<i>In vitro</i>metabolism and<i>in vivo</i>pharmacokinetics of bentysrepinine (Y101), an investigational new drug for anti-HBV-infected hepatitis: focus on interspecies comparison

Fan, Huirong; Zhang, Aijie; Liao, Chenghong; Yang, Yanlan; Zhang, Lihua; Liu, Jianfeng; Xia, Yuanyuan; Si, Duanyun; Su, Dong; Liu, Changxiao

doi:10.1080/00498254.2019.1646946

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…Male rats surgically prepared with indwelling jugular cannula were randomly divided into two groups ( n = 3): (1) Y101 alone (25 mg/kg) as a control and (2) Y101 + PRO (25 mg/kg for Y101 and 100 mg/kg for PRO) as an experimental group. The intravenous dose of Y101 was prepared as previously described [ 24 ]. Both Y101 and PRO were injected by caudal vein to rats at volume of 5 mL/kg.…”

Section: Methodsmentioning

confidence: 99%

“…Non-compartmental analysis with Phenix WinNonlin (version 8.1; Pharsight, Certara Corp, Princeton, NJ) was used to calculate the main pharmacokinetic parameters of ETV, Y101, M8 and M9 for individual rats [ 24 ]. The observed values were reported for maximum concentration ( C max ) and time to reach maximum concentration ( T max ), while the area under the plasma concentration–time curve (AUC) was calculated via the default trapezoidal-up, log-trapezoidal-down approach.…”

Section: Methodsmentioning

confidence: 99%

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OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro

Zhang

Yang

et al. 2023

Molecules

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Bentysrepinine (Y101) is a novel phenylalanine dipeptide for the treatment of hepatitis B virus. Renal excretion played an important role in the elimination of Y101 and its metabolites, M8 and M9, in healthy Chinese subjects, although the molecular mechanisms of renal excretion and potential drug–drug interactions (DDIs) remain unclear. The present study aimed to determine the organic anion transporters (OATs) involved in the renal disposition of Y101 and to predict the potential DDI between Y101 and entecavir, the first-line agent against HBV and a substrate of OAT1/3. Pharmacokinetic studies and uptake assays using rat kidney slices, as well as hOAT1/3-HEK293 cells, were performed to evaluate potential DDI. The co-administration of probenecid (an inhibitor of OATs) significantly increased the plasma concentrations and area under the plasma concentration–time curves of M8 and M9 but not Y101, while reduced renal clearance and the cumulative urinary excretion of M8 were observed in rats. The time course of Y101 and M8 uptake via rat kidney slices was temperature-dependent. Moreover, the uptake of M8 was inhibited significantly by probenecid and benzylpenicillin, but not by p-aminohippurate or tetraethyl ammonium. M8 was found to be a substrate of hOAT3, but Y101 is not a substrate of either hOAT1 or hOAT3. Additionally, the entecavir inhibited the uptake of M8 in the hOAT3-transfected cells and rat kidney slices in vitro. Interestingly, no significant changes were observed in the pharmacokinetic parameters of Y101, M8 or entecavir, regardless of intravenous or oral co-administration of Y101 and entecavir in rats. In conclusion, M8 is a substrate of OAT3 in rats and humans. Furthermore, M8 also mediates the DDI between Y101 and entecavir in vitro, mediated by OAT3. We speculate that it would be safe to use Y101 with entecavir in clinical practice. Our results provide useful information with which to predict the DDIs between Y101 and other drugs that act as substrates of OAT3.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro

Zhang

Yang

et al. 2023

Molecules

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“…Q‐trap combines wide range mass scanning with triple quadrupole‐like high quality fragment ion data production (without the before‐mentioned low mass cut‐off feature of ion traps) and very high sensitivity MRM mode data acquisition. Thus, it is of great value to both metabolic stability and metabolic profiling studies [65–67].…”

Section: Separation Techniques Used In Metabolic Stability Estimationmentioning

confidence: 99%

Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

Ulenberg

Bączek

2020

J of Separation Science

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With metabolism being one of the main routes of drug elimination from the body (accounting for removal of around 75% of known drugs), it is crucial to understand and study metabolic stability of drug candidates. Metabolically unstable compounds are uncomfortable to administer (requiring repetitive dosage during therapy), while overly stable drugs increase risk of adverse drug reactions. Additionally, biotransformation reactions can lead to formation of toxic or pharmacologically active metabolites (either less‐active than parent drug, or even with different action). There were numerous approaches in estimating metabolic stability, including in vitro, in vivo, in silico, and high‐throughput screening to name a few. This review aims at describing separation techniques used in in vitro metabolic stability estimation, as well as chemometric techniques allowing for creation of predictive models which enable high‐throughput screening approach for estimation of metabolic stability. With a very low rate of drug approval, it is important to understand in silico methods that aim at supporting classical in vitro approach. Predictive models that allow assessment of certain biological properties of drug candidates allow for cutting not only cost, but also time required to synthesize compounds predicted to be unstable or inactive by in silico models.

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Novel 1,3,4-oxadiazole hybrids of 3-n-butylphthalide derivatives as potential anti-ischemic stroke agents

Yu,

Li,

Luo

et al. 2024

Bioorganic Chemistry

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In vitrometabolism andin vivopharmacokinetics of bentysrepinine (Y101), an investigational new drug for anti-HBV-infected hepatitis: focus on interspecies comparison

Cited by 4 publications

References 31 publications

OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro

OAT3 Participates in Drug–Drug Interaction between Bentysrepinine and Entecavir through Interactions with M8—A Metabolite of Bentysrepinine—In Rats and Humans In Vitro

Metabolic stability studies of lead compounds supported by separation techniques and chemometrics analysis

Novel 1,3,4-oxadiazole hybrids of 3-n-butylphthalide derivatives as potential anti-ischemic stroke agents

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