Drug Design Development and Therapy
·
2025
·
IF 5.1
Cong Xie,Tongshu Guan,Jin Huang,Jiayu Chen,Yilei Li,Ping Zheng
Purpose Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), undergoes extensive metabolism, with its disposition influenced by drug–drug interactions (DDIs). This study aimed to characterize its in vitro metabolism, in vivo pharmacokinetics (PK), tissue distribution, and the effects of cytochrome P450 3A4 (CYP3A4) modulation in rats.Methods Lorlatinib metabolism was investigated in human liver microsomes (HLM) and rat liver micro- somes (RLM) using ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) with selective CYP inhibitors. Pharmacokinetic (PK) studies were performed in Sprague–Dawley (SD) rats following oral and intravenous dosing, including coadministration with CYP3A4 inhibitors (voriconazole, itraconazole) and inducers (rifampicin, carbamazepine). Tissue distribution was assessed across major organs.Results In vitro assays confirmed CYP3A4 as the primary enzyme mediating lorlatinib metabolism, with distinct differences in kinetic parameters between HLM and RLM. In vivo, lorlatinib displayed nonlinear PK, low oral bioavailability (8.6%), and extensive first-pass metabolism. Voriconazole increased exposure [area under the curve from 0–24 h (AUC(0−24h))] by 120%, whereas rifampicin reduced it by 77%, demonstrating strong CYP3A4-dependent interactions. Lorlatinib distributed rapidly to highly perfused organs and achieved efficient brain penetration (brain-to-plasma ratio = 0.82).Conclusion Lorlatinib undergoes extensive CYP3A4-mediated metabolism, exhibits nonlinear PK, and shows poor oral bioavailability in rats. Significant interspecies differences between HLM and RLM emphasize the need for caution when translating preclinical findings. Coadministration with CYP3A4 modulators markedly altered systemic exposure, while effective brain penetration supports its therapeutic role in central nervous system (CNS) metastases.
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CHEMICAL RESEARCH IN TOXICOLOGY
·
2024
·
IF 3.7
Ximei Li,Lihua Xin,Lan Yang,Yi Yang,Wei Li,Mingyu Zhang,Yufen Liao,Chen Sun,Weiwei Li,Ying Peng,Jiang Zheng
Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.
研究领域:
药理学
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毒理学
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JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Qiwei Liu,Yunwen Xue,Jingjing Liu,Siqi Ren,Jie Xu,Jinni Yang,Yuanyue Xing,Zunjian Zhang,Rui Song
Ethnopharmacological relevance Radix Bupleuri (RB), traditionally used to treat inflammatory disorders and infectious diseases, represents one of the most successful and widely used herbal drugs in Asia over the past 2000 years. Being realized the role in regulating metabolism and controlling Yin/Yang, RB is not only chosen specifically for treating liver meridian and the corresponding organs, but also believed to have liver meridian guiding property and help potentiate the therapeutic effects of liver. However, the ingredients in RB with liver meridian guiding property and the underly mechanism have not been comprehensively investigated. Aim of study Considering the important role of CYP3A4 in first-pass metabolism and the liver exposure of drugs, the present study aimed to determine whether saikosaponins (SSs) and the corresponding saikogenins (SGs) have a role in inhibiting the catalytic activity of CYP3A4 in human liver microsomes and HepG2 hepatoma cells and whether they could suppress CYP3A4 expression by PXR-mediated pathways in HepG2 hepatoma cells. Materials and methods The effect of SSs and SGs on CYP3A4-mediated midazolam1′-hydroxylation activities in pooled human liver microsomes (HLMs) was first studied. Dose-dependent experiments were performed to obtain the half inhibit concentration (IC 50 ) values. HepG2 cells were used to assay catalytic activity of CYP3A4, reporter function, mRNA levels, and protein expression. The inhibitory effects of SSa and SSd on CYP3A4 activity are negligible, while the corresponding SGs (SGF and SGG) have obvious inhibitory effects on CYP3A4 activity, with IC 50 values of 0.45 and 1.30 μM. The similar results were obtained from testing CYP3A4 catalytic activity in HepG2 cells, which correlated well with the suppression of the mRNA and protein levels of CYP3A4. Time-dependent testing of CYP3A4 mRNA and protein levels, as well as co-transfection experiments using the CYP3A4 promoter luciferase plasmid, further confirmed that SSs and SGs could inhibit the expression of CYP3A4 at the transcription level. Furthermore, PXR protein expression decreased in a concentration- and time-dependent manner after cells were exposed to SSs and SGs. PXR overexpression and RNA interference experiments further showed that SSs and SGs down-regulate the catalytic activity and expression of CYP3A4 in HepG2 may be mainly through PXR-dependent manner. Conclusion SSs and SGs inhibit the catalytic activity and expression of CYP3A4 in a PXR-dependent manner, which may be highly related to the liver meridian guiding property of RB.
