目的 建立阿哌沙班的机制性生理药动学 (physiologically based pharmacokinetic, PBPK) 模型,探究阿哌沙班体内代谢清除机制,定量评估 P-糖蛋白 (P-glycoprotein, P-gp)外排作用对阿哌沙班胃肠道吸收的影响。方法 通过整合阿哌沙班理化参数及临床研究数据构建静脉PBPK模型,确保药物参数及作用机制的准确性,在此基础上连接高级房室吸收和转运模型(advanced compartment absorption transit model, ACAT)用于定量评估阿哌沙班P-gp在胃肠道吸收中的贡献,分析肠道P-gp作用机制及胃肠道吸收特性。结果 阿哌沙班不仅是肠道P-gp的底物,肾脏P-gp同样对药物处置具有重要作用。肠道P-gp抑制了阿哌沙班在胃肠道中的吸收,并使得各肠段吸收速率常数具有部位依赖性。此外肾脏重吸收作用也参与阿哌沙班排泄。结论 本研究构建的机制性PBPK模型能定量分析阿哌沙班作用机制,并可为临床用药中药物相互作用等研究奠定基础。
Abstract
OBJECTIVE To establish the mechanism-based physiological pharmacokinetics (PBPK) model of apixaban, explore the metabolic clearance mechanism of apixaban, and quantitatively evaluate the effect of P-glycoprotein (P-gp) outflow on gastrointestinal absorption of apixaban. METHODS The venous PBPK model was constructed by integrating the physical and chemical parameters of apixaban and clinical research data to ensure the accuracy of drug parameters and action mechanisms. On this basis, the advanced compartment absorption transit model (ACAT) was connected to quantitatively evaluate the contribution of apixaban P-gp in gastrointestinal absorption and analyze the action mechanism of intestinal P-gp and gastrointestinal absorption characteristics. RESULTS Apixaban is not only the substrate of intestinal P-gp, the kidney P-gp also plays an important role in the drug disposal. Intestinal P-gp inhibits the absorption of apixaban in the gastrointestinal tract and makes the absorption rate constants in each intestinal segment site-dependent. In addition, renal reabsorption is also involved in the excretion of apixaban. CONCLUSION The mechanistic PBPK model constructed in this study can quantitatively analyze the mechanism of drug action and lays a foundation for the study of drug interaction in clinical medication.
关键词
阿哌沙班 /
生理药动学模型 /
P-糖蛋白 /
高级房室吸收与转运模型
{{custom_keyword}} /
Key words
apixaban /
PBPK model /
P-gp: ACAT
{{custom_keyword}} /
中图分类号：
R969
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] KANADO Y, TSURUDOME Y, OMATA Y, et al. Estradiol regulation of P-glycoprotein expression in mouse kidney and human tubular epithelial cells, implication for renal clearance of drugs[J]. Biochem Biophys Res Commun, 2019, 519(3): 613-619.
[2] AGENO W, GALLUS A S, WITTKOWSKY A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines[J]. Chest, 2012, 141(2): 44-88.
[3] HANIGAN S, DAS J, POGUE K, et al. The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding[J]. J Thromb Thrombolys, 2020, 49(4): 636-643.
[4] VAKKAKAGADDA B, FROST C, BYON W, et al. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa[J]. Am J Cardiovasc Drug, 2016, 16(2): 119-127.
[5] FROST C E, BYON W, SONG Y, et al. Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor[J]. Brit J Clin Pharmacol, 2015, 79(5): 838-846.
[6] ZHANG D, FROST C E, HE K, et al. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats[J]. Drug Metab Dispos, 2013, 41(4): 906-915.
[7] SAGER J E, YU J, RAGUENEAU-MAJLESSI I, et al. Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification[J]. Drug Metab Dispos, 2015, 43(11): 1823-1837.
[8] RAGHAVAN N, FROST C E, YU Z, et al. Apixaban metabolism and pharmacokinetics after oral administration to humans[J]. Drug Metab Dispos, 2009, 37(1): 74-81.
[9] WONG P C, PINTO D J, ZHANG D, et al. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor[J]. J Thromb Thrombolys, 2011, 31(4):478-492.
[10] FROST C, WANG J, NEPAL S, et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects[J]. Brit J Clin Pharmacolo, 2013, 75(2): 476-487.
[11] DAHLGREN D, ROOS C, SJÖGREN E, et al. Direct in vivo human intestinal permeability (Peff) determined with different clinical perfusion and intubation methods[J]. J Pharm Sci-US, 2015, 104(9): 2702-2726.
[12] ICRP. Basic anatomical and physiological data for use in radiological protection: reference values. A report of age-and gender-related differences in the anatomical and physiological characteristics of reference individuals[J]. Ann ICRP, 2002, 32(3-4): 5-265.
[13] ZHANG D, HE K, HERBST J J, et al. Characterization of efflux transporters involved in distribution and disposition of apixaban[J]. Drug Metab Dispos, 2013, 41(4): 827-835.
[14] XU R, TANG H, CHEN L, et al. Developing a physiologically based pharmacokinetic model of apixaban to predict scenarios of drug-drug interactions, renal impairment and paediatric populations[J]. Br J Clin Pharmacol, 2021, 87(8): 3244-3254.
[15] FROST C, GARONZIK S, SHENKER A, et al. Apixaban single-dose pharmacokinetics, bioavailability, renal clearance, and pharmacodynamics following intravenous and oral administration[J]. Clin Pharm Drug Dev, 2021, 10(9): 974-984.
[16] BASHIR B, STICKLE D F, CHERVONEVA I, et al. Drug-drug interaction study of apixaban with cyclosporine and tacrolimus in healthy volunteers[J]. Clin Transl Sci, 2018, 11(6):590-596.
[17] FROST C E, SONG Y, SHENKER A, et al. Effects of age and sex on the single-dose pharmacokinetics and pharmacodynamics of apixaban[J]. Clin Pharmacokinet, 2015, 54(6):651-662.
[18] WANG L, ZHANG D, RAGHAVAN N, et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies [J]. Drug Metab Dispos, 2010, 38(3): 448-458.
[19] FOJO A T, UEDA K, SLAMON D J, et al. Expression of a multidrug-resistance gene in human tumors and tissues[J]. Proc Natl Acad Sci USA, 1987, 84(1): 265-269.
[20] LUO Y F, REN L X, LI X H, et al. Summary of research methods for drug intestinal absorption[J]. Drug Eval Res(药物评价研究), 2017, 40(5): 706-710.
[21] THOMPSON C M, JOHNS D O, SONAWANE B, et al. Database for physiologically based pharmacokinetic (PBPK) modeling: physiological data for healthy and health-impaired elderly[J]. J Toxicol Env Heal B, 2009, 12(1):1-24.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
首都卫生发展科研专项资助(首发2022-2Z-4056)
{{custom_fund}}
PDF(1505 KB)
