Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Absorption, distribution, metabolism, and excretion of [¹⁴C]SHEN211, a nonpeptidic small-molecule 3CL^pro inhibitor, in rats.","authors":"Zihao Zhang, Mengting Jia, Feiyu Wang, Chen Yang, Huanhuan Shi, Yali Yuan, Zhuoran Tian, Congmei Ming, Jinwen Huang, Junfang Pan, Xiaokun Shen, Yuandong Zheng, Xingxing Diao","doi":"10.1016/j.jpet.2025.103623","DOIUrl":"10.1016/j.jpet.2025.103623","url":null,"abstract":"<p><p>SHEN211 is a selective 3-chymotrypsin-like protease inhibitor that can protect against severe acute respiratory syndrome coronavirus 2. It is currently being assessed in clinical trials in China, but few studies have reported its metabolism in preclinical and clinical settings. This study used radioactive isotope labeling to investigate the absorption, distribution, metabolism, and excretion of SHEN211 in rats. After a single intragastric administration of 2.0 mg/kg (100 μCi/kg) of [¹⁴C]SHEN211 in rats, the inhibitor was rapidly absorbed, with feces being the primary route of excretion. The results of tissue distribution indicated that SHEN211-related components were mainly concentrated in the liver. In total, 11 metabolites were identified in rat plasma, urine, feces, and bile, and SHEN211 was the major drug-related component in the systemic circulation. The main metabolic pathways of SHEN211 were N-dealkylation, oxidative defluorination, glucuronidation, and glutathione conjugation. In addition, a physiologically based pharmacokinetic model for rats was constructed and validated using GastroPlus software, and the model was extrapolated to healthy adult males to predict the pharmacokinetic characteristics of SHEN211 in humans, providing invaluable insights into the human mass balance of SHEN211 and paving the way for clinical studies. SIGNIFICANCE STATEMENT: This study characterized the absorption, distribution, metabolism, and excretion of SHEN211, a 3CL^pro inhibitor for severe acute respiratory syndrome coronavirus 2 in rats. SHEN211 exhibited rapid absorption and was mainly distributed in the liver. Fecal excretion was the primary elimination route. The prediction of human pharmacokinetic characteristics using the physiologically based pharmacokinetic model provides an invaluable reference for optimizing the clinical dosing strategy of SHEN211 and advancing its ongoing clinical trials in China.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103623"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Lansoprazole, a Proton Pump Inhibitor, Mediates Anti-Inflammatory Effect in Gastric Mucosal Cells through the Induction of Heme Oxygenase-1 via Activation of NF-E2-Related Factor 2 and Oxidation of Kelch-Like ECH-Associating Protein 1\" [The Journal of Pharmacology and Experimental Therapeutics 331 (2009) 255-264].","authors":"Tomohisa Takagi, Yuji Naito, Hitomi Okada, Takeshi Ishii, Katsura Mizushima, Satomi Akagiri, Satoko Adachi, Osamu Handa, Satoshi Kokura, Hiroshi Ichikawa, Ken Itoh, Masayuki Yamamoto, Hirofumi Matsui, Toshikazu Yoshikawa","doi":"10.1016/j.jpet.2025.103631","DOIUrl":"10.1016/j.jpet.2025.103631","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103631"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antagonism of prostate α_1A-adrenoceptors by verapamil in human prostate smooth muscle contraction.","authors":"Sheng Hu, Guangyang Liu, Oluwafemi Kale, Wenbin Zhu, Yajie Xu, Patrick Keller, Philipp Weinhold, Alexander Tamalunas, Christian G Stief, Martin Hennenberg","doi":"10.1016/j.jpet.2025.103603","DOIUrl":"10.1016/j.jpet.2025.103603","url":null,"abstract":"<p><p>Voiding symptoms and hypertension are common comorbidities. α₁-Blockers are the first-line medication for the treatment of voiding symptoms. Off-target antagonism of α₁-adrenoceptors by cardiovascular drugs may add to the side effects of α₁-blockers but may also hold the potential to avoid polypharmacy. Here, we examined α₁-adrenergic antagonism by the calcium channel blocker verapamil in the human prostate. Prostate tissues were obtained from radical prostatectomy. Contractions were examined by organ bath. Verapamil caused concentration-dependent inhibitions of α₁-adrenergic and electric field stimulation-induced contractions and increases of EC₅₀ values for α₁-agonists. E_max values for phenylephrine, methoxamine, noradrenaline, and electric field stimulation were decreased by 41%, 17%, 41%, and 39% by 1-μM verapamil and by 62%, 36%, 51%, and 93% by 10-μM verapamil. EC₅₀ values for phenylephrine, methoxamine, and noradrenaline were