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PHARMACOKINETIC MODELS IN enterohepatic circulation

生物数学学报 1991年第2期 97-105页

作者： Zhou Huaiwu, Shen Jiaqing, Lu Ming(Division of Biomathematics, Zhejiang Medical University, Hangzhou 310006) Liang Wenquan, Lin Wu(Division of Pharmaceutics, Zhejiang Medical University, Hangzhou 310006)

Two extended one-and two-compartment model are Proposed to explain the multiple-peak phenomena of drugs subject to enterohepatic circulaion. The models are formed by adding a storage compartment on the basis of corresponding classic *** that the circulation will be repeated at regular intervals until the effective amount of drugs released to absorption compartment can be neglected. The concentration (c)-time(t) equations of bolus intravenous and oral administration undergoing n circulations are deduced to express the quantitative contribution of each circulation. Furthermore, the concept of total bioavailability is introduced to describe the bioavailability of drugs obeying the mechanism of entcrohepatic circulation.

关键词： Pharmacokinetics Models enterohepatic circulation Bioavailability.

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Biliary excretion and enterohepatic circulation of thienorphine and its glucuronide conjugate in rats

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Acta Pharmaceutica Sinica B 2012年第2期2卷 174-180页

作者： Jingting Deng Xiaomei Zhuang Guolin Shen Hua Lin Zehui Gong Laboratory of Drug Metabolism Beijing Institute of Pharmacology and ToxicologyBeijing 100850China

Thienorphine(TNP)is a new partial opioid agonist currently developed as a promising drug candidate with the intended clinical indication for the treatment of opioid *** pharmacokinetic profile and biliary excretion of TNP and its glucuronide conjugate(TNP-Glu)were investigated after oral administration of TNP in *** concentrations of TNP and TNP-Glu were simultaneously quantified using a LC-MS/MS method.A double peak phenomenon was observed in TNP plasma concentration–time curves with the secondary peak appeared at 6–8 h.A slower decline of plasma concentrations in the terminal phase was observed for TNP with T1/2 of 7.01 ***-Glu was the predominant component in rat plasma and *** plasma level was about 10 times higher than TNP and the 24 h accumulative bile excretion rate was 23%.enterohepatic circulation of TNP and TNP-Glu was evaluated using a paired rat *** bile-donor rats,no double-peak was detected and the elimination half life of TNP was significantly shortened(3.71 h)when compared to intact rats(7.01 h,Penterohepatic circulation were 15.6%and 42.6%for the parent drug and the metabolite,*** deconjugation of the glucuronide conjugate and the reabsorption of free TNP were further confirmed in in situ perfused rat intestinal *** results indicate that the enterohepatic circulation has a significant influence on the systemic exposure of the parent drug and its glucuronide conjugate,particularly on the terminal elimination of TNP,which may result in the prolonged retention of the drug in body.

关键词： Thienorphine Glucuronide conjugate Biliary excreation enterohepatic circulation LC-MS/MS

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A mechanism based population pharmacokinetic model that describes enterohepatic circulation of ezetimibe

A mechanism based population pharmacokinetic model that desc...

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第十二届全国数学药理学术大会

作者： Zheng JIAO~1,Zhong-dong LI~1,Chen YU~2,Xiao-jin SHI~1 1 Pharmacy Department,Huashan Hospital,Fudan University,Shanghai,200040, P.R.CHINA,2 Central Laboratory,Shanghai Xuhui Central Hospital,Shanghai,200031,P.R.CHINA

Background: Ezetimibe is a novel and selective cholesterol absorption inhibitor that effectively blocks intestinal absorption of dietary and biliary *** is used for the treatment of mild hypercholesterolemia as monotherapy or reduction of LDL-C levels as adjunctive *** is rapidly absorbed and glucuronidated in the *** parent compound and its conjugated metabolite undergo enterohepatic circulation(EHC),resulting in multiple peaks in the plasma concentrationtime profile. Objective: The aim of this study was to develop a mechanism based population pharmacokinetic(PPK) model to describe the EHC of ezetimibe. Methods: The concentration-time data were from a Phase I study and consisted of 20 profiles from healthy subjects who received a single dose of ezetimibe 10 *** was carried out using a nonlinear mixed-effect modelling *** the glucuronide(-90%of the total) and the parent compound both exhibit multiple peaks and exhibit cholesterol lowering activity,the total ezetimibe concentrations(glucuronide + parent) were modeled. Results: The established chain compartment model included an intestinal compartment,a gallbladder compartment,a central and a peripheral *** was incorporated in the PPK model as a secondary input into the intestinal tract and the gallbladder emptying was postulated to be at mealtime. The amount of ezetimibe recycled into the central compartment was estimated to be 36.8%(SE%: 17.7%),independent of the volume of *** typical population clearance(CL/F) estimates was 7.5 L/h(SE%17.7%).The residual error was 26.2%. Conclusion: PPK models adapted for EHC allowed a formal assessment of the magnitude and frequency of the enterohepatic recirculation process,and the associated intersubject and intrasubject variability in healthy subjects.

关键词： Ezetimibe population pharmacokinetics enterohepatic circulation

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Gut-liver axis plays a role in hepatocarcinogenesis of patients with Crohn's disease

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World Journal of Gastroenterology 2011年第26期17卷 3171-3172页

作者： Shu-Mei Zheng De-Jun Cui Qin Ouyang Department ofGastroenterology West China Hospital of Sichuan UniversityChengdu 610041 Sichuan Province China

The development of hepatocellular carcinoma （HCC） is attributed to several factors, including chronic viral infection, alcohol consumption, exposure to aflatoxin 131 and metabolic disorders. Several recent reports have shown that HCC can occur in patients with longstanding Crohn＇s disease （CD） in the absence of other underlying high-risk liver diseases. There may be an association between CD and hepatocarcinogenesis, however, the precise mechanism for this requires further investigations.

关键词： Inflammatory bowel disease Crohn's disease Hepatocellular carcinoma Intestinal flora Aza-thioprine enterohepatic circulation

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The role of bile acids in human aging

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Medical Review 2024年第2期4卷 154-157页

作者： Lihua Jin Linsen Shi Wendong Huang Department of Diabetes Complications and Metabolism Arthur Riggs Diabetes and Metabolism Research InstituteBeckman Research InstituteCity of Hope National Medical Center1500 E.Duarte RoadDuarteCA 91010USA Department of Diabetes Complications and Metabolism Arthur Riggs Diabetes and Metabolism Research InstituteBeckman Research InstituteCity of Hope National Medical CenterDuarteCAUSA Irell&Manella Graduate School of Biomedical Science City of Hope National Medical Center1500 E.Duarte RoadDuarteCA 91010USA

Bile acids are recognized as important signaling molecules that enable fine-tuned inter-communication from the liver,through the intestine,to virtually any organ,thus encouraging their pleiotropic physiological *** is a complex natural process defined as a progressive decline in cellular and organismal functions.A causal link between bile acids and the aging process is ***,there are gaps in our understanding of the molecular mechanisms and precise targets responsible for the alteration of bile acid profiles and their role in the aging *** barrier dysfunction leads to endotoxemia,systemic inflammation,insulin resistance,diabetes,lipid accumulation,obesity and fatty liver diseases,and health decline and *** fact,intestinal barrier dysfunction is suggested to be an evolutionarily conserved hallmark of *** acids may modulate the aging process by regulating intestinal barrier integrity.

关键词： age bile acid gut microbiota enterohepatic circulation intestinal barrier

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