tacrolimus half-life by 0.8- and 2.3-fold (both p < 0.0001), respectively. In rCYP3A4, CBD, 7-hydroxyCBD, and ketoconazole prolonged tacrolimus half-life by 5.8-, 14-, and 7.7-fold, respectively. In rCYP3A5, CBD, 7-hydroxyCBD, and ketoconazole prolonged half-life by 29.3-, 19.7-, and 0.1-fold, respectively. In all experiments, 7-carboxyCBD had minimal effect on tacrolimus depletion. CBD and 7-hydroxyCBD inhibited tacrolimus metabolism in vitro. CBD showed stronger inhibition in rCYP3A5 than rCYP3A4. The demonstrated CYP3A5 selectivity of cannabidiol may contribute to the in vitro identification of CYP3A5 substrates in new drug development. Our results support the potential of a clinical drug-drug interaction between CBD and tacrolimus.
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    NAD+ prevents chronic kidney disease by activating renal tubular metabolism
    (American Society for Clinical Investigation, 2025-03-10) Jones, Bryce A.; Gisch, Debora L.; Myakala, Komuraiah; Sadiq, Amber; Cheng, Ying-Hua; Taranenko, Elizaveta; Panov, Julia; Korolowicz, Kyle; Ferreira, Ricardo Melo; Yang, Xiaoping; Santo, Briana A.; Allen, Katherine C.; Yoshida, Teruhiko; Wang, Xiaoxin X.; Rosenberg, Avi Z.; Jain, Sanjay; Eadon, Michael T.; Levi, Moshe; Medicine, School of Medicine
    Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulated renal PPARα signaling and restored FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing showed that renal metabolic pathways were impaired in Alport mice and activated by NR in both sexes. These transcriptional changes were confirmed by orthogonal imaging techniques and biochemical assays. Single-nuclei RNA sequencing and spatial transcriptomics, both the first of their kind to our knowledge from Alport mice, showed that NAD+ supplementation restored FAO in proximal tubule cells. Finally, we also report, for the first time to our knowledge, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
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    Skeletal muscle metabolic responses to physical activity are muscle type specific in a rat model of chronic kidney disease
    (Springer Nature, 2021-05-07) Avin, Keith G.; Hughes, Meghan C.; Chen, Neal X.; Srinivasan, Shruthi; O’Neill, Kalisha D.; Evan, Andrew P.; Bacallao, Robert L.; Schulte, Michael L.; Moorthi, Ranjani N.; Gisch, Debora L.; Perry, Christopher G.R.; Moe, Sharon M.; O’Connell, Thomas M.; Physical Therapy, School of Health and Human Sciences
    Chronic kidney disease (CKD) leads to musculoskeletal impairments that are impacted by muscle metabolism. We tested the hypothesis that 10-weeks of voluntary wheel running can improve skeletal muscle mitochondria activity and function in a rat model of CKD. Groups included (n = 12–14/group): (1) normal littermates (NL); (2) CKD, and; (3) CKD-10 weeks of voluntary wheel running (CKD-W). At 35-weeks old the following assays were performed in the soleus and extensor digitorum longus (EDL): targeted metabolomics, mitochondrial respiration, and protein expression. Amino acid-related compounds were reduced in CKD muscle and not restored by physical activity. Mitochondrial respiration in the CKD soleus was increased compared to NL, but not impacted by physical activity. The EDL respiration was not different between NL and CKD, but increased in CKD-wheel rats compared to CKD and NL groups. Our results demonstrate that the soleus may be more susceptible to CKD-induced changes of mitochondrial complex content and respiration, while in the EDL, these alterations were in response the physiological load induced by mild physical activity. Future studies should focus on therapies to improve mitochondrial function in both types of muscle to determine if such treatments can improve the ability to adapt to physical activity in CKD.
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    Spatial Transcriptomics and the Kidney
    (Wolters Kluwer, 2022) Melo Ferreira, Ricardo; Gisch, Debora L.; Eadon, Michael T.; Medicine, School of Medicine
    Purpose of review: The application of spatial transcriptomics technologies to the interrogation of kidney tissue is a burgeoning effort. These technologies share a common purpose in mapping both the expression of individual molecules and entire transcriptomic signatures of kidney cell types and structures. Such information is often superimposed upon a histologic image. The resulting datasets are readily merged with other imaging and transcriptomic techniques to establish a spatially anchored atlas of the kidney. This review provides an overview of the various spatial transcriptomic technologies and recent studies in kidney disease. Potential applications gleaned from the interrogation of other organ systems, but relative to the kidney, are also discussed. Recent findings: Spatial transcriptomic technologies have enabled localization of whole transcriptome mRNA expression, correlation of mRNA to histology, measurement of in situ changes in expression across time, and even subcellular localization of transcripts within the kidney. These innovations continue to aid in the development of human cellular atlases of the kidney, the reclassification of disease, and the identification of important therapeutic targets. Summary: Spatial localization of gene expression will complement our current understanding of disease derived from single cell RNA sequencing, histopathology, protein immunofluorescence, and electron microscopy. Although spatial technologies continue to evolve rapidly, their importance in the localization of disease signatures is already apparent. Further efforts are required to integrate whole transcriptome and subcellular expression signatures into the individualized assessment of human kidney disease.
