European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Exploring the Pharmacokinetic Profile of Antiretroviral Efavirenz in Low Protein Malnourished Condition in Wistar Rats.","authors":"Sachin V Tembhurne, Swarupa V Sul, Shubham N Gavade, Swati Jogdand","doi":"10.1007/s13318-025-00953-4","DOIUrl":"10.1007/s13318-025-00953-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>The HIV infection in malnourished conditions raises the concerns with antiretroviral medications, which may worsen the already compromised physiological state. The alteration in the plasma protein binding in malnourished HIV patients exacerbates the unbound fraction of antiretroviral medications, resulting in alterations in the therapeutic effectiveness and toxicity. Thus, the present study investigates the effects of protein deficiency and protein-energy malnutrition on the pharmacokinetics of the antiretroviral efavirenz.</p><p><strong>Method: </strong>Malnutrition was induced in this study through a modified diet containing only 2% protein. The experiment involved 16 Wistar rats, divided into two groups of 8. The control group was provided with a standard pellet diet (AIN 93G) that contained 19% protein, while the second group was subjected to the low-protein (2%) diet for 90 days. Rats were fed ad libitum with their respective diets during this period. On the 90th day, efavirenz (200 mg/kg, p.o.) was administered, and pharmacokinetic parameters were assessed using HPLC analysis.</p><p><strong>Results: </strong>The findings indicate that the protein-deficient diet successfully created a model of malnutrition, evidenced by a significant reduction in body weight (26%), hemoglobin levels (33%), total protein (27%), and blood albumin (41%) compared to the control group on a standard diet. The pharmacokinetic analysis of efavirenz in the protein-deficient rats revealed an increase in half-life (T_½) by 51.27%, maximum concentration (C_max) by 31.57%, and area under the curve (AUC 0-∞) by 51.40%, alongside a decrease in total body clearance (45.81%) and volume of distribution (12.1%) relative to the pharmacokinetic profile observed in rats on the standard AIN 93G diet.</p><p><strong>Conclusion: </strong>These findings indicate that the pharmacokinetic profile of efavirenz is significantly altered under protein-deficient conditions. Therefore, it is recommended that further pharmacokinetic studies be conducted in patients with protein deficiency to determine if standard dosing of efavirenz should be adjusted based on the individual's nutritional status.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"363-369"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336428","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":"The Impact of Hyperuricemia on Pharmacokinetics in Sprague-Dawley Rats.","authors":"Xiaomeng Pan, Dandan Li, Yujuan Chen, JiaMian Lu, Yakun Yang, Yusong Guo, Dezhi Kong, Wei Guo","doi":"10.1007/s13318-025-00950-7","DOIUrl":"10.1007/s13318-025-00950-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Hyperuricemia (HUA) is a metabolic disease closely associated with hypertension. It can induce liver damage, subsequently affecting drug metabolism. However, its specific impacts and underlying mechanisms remain unclear. Therefore, the pharmacokinetics and cytochrome P450 (CYP450) enzyme activities were investigated.</p><p><strong>Methods: </strong>Twelve healthy Sprague-Dawley rats were randomly assigned into two groups, a control group and an experimental group, with six animals per group. To establish the HUA model, rats in the experimental group received a subcutaneous injection of potassium oxonate (POx) (250 mg/kg), combined with oral administration of a fructose solution (5%, w/v). Serum biochemical parameters were subsequently evaluated, while histopathological examinations of liver and kidney tissues were performed. Plasma amlodipine (ALDP) levels were quantified by employing LC-MS/MS, and pharmacokinetic parameters were analyzed using DAS 3.0 software. Furthermore, activities of six major CYP450 enzyme isoforms were simultaneously determined through the cocktail method.</p><p><strong>Results: </strong>In the HUA-induced rats, significant elevations in serum uric acid (SUA), blood urea nitrogen (BUN), and creatinine (Cr) were observed, accompanied by distinct pathological lesions within hepatic and renal tissues. Pharmacokinetic analyses demonstrated marked increases in the peak plasma concentration (C_max), terminal elimination half-life (t_½), and time to reach peak concentration (T_max) of ALDP, which were elevated by approximately 2.7-fold, 1.5-fold, and 2.1-fold, respectively. The apparent oral clearance (CL_z/F) significantly decreased by half. Furthermore, the activities of six CYP450 enzymes notably decreased: CYP2E1 by 94%, CYP2C19 by 92%, CYP2C9 by 91%, CYP2D6 by 80%, CYP3A1 by 73%, and CYP1A2 by 7%.</p><p><strong>Conclusion: </strong>This study successfully established a stable rat model of HUA, and demonstrated that HUA specifically alters drug metabolism by causing liver damage and modulating CYP450 enzyme activities.