European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Pharmacokinetic/Pharmacodynamic Modeling of the Acute Heart Rate Effects of Delta-9 Tetrahydrocannabinol and Its Major Metabolites After Intravenous Injection in Healthy Volunteers.","authors":"W R Wolowich, R Greif, L Theiler, Maren Kleine-Brueggeney","doi":"10.1007/s13318-025-00941-8","DOIUrl":"https://doi.org/10.1007/s13318-025-00941-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>Cannabis consumption is increasing in both the recreational and medical settings. Tetrahydrocannabinol (THC) is known to produce cardiovascular effects, but the specific roles of THC and its metabolites THC-OH and THC-COOH in cannabinoid-induced cardiovascular effects remain unclear. We hypothesized that THC and THC-OH mediate a cannabinoid-induced increase in heart rate in either an additive or synergistic fashion.</p><p><strong>Methods: </strong>The present study uses prospectively obtained data to evaluate the effect of THC and its metabolites on heart rate in healthy volunteers through non-linear mixed-effect pharmacokinetic/pharmacodynamic (PK/PD) modeling.</p><p><strong>Results: </strong>The PK/PD models reveal that THC, THC-OH and a combination of THC and THC-OH, but not THC-COOH, are responsible for THC-induced tachycardia. The EC50 of the THC Emax model was 0.53 µM, 25-fold the EC50 for the THC-OH Emax model. The General Empiric Dynamic Model indicates that THC and THC-OH act synergistically to increase heart rate. Neither sex nor CYP2C9 polymorphism contributes to THC-induced tachycardia.</p><p><strong>Conclusion: </strong>THC-OH but not THC-COOH contributes to the heart rate effect of THC and THC-OH may be acting in a synergistic manner with THC. This contributes to understanding the cardiovascular effects of THC and cannabis-induced cardiovascular events. Future research including further hemodynamic data will allow a detailed systems pharmacology or response surface model approach.</p><p><strong>Trial registration: </strong>www.isrctn.com ; registration number ISRCTN53019164.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of Polymorphisms in Pharmacokinetics-Related Genes on the Areas Under the Plasma Concentration-Time Curves of Doxorubicin and Doxorubicinol in Patients with Diffuse Large B-Cell Lymphoma Receiving CHOP Therapy.","authors":"Keigo Saito, Takenori Takahata, Junichi Nakagawa, Yu Chen, Kensuke Saito, Kosuke Kamata, Takuto Tachita, Satoru Yamashita, Kayo Ueno, Atsushi Sato, Hirotake Sakuraba, Takenori Niioka","doi":"10.1007/s13318-025-00940-9","DOIUrl":"https://doi.org/10.1007/s13318-025-00940-9","url":null,"abstract":"<p><strong>Background and objectives: </strong>Doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) are drugs with large differences in pharmacokinetics (PK) between patients. In this study, we investigated the effects of polymorphisms in PK-related genes on the areas under the plasma concentration-time curves (AUCs) of DOX and DOXol.</p><p><strong>Methods: </strong>This study included 43 patients diagnosed with non-Hodgkin lymphoma undergoing the first round of CHOP therapy. The AUCs of DOX and DOXol were calculated using the linear trapezoidal rule based on the plasma concentrations in blood sampled from 1.5 to 25.5 h after the start of administration. Genotyping was performed for genes encoding carbonyl reductase (CBR1, CBR3), aldo-keto reductase (AKR1C3), and transporters (ABCB1, ABCG2).</p><p><strong>Results: </strong>Although the dose of DOX was adjusted for body surface area for each patient, the coefficients of variation for the AUCs of DOX and DOXol were substantial. Serum albumin was identified as an independent factor significantly influencing the dose-adjusted AUC of DOX (AUC/D; R² = 0.116, P = 0.015). Additionally, body mass index was identified as an independent factor significantly influencing the AUC/D of DOXol and the DOX-DOXol AUC ratio (DOXol/DOX; R² = 0.181, P = 0.003 and R² = 0.134, P = 0.009, respectively). Nonetheless, no significant differences in PK parameters were observed among polymorphisms in PK-related genes.</p><p><strong>Conclusions: </strong>Our findings suggested that polymorphisms in CBR1, CBR3, AKR1C3, ABCB1, and ABCG2 were unlikely to be reliable predictors of cumulative plasma exposure to DOX and DOXol. Therefore, mitigating the risk of cumulative plasma exposure to DOX and DOXol through PK approaches may require the development of novel therapeutic drug monitoring strategies. Supplementary file1 (MP4 3804 KB).