increased by 0.47, 0.36, and 0.18 orders of magnitude by 1-μM verapamil and by 0.83, 1.22, and 1.54 orders of magnitude by 10-μM verapamil. The 100-nM verapamil increased the EC₅₀ values for noradrenaline by 0.43 magnitudes but only slightly (<0.2 magnitudes) for phenylephrine and methoxamine. U46619-induced contractions were unchanged by 10-μM verapamil. E_max values for endothelin-1-induced contractions were reduced by 14% by 10-μM verapamil. Antagonism of α₁-adrenoceptors by verapamil in the human prostate begins at concentrations corresponding to plasma concentrations at high doses. Improvements of voiding symptoms through this antagonism may help to avoid polypharmacy in elderly populations, but application in BPH may be limited by drug-drug interactions and additive side effects. SIGNIFICANCE STATEMENT: Our findings align verapamil concentrations antagonizing α₁-adrenergic contractions of human prostate tissues with known plasma levels. Improvements of voiding symptoms appear possible, but application in benign prostatic hyperplasia may be limited by drug-drug interactions and additive side effects.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103603"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144285046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Artificial Oxygen Carriers-Past, Present, and Future-a Review of the Most Innovative and Clinically Relevant Concepts\": [The Journal of Pharmacology and Experimental Therapeutics 369 (2019) 300-310].","authors":"Katja B Ferenz, Andrea U Steinbicker","doi":"10.1016/j.jpet.2025.103632","DOIUrl":"10.1016/j.jpet.2025.103632","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103632"},"PeriodicalIF":3.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral mechanisms of oxycodone's effects in female and male rats: Rate-dependent effects on impulsive choice.","authors":"Ryan C Blejewski, Justin T Van Heukelom, Pedro Vidal, Christine E Hughes, Raymond C Pitts","doi":"10.1016/j.jpet.2025.103648","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103648","url":null,"abstract":"<p><p>Impulsive choice may be empirically defined as a preference for a smaller-sooner reinforcer over a larger-later reinforcer with choices involving different reinforcement magnitudes and delays. Opioid agonists increase impulsive choice; however, opioids other than morphine have not been examined extensively. The aim of the current study was to examine the acute effects of the prescription opioid oxycodone on impulsive choice by characterizing its effects on the relative impact of reinforcement magnitude and delay in female (n = 6) and male (n = 8) rats. It was hypothesized that oxycodone would decrease sensitivity to both magnitude and delay. Rats responded under a concurrent-chains procedure in which combinations of magnitude and delay were manipulated within sessions. The combination of magnitude and delay for one option was constant across the experiment, whereas the combination for the other option was varied within the session. For both sexes, choice was controlled by the combined effects of magnitude and delay; on average, sensitivity to magnitude was higher than to delay. Oxycodone decreased sensitivity to magnitude and delay in both sexes, with a greater reduction in sensitivity to magnitude relative to delay, suggesting oxycodone may increase impulsive choice by decreasing sensitivity to magnitude more than sensitivity to delay. These effects, however, varied across rats. Additional analyses indicated that oxycodone's effects on sensitivity to both magnitude and delay were an outcome of rate-dependent effects on responding on the individual levers. These data illustrate the enduring contributions of Peter Dews to the understanding of behavioral effects of drugs. SIGNIFICANCE STATEMENT: Opioid use disorder is associated with an increased likelihood of impulsive and risky behaviors. This study investigated the behavioral mechanisms of the effects of the prescription opioid, oxycodone, in a preclinical rodent model of impulsive choice. Effects of oxycodone under this procedure were rate-dependent, a finding that may have important implications for the treatment of impulsive disorders, including opioid use, and one that illustrates the enduring contributions of Peter Dews to behavioral pharmacology.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103648"},"PeriodicalIF":3.