دورية أكاديمية
Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption.
| العنوان: | Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption. |
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| المؤلفون: | Ping X; Basic Teaching Department, Baoding Technical College of Electric Power, Baoding, Hebei, China., Wang G; Zhongcai Health (Beijing) Biological Technology Development Co., Ltd, Beijing, China., Gao D; Department of Medical Oncology, Bethune International Peace Hospital, Shijiazhuang, Hebei, China. |
| المصدر: | Journal of clinical pharmacology [J Clin Pharmacol] 2024 Jun; Vol. 64 (6), pp. 672-684. Date of Electronic Publication: 2024 Feb 16. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley Country of Publication: England NLM ID: 0366372 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4604 (Electronic) Linking ISSN: 00912700 NLM ISO Abbreviation: J Clin Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2013- : Oxford : Wiley Original Publication: Stamford, Conn., Hall Associates. |
| مواضيع طبية MeSH: | Glucosides*/pharmacokinetics , Benzhydryl Compounds*/pharmacokinetics , Benzhydryl Compounds*/urine , Sodium-Glucose Transporter 1*/metabolism , Models, Biological* , Sodium-Glucose Transporter 2 Inhibitors*/pharmacokinetics , Sodium-Glucose Transporter 2 Inhibitors*/pharmacology, Humans ; Glucose/metabolism ; Male ; Sodium-Glucose Transporter 2/metabolism ; Adult ; Hypoglycemic Agents/pharmacokinetics ; Hypoglycemic Agents/pharmacology ; Renal Reabsorption/drug effects ; Kidney/metabolism ; Glycosuria ; Female ; Middle Aged |
| مستخلص: | The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na + reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP. (© 2024, The American College of Clinical Pharmacology.) |
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| فهرسة مساهمة: | Keywords: PBPK model; SGLT1 compensation; SGLT2 occupancy; UGE; empagliflozin |
| المشرفين على المادة: | HDC1R2M35U (empagliflozin) 0 (Glucosides) 0 (Benzhydryl Compounds) 0 (Sodium-Glucose Transporter 1) 0 (Sodium-Glucose Transporter 2 Inhibitors) 0 (SLC5A1 protein, human) IY9XDZ35W2 (Glucose) 0 (Sodium-Glucose Transporter 2) 0 (Hypoglycemic Agents) 0 (SLC5A2 protein, human) |
| تواريخ الأحداث: | Date Created: 20240216 Date Completed: 20240527 Latest Revision: 20240604 |
| رمز التحديث: | 20240604 |
| DOI: | 10.1002/jcph.2413 |
| PMID: | 38363006 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1552-4604 |
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| DOI: | 10.1002/jcph.2413 |