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"327-339"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274515","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":"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":"187-204"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","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":"Comparison of Machine Learning Algorithms and Bayesian Estimation in Predicting Tacrolimus Concentration in Tunisian Kidney Transplant Patients During the Early Post-Transplant Period.","authors":"Nadia Ben-Fredj, Issam Dridi, Ichrak Dridi, Noureddine Ben-Yahya, Karim Aouam","doi":"10.1007/s13318-025-00942-7","DOIUrl":"10.1007/s13318-025-00942-7","url":null,"abstract":"<p><strong>Background and objective: </strong>Model-informed precision dosing (MIPD), based on a Bayesian approach and machine learning (ML) algorithms, is a suitable approach to personalize dosage recommendations and to improve the concentration target attainment for each patient. The objective of this study is to compare the predictive performance of two ML approaches, XGBoost and LSTM, with a previously developed Bayesian model of tacrolimus (Tac) in a cohort of Tunisian kidney transplant patients during the early post-transplant period (0-3 months) METHOD: This was a cross-sectional study conducted at the Pharmacology department in Fattouma Bourguiba's hospital in Monastir, Tunisia. We included patients who had undergone kidney transplantation in the Nephrology department of Monastir Hospital and received the Tac immunosuppressant protocol, for whom routine therapeutic drug monitoring (TDM) during the early post-transplant period (0-3 months) had been performed in our department.</p><p><strong>Results: </strong>A total of 187 Tac predose concentration (C₀) issued from 56 adult renal transplant patients were included in the present study. The whole population was divided into building (n = 39 patients, 119 C₀) and validation groups (n = 17 patients, 68 C₀). In the validation dataset, the RMSE was 0.76, 0.19, and 0.01, and the MAE was 0.55, 0.36, and 0.06, respectively, for the Bayesian approach, XGBoost, and LSTM.</p><p><strong>Conclusion: </strong>Our study demonstrates that the LSTM approach outperforms XGBoost and Bayesian estimation in predicting tacrolimus concentration in Tunisian kidney transplant patients. Implementing TDM-based LSTM models during the first PT 3 months in clinical practice can significantly enhance patient outcomes and prevent acute kidney rejection in this population.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"243-250"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987050","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":"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":"251-263"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081501/pdf/","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":"OA","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":"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":"205-218"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","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":"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":"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":"229-242"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081532/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study to Evaluate the Relative Bioavailability, Pharmacodynamics, and Safety of a Single Subcutaneous Injection of Recaticimab at Three Different Sites in Healthy Chinese Subjects.","authors":"Ying Wang, Yuanzhi Cheng, Yuhan Guo, Yang Fan, Renpeng Zhou, Qian Zhang, Ye Xu, Sheng Feng, Kai Shen, Wei Hu","doi":"10.1007/s13318-025-00944-5","DOIUrl":"10.1007/s13318-025-00944-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Recaticimab (SHR-1209) is a humanized monoclonal antibody that binds to the proprotein convertase subtilisin/kexin type 9 (PCSK9) with high affinity. This study was conducted to compare the relative bioavailability, pharmacokinetics (PK), pharmacodynamics (PD), and safety of recaticimab following subcutaneous injection at three different sites in healthy Chinese subjects.</p><p><strong>Methods: </strong>In this randomized, parallel, open-label, phase I study, 159 healthy Chinese subjects were randomized to receive a single dose of 450 mg recaticimab subcutaneously into the abdomen, upper-arm, or thigh and were followed up until 113 days postdose. Adverse events were monitored, and serum samples were collected for PK, PD, and immunogenicity evaluation during the study.</p><p><strong>Results: </strong>The PK profiles of recaticimab were similar among different injection site groups. The geometric mean ratios of maximum serum concentration (C_max), area under the serum concentration versus time curve (AUC) from time zero to the time of last quantifiable concentration (AUC_0-last), and AUC from time zero extrapolated to infinity (AUC_0-inf) between groups were all close to 1, with two-sided 90% confidence intervals within 0.8-1.25. Recaticimab showed similar effects on low-density lipoprotein cholesterol levels in all groups, with mean maximum percentage decreases ranging from 56.88% to 59.04%. The percentage changes from baseline in free PCSK9 and other lipid variables were similar across the three groups as well. Treatment-emergent adverse events were reported in 41/53 (77.4%, abdomen), 29/53 (54.7%, upper-arm), and 42/53 (79.2%, thigh) subjects, most of which were mild and resolved without treatment. The incidence of antidrug antibodies among the three groups was comparable.</p><p><strong>Conclusions: </strong>A single subcutaneous injection of 450 mg recaticimab into the abdomen, upper-arm, or thigh was well-tolerated and presented similar PK and PD profiles, which supported the interchangeable use of the three injection sites for patients.</p><p><strong>Clinical trial identifier: </strong>( www.</p><p><strong>Clinicaltrials: </strong>gov ) NCT05370950 2022-05-07.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"265-272"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989610","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":"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":"219-227"},"PeriodicalIF":1.9,"publicationDate":"2025-05-01","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":"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}