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming growth factor β receptor 1 and mitogen-activated protein 4 kinase 4 dual inhibitor, TK-850, reduces renal fibrosis in unilateral ureteral-obstructed mice.","authors":"Henry A Palfrey, Samaneh Goorani, Abhishek Mishra, Md Abdul Hye Khan, Baku Acharya, Brendan Frett, John D Imig","doi":"10.1016/j.jpet.2025.103644","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103644","url":null,"abstract":"<p><p>Renal fibrosis is a common progression from chronic kidney disease to end-stage renal disease, and its causes are multifactorial. Effective treatment for renal fibrosis requires strategies that address various molecular mechanisms simultaneously. In this study, we investigated the preventive and interventional anti-fibrotic effects of TK-850, a novel dual inhibitor of transforming growth factor-β receptor (TGF-βR)1 and mitogen-activated protein 4 kinase (MAP4K)4. The antifibrotic potential of TK-850 was evaluated using 8-10-week-old male and female C57Bl/6 mice that were subjected to unilateral ureteral obstruction (UUO) surgery to induce renal fibrosis. Rodents were subjected to UUO and were administered TK-850 (20 mg/kg per day intraperitoneally) 7 days before or 3 days following UUO. The contralateral kidneys served as the control. Kidneys and blood were collected 10 days post-UUO for histopathologic and biochemical analyses. Kidney hydroxyproline levels, a marker for collagen content and fibrosis, increased by UUO in all groups; however, TK-850 preventive and interventional administration effectively reduced these levels, indicating its potential to mitigate renal fibrosis. Gene array data demonstrated upregulation of several profibrotic genes, notably Timp1, which promote extracellular matrix accumulation. Preventive or interventional TK-850 administration reduced Timp1 expression in UUO mice. Renal interstitial collagen increased in UUO mice, and it was reduced by preventive and interventional TK-850. Notably, neither preventive nor interventional administration of TK-850 affected the terminal body weight or caused any mortality. Overall, these data provide proof of concept that the novel dual-acting TGF-βR1/MAP4K4 inhibitor, TK-850, is a renal antifibrotic agent. SIGNIFICANCE STATEMENT: TK-850, a novel dual transforming growth factor-β receptor 1/ mitogen-activated protein 4 kinase 4 inhibitor, reduces renal fibrosis in a unilateral ureteral obstruction mouse model by lowering hydroxyproline and tissue inhibitor of metalloproteinase 1 levels without impacting body weight or mortality, supporting its therapeutic potential.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103644"},"PeriodicalIF":3.1,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144707847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic analysis of morphine-3-glucuronide after acute morphine intravenous bolus administration to rats with traumatic brain injury.","authors":"Jonathan Birabaharan, Jeremy Henchir, Sarah Svirsky, Thomas D Nolin, Philip E Empey, Shaun W Carlson","doi":"10.1016/j.jpet.2025.103645","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103645","url":null,"abstract":"<p><p>This study investigates the effects of traumatic brain injury (TBI) on the pharmacokinetics of morphine and its metabolite, morphine-3-glucuronide (M3G), and their influence on neuroinflammation and systemic inflammation. We hypothesized that disruptions in the blood-brain barrier (BBB) due to TBI would enhance M3G exposure to the brain, which could potentially trigger inflammatory responses. We implemented a rat model of controlled cortical impact (CCI) injury to assess systemic pharmacokinetics of morphine and M3G over 24 hours postintravenous bolus administration. To gain an understanding of relative levels in the brain, we measured the drug and metabolite concentrations in both brain tissue and plasma at the systemic maximum concentration, which occurred at 1 hour post-CCI. While this study was designed to conduct a thorough acute pharmacokinetic analysis, the design also afforded an early examination of potential pharmacodynamic effects. Markers of neuroinflammation and systemic inflammation were measured in plasma and cerebrospinal fluid at 24 hours post-CCI. Results showed a 2-fold increase in systemic M3G exposure and doubled concentrations of both morphine and M3G in the brain. Notably, only M3G demonstrated a significant increase in the brain/plasma ratio at 1 hour. Despite these pharmacokinetic changes following a single bolus, there were limited morphine-induced or M3G-induced increases in markers of neuroinflammation or systemic inflammation at 24 hour post-CCI. This study highlights that TBI significantly