研究领域:
药理学
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民族药理学
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分子生物学
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中医
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JOURNAL OF MEDICINAL CHEMISTRY
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2023
·
IF 7.3
Rong-Jing He,Zhen-Hao Tian,Jian Huang,Meng-Ru Sun,Feng Wei,Chun-Yu Li,Hai-Rong Zeng,Feng Zhang,Xiao-Qing Guan,Yan Feng,Xiang-Ming Meng,Hui Yang,Guang-Bo Ge
Cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme-mediated drug metabolism and drug–drug interaction (DDI). Herein, an effective strategy was used to rationally construct a practical two-photon fluorogenic substrate for hCYP3A4. Following two-round structure-based substrate discovery and optimization, we have successfully constructed a hCYP3A4 fluorogenic substrate (F8) with desirable features, including high binding affinity, rapid response, excellent isoform specificity, and low cytotoxicity. Under physiological conditions, F8 is readily metabolized by hCYP3A4 to form a brightly fluorescent product (4-OH F8) that can be easily detected by various fluorescence devices. The practicality of F8 for real-time sensing and functional imaging of hCYP3A4 has been examined in tissue preparations, living cells, and organ slices. F8 also demonstrates good performance for high-throughput screening of hCYP3A4 inhibitors and assessing DDI potentials in vivo. Collectively, this study develops an advanced molecular tool for sensing CYP3A4 activities in biological systems, which strongly facilitates CYP3A4-associated fundamental and applied research studies.
研究领域:
药理学
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分子生物学
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化学生物学
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Hualu Wu,Haoxin Fu,Fangyuan Xia,Jun Wu,Peiqi Wang,Lu Cao,Ren-ai Xu,Lu Shi
Cariprazine is an antipsychotic medication that has been approved for the treatment of schizophrenia and manic or mixed episodes. Patients with tumors frequently develop psychiatric disorders, necessitating the combination of antitumor and antipsychotic drugs. The objective of the present study was to examine the inhibitory impacts of three antitumor drugs (olmutinib, napabucasin and ponatinib) on the metabolism of cariprazine, and the molecular docking of cariprazine and ponatinib in relation to CYP3A4 was also evaluated. As the results, the half-maximal inhibitory concentration (IC 50 ) values of ponatinib and olmutinib in vitro were < 10 μM, whereas napabucasin was >20 μM. Among these, ponatinib exhibited the smallest IC 50 value. The metabolic stability of cariprazine was observed in the presence or absence of ponatinib in rat liver microsomes (RLM). The IC 50 shift experiments demonstrated that the inhibition of cariprazine by ponatinib was non-time-dependent. In addition, ponatinib was shown to inhibit cariprazine in a mixed manner (RLM) and a competitive manner (HLM), respectively. In the in vivo study, the co-administration of ponatinib resulted in a significant 0.35-fold increase in both AUC (0-t) and AUC (0-∞) for cariprazine, accompanied by a significant 0.25-fold decrease in the CL z/F . Furthermore, the metabolites desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR) exhibited disparate increases in both AUC (0-t) and AUC (0-∞) . Molecular docking studies had demonstrated that both cariprazine and ponatinib could engage in hydrophobic interactions with residue PHE-304 on CYP3A4. Consequently, when ponatinib is employed in conjunction with cariprazine in a clinical setting, it is imperative to assess the efficacy and adverse effects, and adjust the dosage to attain the optimal efficacy.