</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minimal Physiologically-Based Pharmacokinetic Modeling of Atenolol and Metoprolol Absorption in Malnourished Rats.","authors":"Fatma Kir, Selma Sahin, William J Jusko","doi":"10.1007/s13318-025-00943-6","DOIUrl":"https://doi.org/10.1007/s13318-025-00943-6","url":null,"abstract":"<p><strong>Background and objective: </strong>The pharmacokinetics of drugs can be altered by pathophysiological changes in the body that result from malnutrition. The objective of this study was to evaluate the profiles derived from in vivo studies conducted on non-malnourished (control) and malnourished rats using minimal physiologically based pharmacokinetic (mPBPK) models.</p><p><strong>Methods: </strong>Single oral doses of atenolol (ATN) and metoprolol (MET) were administered to non-malnourished and malnourished rats. We demonstrate how plasma profiles can be evaluated using mPBPK models with high and low tissue-to-plasma partition coefficients (K_p) and elimination by either kidney or liver. A decrease in blood flow and cardiac output due to beta-blocker administration was assumed. Reference IV profiles from the literature were included to inform the mPBPK model and to help assess the absorption phases of individual oral profiles. Absorption was captured as two or three sequential zero-order processes for both drugs, and IV and oral profiles were assessed by joint fitting. Modeling was performed using both naïve pooling (ADAPT) and population (Monolix) analyses.</p><p><strong>Results: </strong>The experimental data show increased AUC values of MET and ATN in malnourished rats. Accordingly, an increased bioavailability (from 0.43 to 0.67) for ATN and an increased bioavailability (from 0.42 to 0.84) for MET in the malnourished group were related to higher absorption rates in both absorption phases.</p><p><strong>Conclusions: </strong>This study demonstrated advantageous use of mPBPK modeling with malnutrition primarily altering drug absorption in this animal model. Also, our analysis offers a blend of known and assumed components assembled mechanistically to suggest a reasonable interpretation of the PK profiles.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Vitro and In Vivo Pharmacokinetic Characterization of 7-Hydroxymitragynine, an Active Metabolite of Mitragynine, in Sprague-Dawley Rats.","authors":"Yi-Hua Chiang, Siva Rama Raju Kanumuri, Michelle A Kuntz, Alexandria S Senetra, Erin C Berthold, Shyam H Kamble, Sushobhan Mukhopadhyay, Aidan J Hampson, Christopher R McCurdy, Abhisheak Sharma","doi":"10.1007/s13318-025-00939-2","DOIUrl":"https://doi.org/10.1007/s13318-025-00939-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>Kratom, a Southeast Asian tree, has been researched for its potential as a therapeutic for substance use disorders. The most abundant alkaloid in kratom, mitragynine, is being investigated individually for opioid use disorder. However, the active metabolite of mitragynine,7-hydroxymitragynine (7-HMG) has raised concerns because of its high binding affinity to μ-opioid receptors and abuse potential. This study examines various pharmacokinetic parameters of 7-HMG in both in vitro and in vivo models.</p><p><strong>Methods: </strong>In vitro pharmacokinetic properties were investigated using human colorectal adenocarcinoma cell monolayers (Caco-2 cells), rat plasma, rat liver microsomes, and rat hepatocytes to determine the permeability, plasma protein binding, and microsomal and hepatocyte stability of 7-HMG, respectively. Oral and intravenous (IV) pharmacokinetic studies of 7-HMG were performed in male Sprague-Dawley rats.</p><p><strong>Results: </strong>7-HMG exhibits high permeability across Caco-2 cells (19.7 ± 1.0 × 10^-6 cm/s), with a relatively low plasma protein binding of 73.1 ± 0.6% to mitragynine. The hepatic extraction ratio was 0.3 and 0.6 in rat liver microsomes and hepatocytes, respectively, indicating that 7-HMG is an intermediate hepatic extraction compound. Oral and IV pharmacokinetic studies were performed in male rats. The volume of distribution was 2.7 ± 0.4 l/kg and the clearance was 4.0 ± 0.3 l/h/kg after IV administration. After oral dosing (5 mg/kg), a C_max of 28.5 ± 5.0 ng/ml and T_max of 0.3 ± 0.1 h were observed. However, the oral bioavailability of 7-HMG was only 2.7 ± 0.3%. The results demonstrate 7-HMG is rapidly absorbed but has low oral bioavailability. Mitragynine pseudoindoxyl (MGPI) is a metabolite of 7-HMG that is a more potent µ-opioid agonist than 7-HMG. The parent-to-metabolite ratio for MGPI following IV 7-HMG administration was 0.5 ± 0.1%, indicating very limited systemic exposure to MGPI.</p><p><strong>Conclusions: </strong>This study reports the pharmacokinetic parameters of 7-HMG to help with the development of mitragynine, as a therapeutic.