alters the pharmacokinetics of morphine and M3G, increasing their brain penetration without worsening acute inflammation. Future research will need to explore the implications of extended and repeated dosing on these pharmacokinetic and inflammatory outcomes after TBI. SIGNIFICANCE STATEMENT: To our knowledge, this is the first pharmacokinetic analysis of morphine and its metabolite morphine-3-glucuronide (M3G) following traumatic brain injury (TBI). This research provides the first evidence that morphine and M3G show increased systemic and brain concentrations following experimental TBI, with an acute rise in M3G's brain/plasma ratio. Although no exacerbation of acute TBI-induced inflammation was observed with either morphine or M3G, the impact of longer, more frequent dosing needs evaluation because its longer administration could exacerbate TBI's neuroinflammatory response.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103645"},"PeriodicalIF":3.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144742321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between inflammation, voiding dysfunction, and psychiatric symptoms: novel hypothesis and therapeutics for urinary incontinence.","authors":"Yutaka Nakagawa, Shizuo Yamada","doi":"10.1016/j.jpet.2025.103640","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103640","url":null,"abstract":"<p><p>The lower urinary tract, composed of the urinary bladder and urethra, is responsible for urine storage and excretion, which are regulated by the peripheral nervous system, spinal cord, and brain. Whereas micturition is a voluntary behavior depending on executive control and social cognition, it is unclear how brain neural network disruption causes urinary incontinence. Data suggest that when bladder volume increases, healthy individuals experience dorsolateral prefrontal cortex activation with executive control to preserve continence, and this brain region regulates the cingulate cortex and emotional system to modulate urinary urgency and emotions. In patients with urge urinary incontinence, proinflammatory diets can induce inflammation in the lower urinary tract with voiding dysfunction and resultant increases in blood proinflammatory cytokine levels. The proinflammatory cytokines likely cause blood-cerebrospinal fluid barrier disruption, presumably accompanied by an elevation of proinflammatory cytokine concentrations in the cerebrospinal fluid, resulting in glial cell aberration-related hyperactivation of the cingulate cortex and emotional system as well as deactivation of the dorsolateral prefrontal cortex. The impaired dorsolateral prefrontal cortex regulation of these brain regions can contribute to executive control impairment with incontinence, uncontrollable urinary urgency, involuntary urination-associated anxiety, depressed mood caused by anticipatory anxiety, and catastrophizing about bladder fullness with urinary urgency due to cognitive distortion or catastrophic thinking, leading to a vicious spiral along with dysfunctional voiding. These symptoms suggest that while diet-related inflammation presumably initiates lower urinary tract dysfunction, neuroinflammation-induced brain neural network disturbance may promote the progression of urge urinary incontinence. Our model could predict novel medications for this condition. SIGNIFICANCE STATEMENT: Our hypothesis suggests that promoting anti-inflammation and/or resolution of inflammation in the brain as well as lower urinary tract may have therapeutic potential in the management of urinary incontinence with uncontrollable urinary urgency. Nonsteroidal anti-inflammatory drugs prevent cyclooxygenase activity and prostaglandin production, and prostaglandin E₂ is responsible for resolution of inflammation as well as inflammatory responses; therefore, we propose novel medications for this condition that can prompt anti-inflammatory and proresolution properties without inhibition of prostaglandin production.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103640"},"PeriodicalIF":3.