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    The chromatin landscape of healthy and injured cell types in the human kidney
    (Springer Nature, 2024-01-10) Gisch, Debora L.; Brennan, Michelle; Lake, Blue B.; Basta, Jeannine; Keller, Mark S.; Ferreira, Ricardo Melo; Akilesh, Shreeram; Ghag, Reetika; Lu, Charles; Cheng, Ying-Hua; Collins, Kimberly S.; Parikh, Samir V.; Rovin, Brad H.; Robbins, Lynn; Stout, Lisa; Conklin, Kimberly Y.; Diep, Dinh; Zhang, Bo; Knoten, Amanda; Barwinska, Daria; Asghari, Mahla; Sabo, Angela R.; Ferkowicz, Michael J.; Sutton, Timothy A.; Kelly, Katherine J.; De Boer, Ian H.; Rosas, Sylvia E.; Kiryluk, Krzysztof; Hodgin, Jeffrey B.; Alakwaa, Fadhl; Winfree, Seth; Jefferson, Nichole; Türkmen, Aydın; Gaut, Joseph P.; Gehlenborg, Nils; Phillips, Carrie L.; El-Achkar, Tarek M.; Dagher, Pierre C.; Hato, Takashi; Zhang, Kun; Himmelfarb, Jonathan; Kretzler, Matthias; Mollah, Shamim; Kidney Precision Medicine Project (KPMP); Jain, Sanjay; Rauchman, Michael; Eadon, Michael T.; Medicine, School of Medicine
    There is a need to define regions of gene activation or repression that control human kidney cells in states of health, injury, and repair to understand the molecular pathogenesis of kidney disease and design therapeutic strategies. Comprehensive integration of gene expression with epigenetic features that define regulatory elements remains a significant challenge. We measure dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and H3K27ac, H3K4me1, H3K4me3, and H3K27me3 histone modifications to decipher the chromatin landscape and gene regulation of the kidney in reference and adaptive injury states. We establish a spatially-anchored epigenomic atlas to define the kidney's active, silent, and regulatory accessible chromatin regions across the genome. Using this atlas, we note distinct control of adaptive injury in different epithelial cell types. A proximal tubule cell transcription factor network of ELF3, KLF6, and KLF10 regulates the transition between health and injury, while in thick ascending limb cells this transition is regulated by NR2F1. Further, combined perturbation of ELF3, KLF6, and KLF10 distinguishes two adaptive proximal tubular cell subtypes, one of which manifested a repair trajectory after knockout. This atlas will serve as a foundation to facilitate targeted cell-specific therapeutics by reprogramming gene regulatory networks.
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    Utilization of Cannabidiol in Post-Organ-Transplant Care
    (MDPI, 2025-01-15) Koyama, Sachiko; Etkins, Jumar; Jun, Joshua; Miller, Matthew; So, Gerald C.; Gisch, Debora L.; Eadon, Michael T.; Medicine, School of Medicine
    Cannabidiol (CBD) is one of the major phytochemical constituents of cannabis, Cannabis sativa, widely recognized for its therapeutic potential. While cannabis has been utilized for medicinal purposes since ancient times, its psychoactive and addictive properties led to its prohibition in 1937, with only the medical use being reauthorized in 1998. Unlike tetrahydrocannabinol (THC), CBD lacks psychoactive and addictive properties, yet the name that suggests its association with cannabis has significantly contributed to its public visibility. CBD exhibits diverse pharmacological properties, most notably anti-inflammatory effects. Additionally, it interacts with key drug-metabolizing enzyme families, including cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT), which mediate phase I and phase II metabolism, respectively. By binding to these enzymes, CBD can inhibit the metabolism of co-administered drugs, which can potentially enhance their toxicity or therapeutic effects. Mild to moderate adverse events associated with CBD use have been reported. Advances in chemical formulation techniques have recently enabled strategies to minimize these effects. This review provides an overview of CBD, covering its historical background, recent clinical trials, adverse event profiles, and interactions with molecular targets such as receptors, channels, and enzymes. We particularly emphasize the mechanisms underlying its anti-inflammatory effects and interaction with drugs relevant to organ transplantation. Finally, we explore recent progress in the chemical formulation of CBD in order to enhance its bioavailability, which will enable decreasing the dose to use and increase its safety and efficacy.