European Journal of Drug Metabolism and Pharmacokinetics最新文献

{"title":"Uridine 5′-Diphospho-glucuronosyltransferase 1A3 (UGT1A3) Prediction of Hepatic Clearance of Organic Anion Transporting Polypeptide 1B3 (OATP1B3) Substrate Telmisartan by Glucuronidation Using In Vitro–In Vivo Extrapolation (IVIVE)","authors":"Ewelina Gabor-Worwa, Anna Kowal-Chwast, Nilesh Gaud, Dawid Gogola, Peter Littlewood, Marek Smoluch, Krzysztof Brzózka, Kamil Kus","doi":"10.1007/s13318-024-00895-3","DOIUrl":"https://doi.org/10.1007/s13318-024-00895-3","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background and Objective</h3><p>The prediction of pharmacokinetic parameters for drugs metabolised by cytochrome P450 enzymes has been the subject of active research for many years, while the application of in vitro–in vivo extrapolation (IVIVE) techniques for non-cytochrome P450 enzymes has not been thoroughly evaluated. There is still no established quantitative method for predicting hepatic clearance of drugs metabolised by uridine 5′-diphospho-glucuronosyltransferases (UGTs), not to mention those which undergo hepatic uptake. The objective of the study was to predict the human hepatic clearance for telmisartan based on in vitro metabolic stability and hepatic uptake results.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Telmisartan was examined in liver systems, allowing to estimate intrinsic clearance (CL_{int, in vitro}) based on the substrate disappearance rate with the use of liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Obtained CL_{int, in vitro} values were corrected for corresponding unbound fractions. Prediction of human hepatic clearance was made from scaled unbound CL_{int, in vitro} data with the use of the well-stirred model, and finally referenced to the literature value of observed clearance in humans, allowing determination of the essential scaling factors.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>The in vitro scaled CL_{int, in vitro} by UGT1A3 was assessed using three systems, human hepatocytes, liver microsomes, and recombinant enzymes. Obtained values were scaled and hepatic metabolism clearance was predicted, resulting in significant clearance underprediction. Utilization of the extended clearance concept (ECC) and hepatic uptake improved prediction of hepatic metabolism clearance. The scaling factors for hepatocytes, assessing the in vitro–in vivo difference, changed from sixfold difference to only twofold difference with the application of the ECC.</p><h3 data-test=\"abstract-sub-heading\">Conclusions</h3><p>The study showed that taking into consideration hepatic uptake of a drug allows us to obtain satisfactory scaling factors, hence enabling the prediction of in vivo hepatic glucuronidation from in vitro data.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140627017","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":"Long-Acting Strategies for Antibody Drugs: Structural Modification, Controlling Release, and Changing the Administration Route","authors":"Hao Wang, Mengdi Song, Jiaqi Xu, Zhenjing Liu, Mingyue Peng, Haoqiang Qin, Shaoqian Wang, Ziyang Wang, Kehai Liu","doi":"10.1007/s13318-024-00891-7","DOIUrl":"https://doi.org/10.1007/s13318-024-00891-7","url":null,"abstract":"<p>Because of their high specificity, high affinity, and targeting, antibody drugs have been widely used in the treatment of many diseases and have become the most favored new drugs for research in the world. However, some antibody drugs (such as small-molecule antibody fragments) have a short half-life and need to be administered frequently, and are often associated with injection-site reactions and local toxicities during use. Increasing attention has been paid to the development of antibody drugs that are long-acting and have fewer side effects. This paper reviews existing strategies to achieve long-acting antibody drugs, including modification of the drug structure, the application of drug delivery systems, and changing their administration route. Among these, microspheres have been studied extensively regarding their excellent tolerance at the injection site, controllable loading and release of drugs, and good material safety. Subcutaneous injection is favored by most patients because it can be quickly self-administered. Subcutaneous injection of microspheres is expected to become the focus of developing long-lasting antibody drug strategies in the near future.