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Physiologically-Based Pharmacokinetic Model for Quantitative Interpretation of Transdermal Drug Delivery of Rotigotine, a Dopamine Agonist for Treating Parkinson's Disease.","authors":"Ji-Hun Jang, Seung-Hyun Jeong","doi":"10.1007/s13318-025-00938-3","DOIUrl":"https://doi.org/10.1007/s13318-025-00938-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Rotigotine, a dopamine agonist, is used to treat Parkinson's disease and restless leg syndrome, with transdermal patches being the primary delivery method in clinical practice. However, quantitative information on the in vivo pharmacokinetics of rotigotine across various dosage regimens via transdermal administration remains limited, and this has been identified as a significant barrier to achieving precision medicine. This study aims to develop a novel physiologically-based systematic pharmacokinetic model tailored to rotigotine transdermal drug delivery. Based on the model, we quantitatively predicted rotigotine distribution patterns in target tissues to assess its in vivo efficacy and safety and to interpret the pharmacokinetic variability in transdermal patches according to covariate reflection.</p><p><strong>Methods: </strong>The data used to develop the quantitative model included clinical outcomes from single (2-8 mg/24 h) and multiple doses (0.5-8 mg/24 h) of rotigotine transdermal patches administered to healthy adults and patients with idiopathic Parkinson's disease or restless legs syndrome. The model was designed to represent whole-body physiological systems, incorporate liver and kidney clearance mechanisms, and account for the specific physicochemical properties influencing drug permeation and distribution across various tissues.</p><p><strong>Results: </strong>The model developed in this study effectively quantified the pharmacokinetic profiles of transdermal rotigotine within an acceptable variability. After transdermal application, rotigotine delivery to the target tissue, the brain, occurred rapidly, and the tissue concentrations at steady-state were approximately 10-fold higher than those in plasma. Incorporating weight as a covariate showed that in underweight individuals, tissue exposure to rotigotine increased by 1.61-fold, with a mean half-life extension of 1.50-fold compared to that of the normal weight population.</p><p><strong>Conclusion: </strong>The quantitative model proposed in this study serves as a foundational tool for advancing precision medicine, reliably characterizing the in vivo pharmacokinetics of rotigotine transdermal delivery across various doses and regimens.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":""},"PeriodicalIF":1.9,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical Care Pharmacology of Antiretroviral Therapy in Adults.","authors":"Luigi La Via, Andrea Marino, Giuseppe Cuttone, Giuseppe Nunnari, Cristian Deana, Manfredi Tesauro, Antonio Voza, Raymond Planinsic, Yaroslava Longhitano, Christian Zanza","doi":"10.1007/s13318-025-00934-7","DOIUrl":"10.1007/s13318-025-00934-7","url":null,"abstract":"<p><p>The clinical pharmacology of antiretroviral therapy (ART) in critical care presents unique challenges due to the complex interplay between HIV infection, critical illness, and drug management. This comprehensive review examines the pharmacokinetic and pharmacodynamic considerations of antiretroviral drugs in critically ill patients, where altered absorption, distribution, metabolism, and excretion significantly impact drug effectiveness and safety. Critical illness can substantially modify drug pharmacokinetics through various mechanisms, including impaired gastrointestinal motility, fluid shifts, hypoalbuminemia, hepatic dysfunction, and altered renal function. These changes, combined with potential drug-drug interactions in the polypharmacy environment of intensive care units, necessitate careful consideration of dosing strategies and monitoring approaches. The review addresses specific challenges in various critical care scenarios, including management of ART in patients with organ dysfunction, during renal replacement therapy, and in special populations such as those with sepsis or acute respiratory distress syndrome. It also explores the role of therapeutic drug monitoring in optimizing antiretroviral therapy and managing drug toxicities in critical care settings. Emerging areas of research, including long-acting formulations, nanotechnology-based drug delivery systems, and personalized medicine approaches, are discussed as potential future directions for improving ART management in critical care. The review emphasizes the importance of a multidisciplinary approach involving critical care physicians, infectious disease specialists, and clinical pharmacists to optimize outcomes in this complex patient population. This review provides clinicians with practical guidance for managing ART in critically ill patients while highlighting areas requiring further research to enhance our understanding and improve patient care in this challenging setting.