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer disease: Amyloid peptide controversies and challenges of anti-Aβ immunotherapy.","authors":"Najlaa Hamed Almohmadi, Hayder M Al-Kuraishy, Ali K Albuhadily, Ali I Al-Gareeb, Ahmed M Abdelaziz, Athanasios Alexiou, Marios Papadakis, Gaber El-Saber Batiha","doi":"10.1016/j.jpet.2025.103639","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103639","url":null,"abstract":"<p><p>Alzheimer disease (AD) is a progressive neurodegenerative disease marked by the accumulation of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles containing tau protein. Given the relentless deterioration in AD, strategies to slow its progression often focus on inhibiting Aβ production or aggregation. However, numerous clinical trials targeting Aβ in later disease stages have shown limited success in reversing cognitive decline, potentially due to intervening too late in the disease course. Emerging evidence suggests that addressing Aβ pathology during the earliest phases of AD, before the occurrence of neuronal damage, may be beneficial for preserving cognitive function. Thus, therapeutic approaches aimed at reducing Aβ levels, such as anti-Aβ antibodies, are likely to yield greater benefits when implemented early in the disease trajectory. Such evidence underscores the rationale for prioritizing early-stage interventions in AD drug development. However, disrupting the physiological role of Aβ, which plays a role in normal brain function, might inadvertently worsen clinical outcomes, highlighting the need for nuanced therapeutic strategies. Therefore, this review aims to explore the dual aspects of Aβ biology: its natural role in the brain and the potential of anti-Aβ immunotherapy, particularly targeting amyloid plaques, as a promising avenue for modifying AD progression when timed appropriately. SIGNIFICANCE STATEMENT: This review highlights that β-amyloid (Aβ) has a dual role in both supporting synaptic plasticity and memory via nicotinic receptor activation and driving Alzheimer disease neuropathology, emphasizing that early-stage Aβ-targeted immunotherapy may prevent cognitive decline while preserving the neuroprotective functions of Aβ, thereby refining therapeutic strategies and advancing understanding of the complex role of Aβ in neural health and disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103639"},"PeriodicalIF":3.1,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-body physiologically based pharmacokinetic modeling of the nonlinear pharmacokinetics of prednisolone and its reversible metabolite prednisone in rats.","authors":"Xiaonan Li, William J Jusko","doi":"10.1016/j.jpet.2025.103637","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103637","url":null,"abstract":"<p><p>The pharmacokinetics (PK) and interconversion of prednisolone (PNL) and prednisone (PN) were assessed in the rat following single doses and intravenous infusions of PNL and PN. Their concentrations in blood and 11 tissues were determined by liquid chromatography-tandem mass spectrometry, and unbound drug by ultrafiltration. The PK of both steroids were nonlinear, featuring dose/concentration-dependent decreases in apparent steady-state plasma clearance and volume of distribution, with interconversion exhibiting continual rapid equilibria. The plasma and tissue profiles of PNL and PN were assessed with a comprehensive dual physiologically based pharmacokinetic model incorporating saturable plasma and tissue binding of PNL linked by their interconversion in liver and kidneys. All PK data were fitted jointly using Adapt software. Nonlinear tissue binding of PNL exhibited a range of equilibrium dissociation rate constants with highest in lung and 5 groups of binding capacity values. PN showed linear binding in most tissues, with a wide range of tissue-to-plasma partition coefficients with lowest in kidney to highest in lung. Conversion clearances of PN to PNL were found highest in liver and lesser in kidneys, whereas PNL to PN conversion occurred only in kidneys. Further irreversible elimination of PNL from venous plasma was nonlinear, whereas PN elimination was linear. The established physiologically based pharmacokinetic model well described the nonlinear whole-body disposition and interconversion of PNL and PN with relevance to humans and providing important insights into local steroid concentrations that drive diverse pharmacodynamic responses. SIGNIFICANCE STATEMENT: This work provides a detailed quantitative characterization of whole-body disposition of prednisolone and prednisone using a comprehensive dual physiologically based pharmacokinetic model that incorporates various complexities. This offers an instructive quantitative framework for other drugs that exhibit or affect metabolic interconversion and/or nonlinear disposition kinetics.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 8","pages":"103637"},"PeriodicalIF":3.1,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144618687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}