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140627014","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":"Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Ocedurenone (KBP-5074) in Individuals with Moderate Hepatic Impairment.","authors":"James McCabe, Jay Zhang, Fred Yang, Vincent Benn","doi":"10.1007/s13318-024-00879-3","DOIUrl":"10.1007/s13318-024-00879-3","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of ocedurenone in individuals with moderate hepatic impairment.</p><p><strong>Methods: </strong>This study was an open-label, nonrandomized, multi-center study investigating the pharmacokinetics, safety, and tolerability of a single dose of 0.5 mg ocedurenone administered orally in male and female subjects with moderate hepatic impairment (Child-Pugh B, score 7-9) compared with subjects with normal hepatic function. Serial blood samples were obtained from predose through 264 h postdose for analysis of ocedurenone concentrations using a validated liquid chromatography-tandem mass spectrometry method. Free ocedurenone concentrations in plasma were determined ex vivo using equilibrium dialysis.</p><p><strong>Results: </strong>Following a single oral dose of 0.5 mg ocedurenone administered to subjects with moderate hepatic impairment and subjects with normal hepatic function, ocedurenone was steadily absorbed with median time to peak drug concentration (T_max) values of 4 and 3 h, respectively. After reaching maximum plasma concentration (C_max), the disposition of ocedurenone appeared to be biphasic. The geometric mean t_1/2 values for the moderate hepatic impairment group and normal hepatic function group were 75.6 and 65.7 h, respectively. Ocedurenone systemic exposure, as assessed by area under the plasma concentration-time curve (AUC) was 23.5-26.6% lower in subjects with moderate hepatic impairment versus subjects with normal hepatic function, whereas C_max was 41.2% lower. Ocedurenone was determined to be > 99.7% bound to total protein in plasma. Hepatic impairment appeared not to change plasma protein binding or the unbound free fraction. Ocedurenone was safe and well-tolerated in all participants.</p><p><strong>Conclusions: </strong>Considering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and C_max do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. CLINICAL TRIAL IDENTIFIER ( WWW.</p><p><strong>Clinicaltrials: </strong>GOV ): NCT04534699.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10904433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702186","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":"Novel Techniques and Models for Studying the Role of the Gut Microbiota in Drug Metabolism.","authors":"Jianling Tan, Bingxuan Fu, Xiaojie Zhao, Ling Ye","doi":"10.1007/s13318-023-00874-0","DOIUrl":"10.1007/s13318-023-00874-0","url":null,"abstract":"<p><p>The gut microbiota, known as the second human genome, plays a vital role in modulating drug metabolism, significantly impacting therapeutic outcomes and adverse effects. Emerging research has elucidated that the microbiota mediates a range of modifications of drugs, leading to their activation, inactivation, or even toxication. In diverse individuals, variations in the gut microbiota can result in differences in microbe-drug interactions, underscoring the importance of personalized approaches in pharmacotherapy. However, previous studies on drug metabolism in the gut microbiota have been hampered by technical limitations. Nowadays, advances in biotechnological tools, such as microbially derived metabolism screening and microbial gene editing, have provided a deeper insight into the mechanism of drug metabolism by gut microbiota, moving us toward personalized therapeutic interventions. Given this situation, our review summarizes recent advances in the study of gut-microbiota-mediated drug metabolism and showcases techniques and models developed to navigate the challenges posed by the microbial involvement in drug action. Therefore, we not only aim at understanding the complex interaction between the gut microbiota and drugs and outline the development of research techniques and models, but we also summarize the specific applications of new techniques and models in researching gut-microbiota-mediated drug metabolism, with the expectation of providing new insights on how to study drug metabolism by gut microbiota.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138828887","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":"Pharmacokinetics, Safety Profile, and Tolerability of Tetramethylpyrazine Nitrone Tablets After Single and Multiple Ascending Doses in Healthy Chinese Volunteers.","authors":"Gangzhi Zhu, Liu Wang, Shaojin Zhong, Shengnan Han, Hui Peng, Mei Tong, Xiaoai He","doi":"10.1007/s13318-024-00877-5","DOIUrl":"10.1007/s13318-024-00877-5","url":null,"abstract":"<p><strong>Background and objectives: </strong>Tetramethylpyrazine nitrone (TBN) is a novel tetramethylpyrazine derivative armed with a strong free radical scavenging nitrone moiety. This study aims to evaluate the pharmacokinetics, safety profile, and tolerability of TBN tablets after a single ascending dose (SAD) and multiple ascending doses (MAD) in healthy Chinese volunteers.