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"105-118"},"PeriodicalIF":1.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11882694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143398701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leveraging Model-Based Simulations to Optimize Extended Dosing of Leuprolide 6-Month Intramuscular Depot Formulation.","authors":"Li-Feng Hsu","doi":"10.1007/s13318-024-00932-1","DOIUrl":"10.1007/s13318-024-00932-1","url":null,"abstract":"<p><strong>Background and objective: </strong>A gonadotropin-releasing hormone (GnRH) agonist such as leuprolide is widely used to achieve sustained suppression of testosterone levels, which play a critical role in the treatment of prostate cancer. Recent advances in drug delivery systems have led to the development of long-acting depot formulations, such as the 6-month intramuscular (IM) leuprolide formulation, which aim to simplify dosing and improve convenience for both patients and healthcare providers. Exploring extended dosing intervals for such formulations represents a promising approach to further optimize treatment regimens, potentially balancing efficacy with patient-centered care. The objective was to evaluate the efficacy of various extended dosing regimens of the leuprolide 6-month IM depot formulation for prostate cancer treatment. The primary objective was to assess whether extended dosing intervals could maintain testosterone concentrations below the castrate threshold of < 0.5 ng/ml and < 0.2 ng/ml in over 90% of subjects, as outlined in regulatory criteria.</p><p><strong>Methods: </strong>The study utilized a previously published pharmacokinetic/pharmacodynamic model to simulate the testosterone suppression profiles for different extended dosing regimens, including every 6 months (Q6M), 7 months (Q7M), 8 months (Q8M), 9 months (Q9M), 10 months (Q10M), 11 months (Q11M), and 12 months (Q12M). The simulations were carried out with 1000 virtual subjects. Sensitivity analyses were also conducted to account for variability in baseline testosterone levels and fraction of drug absorbed.</p><p><strong>Results: </strong>The simulation results indicated that extending the dosing interval from Q6M to Q8M could ensure that over 90% of subjects maintain testosterone concentrations below 0.2 ng/ml. Similarly, extending the dosing interval to Q9M would keep testosterone concentrations below 0.5 ng/ml in over 90% of subjects. The sensitivity analyses confirmed that these extended dosing regimens consistently achieved and maintained target testosterone levels across various scenarios.</p><p><strong>Conclusion: </strong>The findings support the feasibility of extending the dosing intervals for the leuprolide 6-month IM depot formulation beyond the label-recommended 6 months. Specifically, the Q8M and Q9M regimens emerged as viable candidates for further clinical evaluation, offering potential benefits in reducing injection frequency while maintaining therapeutic efficacy. Further clinical studies are necessary to confirm the long-term efficacy of these extended dosing regimens.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"139-149"},"PeriodicalIF":1.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Determination of Intrinsic Clearance and Fraction Unbound in Human Liver Microsomes and In Vitro-In Vivo Extrapolation of Human Hepatic Clearance for Marketed Central Nervous System Drugs.","authors":"Veera Raghava Chowdary Palacharla, Ramakrishna Nirogi, Nitesh Kumar, Krishnadas Nandakumar","doi":"10.1007/s13318-025-00935-6","DOIUrl":"10.1007/s13318-025-00935-6","url":null,"abstract":"","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"137"},"PeriodicalIF":1.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Herb-Drug Interaction of Total Glucosides of Paeony and Tripterygium Glycoside with Celecoxib in Beagle Dogs by UPLC-MS/MS.","authors":"Zhifei Zhang, Huijun Wang, Xinli Ren, Xiaotong Li, Xinyu Peng, Xiangjun Qiu","doi":"10.1007/s13318-025-00933-8","DOIUrl":"10.1007/s13318-025-00933-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Total glucosides of paeony (TGP) capsules, tripterygium glycoside tablets (TGT), and celecoxib are commonly used drugs in clinical practice for the treatment of Rheumatoid arthritis (RA). An UPLC-MS/MS method for the analysis of celecoxib in beagle dogs was developed, the herb-drug interactions (HDIs) between TGP and TGT with celecoxib were studied based on pharmacokinetics.