</p><p><strong>Methods: </strong>This phase I, single-center, open-label study was conducted in China. The SAD portion consisted of four cohorts with dose levels of 400-1800 mg. The MAD portion included three cohorts in which subjects received doses of 600-1800 mg twice daily for 7 days (13 consecutive doses). The third portion was a randomized, two-period, crossover design to assess the influence of food with a single dose of TBN tablets (1200 mg). The safety profile was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, physical examinations, and laboratory test results.</p><p><strong>Results: </strong>Fifty-two healthy subjects aged 18 to 45 years with a body mass index between 19.0 and 26.0 kg/m² were enrolled. After a single dose of TBN, the median time to maximum plasma concentration (T_max) was 2.48-3.24 h and the mean half-life (t_1/2) was 1.28 to 2.10 h across all doses. In the MAD study, the median T_max was 2.48 to 3.48 h. In the 400-1800 mg dose range, there was a tendency for less than proportional increases in the maximum plasma concentration (C_max), the area under the concentration-time curve from 0 to time of last measurable concentration (AUC_0-t), and the area under the concentration-time curve from 0 to infinity (AUC_0-inf) in both single- and multiple-dose periods. A significantly higher TBN exposure was observed in females than males in both a single and multiple doses of the 600 mg and 1200 mg groups, with a geometric mean female-to-male ratio of 138.69-203.18%. Food decreased the C_max and AUC_0-t of TBN to 45.19% and 59.73%, respectively. Each dose group reached a steady state after 4 days. No drug accumulation was observed. Two subjects had drug-related AEs. A decreased neutrophil count and drug eruption in the SAD portion (1200 mg group) and an increased alanine aminotransferase level in the food effect group were found. All AEs were mild and tolerable (CTCAE grade 1) and resolved without any medical intervention.</p><p><strong>Conclusion: </strong>TBN tablets had a good safety profile and were well tolerated in healthy Chinese volunteers. Steady-state concentrations were reached after 4 consecutive days of oral administration. The results of this phase I study will provide guidance for the design of future TBN clinical studies.</p><p><strong>Chinese clinical trial registry: </strong>ChiCTR1900022092.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139912368","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":"Pharmacokinetics of Dasatinib in Rats: a Potential Food-Drug Interaction with Naringenin.","authors":"Mohammad Raish, Ajaz Ahmad, Badr Abdul Karim, Yousef A Bin Jardan, Abdul Ahad, Muzaffar Iqbal, Khalid M Alkharfy, Fahad I Al-Jenoobi, Omer Mansour Mohammed","doi":"10.1007/s13318-024-00881-9","DOIUrl":"10.1007/s13318-024-00881-9","url":null,"abstract":"<p><strong>Background and objectives: </strong>The novel tyrosine kinase inhibitor (TKI) dasatinib, a multitarget inhibitor of Bcr-Abl and Src family kinases, has been licensed for the treatment of Ph+ acute lymphoblastic leukemia and chronic myeloid leukemia. Many citrus-based foods include the flavonoid naringenin, which is commonly available. Dasatinib is a Cyp3a4, P-gp, and Bcrp1 substrate, which makes it sensitive to potential food-drug interactions. The concurrent use of naringenin may change the pharmacokinetics of dasatinib, which could result in adverse effects and toxicity. The present investigation examined the impact of naringenin on the pharmacokinetics interactions of DAS and proposes a possible interaction mechanism in Wistar rats.</p><p><strong>Methods: </strong>Rats were provided with a single oral dose of dasatinib (25 mg/kg) with or without naringenin pretreatment (150 mg/kg p.o. daily for 7 days, n = 6 in each group). Dasatinib was quantified in plasma by UHPLC MS/MS assay. Noncompartmental analysis was used to compute the pharmacokinetic parameters, and immunoblot was used to assess the protein expression in the hepatic and intestinal tissues.</p><p><strong>Results: </strong>Following 7 days of naringenin pretreatment, the plasma mean concentration of dasatinib was enhanced compared with without pretreatment. In rats that were pretreated with naringenin, the pharmacokinetics of the orally administered dasatinib (25 mg/kg) was shown to be significantly different from that of dasatinib given without pretreatment (p < 0.05). There was a significant enhancement in pharmacokinetic parameters elimination half-life (T_1/2), time to maximum concentration ( T_max), maximum concentration )C_max), area under the concentration-time curve (AUC_0-t), area under the moment curve (AUMC_0-∞), and mean residence time (MRT) by 28.41%, 50%, 103.54%, 72.64%, 115.08%, and 15.19%, respectively (p < 0.05) and suppression in elimination rate constant (K_el), volume of distribution (V_d), and clearance (CL) by 21.09%, 31.13%, and 46.25%, respectively, in comparison with dasatinib alone group (p < 0.05). The enhancement in dasatinib bioavailability and systemic exposure resulted from the significant inhibition of Cyp3a2, Mdr1/P-gp, and Bcrp1 expression and suppression of the dasatinib hepatic and intestinal metabolism, which enhanced the rate of dasatinib absorption and decreased its elimination.</p><p><strong>Conclusion: </strong>Concurrent use of naringenin-containing supplements, herbs, or foods with dasatinib may cause serious and potentially life-threatening drug interactions. Further studies are necessary to determine the clinical significance of these findings.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905267","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 Bile Acids on Clindamycin Hydrochloride Skin Permeability: In Vitro and In Silico Preliminary Study.","authors":"Dragana Zaklan, Dušan Nešić, Darko Mitrović, Slavica Lazarević, Maja Đanić, Momir Mikov, Nebojša Pavlović","doi":"10.1007/s13318-024-00878-4","DOIUrl":"10.1007/s13318-024-00878-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Topical clindamycin formulations are widely used in clinical practice, but poor bioavailability and restricted skin penetration considerably limit their therapeutic efficacy. Penetration enhancement represents a promising and rational strategy to overcome the drawbacks of conventional topical pharmaceutical formulations. We aim to assess the influence of cholic acid (CA) and deoxycholic acid (DCA) on the permeability of clindamycin hydrochloride by performing the in vitro skin parallel artificial membrane permeability assay (skin-PAMPA) at two relevant pH values (5.5 and 6.5) and the interactions of tested substances with skin ATP-binding cassette (ABC) transporters in silico.</p><p><strong>Methods: </strong>After the incubation period, the clindamycin hydrochloride concentrations in both compartments were determined spectrophotometrically, and the apparent permeability coefficients (P_app) were calculated. Vienna LiverTox web service was used to predict the interactions of clindamycin and bile acids with potential drug transporters located in human skin.</p><p><strong>Results: </strong>Both CA and DCA at the highest studied concentration of 100 μM in the tested solutions increased the skin-PAMPA membrane permeability of clindamycin hydrochloride. This effect was more pronounced for CA and at a higher studied pH value of 6.5, which is characteristic of most dermatological indications treated with topical clindamycin preparations. Clindamycin transport may also be mediated by ABC transporters located in skin and facilitated in the presence of bile acids.</p><p><strong>Conclusions: </strong>The results of this study provide a solid foundation for further research directed at the improvement of topical formulations using bile acids as penetration-enhancing excipients, as well as the therapeutic efficacy of clindamycin hydrochloride.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706458","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":"Optimizing Antibiotic Therapy for Intravenous Drug Users: A Narrative Review Unraveling Pharmacokinetics/Pharmacodynamics Challenges.","authors":"Marta Colaneri, Camilla Genovese, Pietro Valsecchi, Matteo Calia, Dario Cattaneo, Andrea Gori, Raffaele Bruno, Elena Seminari","doi":"10.1007/s13318-024-00882-8","DOIUrl":"10.1007/s13318-024-00882-8","url":null,"abstract":"<p><p>Intravenous drug users (IVDUs) face heightened susceptibility to life-threatening gram-positive bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA). While the standard antibiotic dosing strategies for special patients, such as obese or critically ill individuals, are known to be inadequate, raising concerns about treatment efficacy, a similar sort of understanding has not been assessed for IVDUs yet. With this in mind, this review examines the pharmacokinetic/pharmacodynamic characteristics of antibiotics commonly used against gram-positive