</p><p><strong>Methods: </strong>The method of acetonitrile precipitation was applied to process plasma samples. Celecoxib and furosemide (internal standard, IS) was separated by gradient elution, and detected using multiple reaction monitoring mode under the positive ion. The ion reactions used for quantitative analysis were m/z 379.82 → 315.82 for celecoxib, and m/z 328.74 → 204.88 for IS. HDIs experiments adopt a three-stage experimental design. In the first period, six beagle dogs was orally administered 6.67 mg/kg celecoxib. In the second period, TGP 20 mg/kg was given orally twice a day for 7 consecutive days, then celecoxib was orally administered. And, in the third period, TGT 1.5 mg/kg was orally given, twice a day for 7 consecutive days, then celecoxib was orally administered. The concentration of celecoxib in the three periods was detected, and HDIs were evaluated based on pharmacokinetics.</p><p><strong>Results: </strong>Celecoxib exhibited good linearity in the range of 10-2000 ng/mL. The accuracy, precision, recoveries, matrix effects, and stability all met the standards. When celecoxib was used in combination with TGPC or TGT, the main pharmacokinetic parameters of celecoxib changed, C_max, AUC_(0-t) and AUC_(0-∞) increased, t_½ was prolonged, and CL and V_d decreased.</p><p><strong>Conclusion: </strong>A novel UPLC-MS/MS approach was successfully performed and applied to measure celecoxib in beagle dog plasma. TGP and TGT could inhibit the metabolism of celecoxib in beagle dogs, thereby affecting the pharmacokinetic parameters of celecoxib and increasing plasma exposure to celecoxib.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"151-159"},"PeriodicalIF":1.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determination of Intrinsic Clearance and Fraction Unbound in Human Liver Microsomes and In Vitro-In Vivo Extrapolation of Human Hepatic Clearance for Marketed Central Nervous System Drugs.","authors":"Veera Raghava Chowdary Palacharla, Ramakrishna Nirogi, Nitesh Kumar, Krishnadas Nandakumar","doi":"10.1007/s13318-024-00931-2","DOIUrl":"10.1007/s13318-024-00931-2","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to determine the apparent intrinsic clearance (Cl_{int, app}) and fraction unbound in human liver microsomes (f_{u, mic}) of 86 marketed central nervous system (CNS) drugs and to predict the in vivo hepatic blood clearance (CL_{h, b}).</p><p><strong>Methods: </strong>Cl_{int, app} in human liver microsomes (HLM) was determined by substrate depletion, and f_{u, mic} was determined by equilibrium dialysis. The relationship between lipophilicity (logP) and unbound intrinsic clearance (Cl_{int, u}) was explored using the Biopharmaceutical Drug Disposition Classification System (BDDCS) and Extended Clearance Classification System (ECCS). The predicted hepatic blood clearance by direct scaling, conventional method and Poulin method using well-stirred (WS) and parallel-tube (PT) models were compared with observed values.</p><p><strong>Results: </strong>The Cl_{int, app} in HLM ranged from < 5.8 to 477 µl/min/mg. The f_{u, mic} in HLM ranged from 0.02 to 1.0. The scaled Cl_int values ranged from < 5 to 4496 ml/min/kg. The metabolic rate increased with an increase in logP (logP ≥ 2.5) of the CNS compounds. The direct scaling and Poulin methods showed comparable results based on the percentage of clearance predictions within a two-fold error. The conventional method resulted in under-predictions of Cl_{int, in vivo} or CL_{h, b} using the WS or PT models. The Poulin method is favored over the other methods based on the statistical parameters.</p><p><strong>Conclusions: </strong>Experimental Cl_{int, app} and f_{u, mic} for 86 CNS compounds were successfully determined, and the scaled clearance was used to predict the hepatic blood clearance of 34 drugs. The success of prospective clearance predictions using HLM is expected to be high for most of the lipophilic BDDCS class 1 and class 2 and ECCS class 2 CNS compounds. The Poulin method resulted in more accurate predictions falling within a two-fold error of the observed values using the WS or PT models.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"119-135"},"PeriodicalIF":1.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}