bacteria in IVDUs. Focusing on daptomycin, vancomycin, teicoplanin, aminoglycosides, and the novel lipoglycopeptide dalbavancin, the study reveals significant pharmacokinetic variations in IVDUs, suggesting the need for personalized dosing. Concomitant opioid substitution therapy and other factors, such as malnutrition, contribute to altered pharmacokinetics/pharmacodynamics, emphasizing the importance of targeted therapeutic drug monitoring. Overall, our study calls for increased awareness among clinicians regarding the unique pharmacokinetic/pharmacodynamic challenges in IVDUs and advocates for tailored antibiotic dosing strategies to enhance treatment outcomes in this marginalized population.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706459","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":"Pharmacokinetics of Long-Acting Methylphenidate: Formulation Differences, Bioequivalence, Interchangeability.","authors":"Mostafa Moharram, Tony Kiang","doi":"10.1007/s13318-023-00873-1","DOIUrl":"10.1007/s13318-023-00873-1","url":null,"abstract":"<p><p>BACKGROUND AND OBJECTIVE: Attention deficit hyperactivity disorder is one of the most common neuropsychiatric conditions in children, and methylphenidate (MPH) is one of the first-line therapies. MPH is available in a variety of extended-release (ER) formulations worldwide, and most formulations are not considered bioequivalent due to differences in pharmacokinetics. It is hypothesized that the current bioequivalence guidelines from the different regulatory bodies may generate inconsistent findings or recommendations when assessing the bioequivalence of ER MPH formulations. This manuscript aims to conduct a comprehensive and narrative critical literature review to analyze pharmacokinetic data pertaining to ER formulations of MPH in order to assess bioequivalence, differences in regulatory guidelines, and additional pharmacokinetic-pharmacodynamic parameters that may help define interchangeability.</p><p><strong>Methods: </strong>A literature search was conducted in EMBASE, Medline, and Cochrane Library with no time limits. Study characteristics, non-compartmental pharmacokinetic parameters, and bioequivalence data were extracted for analysis.</p><p><strong>Results: </strong>Thirty-three studies were identified with primary pharmacokinetic data after the administration of ER MPH, of which 10 were direct comparative studies (i.e., at least 2 formulations tested within a single setting) and 23 were indirect comparisons (i.e., different experimental settings). Two formulations were consistently reported as bioequivalent across the regulatory bodies using criteria from their guidance documents, although inconsistencies have been observed. However, when additional kinetic criteria (discussed in this manuscript) were imposed, only one study met the more stringent definition of bioequivalence. Various clinical factors also had inconsistent effects on the pharmacokinetics and interchangeability of the different formulations, which were associated with a lack of standardization for assessing covariates across the regulatory agencies.</p><p><strong>Conclusion: </strong>Additional pharmacokinetic parameters and consistency in guidelines across the regulatory bodies may improve bioequivalence assessments. Based on our findings, more research is also required to understand whether bioequivalence is an appropriate measure for determining MPH interchangeability. This critical review is suitable for formulation scientists, clinical pharmacologists, and clinicians.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138828888","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 Interaction Between Imatinib and Metformin in Rats.","authors":"Naling Fan, Liying Du, Teng Guo, Mingfeng Liu, Xinran Chen","doi":"10.1007/s13318-023-00869-x","DOIUrl":"10.1007/s13318-023-00869-x","url":null,"abstract":"<p><strong>Background and objective: </strong>Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats.</p><p><strong>Methods: </strong>Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software.</p><p><strong>Results: </strong>After single-dose co-administration of imatinib and metformin on day 1, the AUC_0-24 (area under the plasma concentration-time curve) and C_max (maximum concentration) of imatinib and the MRT (mean residence time) and C_max of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC_0-24 and C_max of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05).</p><p><strong>Conclusion: </strong>With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138884750","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}