研究领域:
药理学
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临床医学
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生物化学
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JOURNAL OF CHROMATOGRAPHIC SCIENCE
·
2022
·Vol. 61
·期 2
·130-139
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IF 1.555
Sun Lu-Ning,Shen Ye,Yang Yu-Qing,Chen Xiang-Long,Huang Feng-Ru,Wang Dun-Jian,Zhang Ye,Wang Da-Wei,Wang Yong-Qing
The feasibility of taking the ratio of 6β-hydroxycortisol (6β-OHCOR) to cortisol (COR) in plasma as a biomarker to reflect CYP3A4 activity needs to be verified, but the low concentration of 6β-OHCOR which is an endogenous substance in plasma presents a challenge for determination. In this study, a Liquid chromatography with tandem mass spectrometry (LC–MS/MS) method was established to simultaneously quantify the COR and 6β-OHCOR in plasma with COR-d4 and 6β-OHCOR-d4 as internal standards (ISs). Plasma samples were treated by protein precipitation using acetonitrile. Separation with a gradient elution within 5 min was achieved on C18+ column utilizing 5 mM ammonium formate and methanol. An API 4,000 MS in multiple reaction monitoring mode with transitions of 407.1 → 361.1 and 423.1 → 347.1 was utilized. Albumin solution was used as a surrogate matrix, with good linearities over the concentration of 1.20–300 ng/mL for COR and 0.0400–10.0 ng/mL for 6β-OHCOR. The precisions for intrarun and interrun were < 6.8%, and the accuracy was fell in the interval of −5.2 to 3.5%. Matrix effect was not found. Recovery was close to 100.0%. Stability was confirmed under the storage and processing conditions. The validated method was applied to evaluate the inhibitory effect of voriconazole to CYP3A by the ratio of 6β-OHCOR to COR.
研究领域:
分析化学
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药理学
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临床医学
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Thoracic Cancer
·
2023
·Vol. 14
·期 33
·3331-3341
·
IF 2.9
Mengming Xia,Xueyi Song,Zebei Lu,Yu Wang,Quan Zhou,Peiwu Geng,Shuanghu Wang,Yunfang Zhou,Qingjun Wu,Aixia Han
Background Lenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats. Methods A total of 30 Sprague–Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC-Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC-MS–MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina. Results AUC and C max of lenvatinib significantly increased with each of the azoles ( p < 0.05), whereas CLz/F decreased 0.83-flod, 0.41-fold ( p < 0.05) and 0.72-fold ( p < 0.01) in voriconazole, isavuconazole and ketoconazole in rats. The IC50 of lenvatinib with the azoles were 0.237, 1.300, 0.355 and 2.403 μM in RLMs and 0.160, 1.933, 3.622 and 1.831 μM in HLMs. Molecular docking analysis suggested that azoles exhibited a strong binding ability towards the target enzymes. Conclusion It is imperative to acknowledge the potential drug–drug interactions mediated by CYP3A4 between azoles and lenvatinib, as these interactions hold significant implications for their clinical utilization.
研究领域:
药理学
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临床医学
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分子生物学
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BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Xiaohai Chen,Fengsheng Hong,Yuxin Shen,Hailun Xia,Lu Shi,Zheli Jiang,Ren-ai Xu
Tamoxifen, a selective estrogen receptor modulator (SERM) used in breast cancer therapy, requires metabolic activation by CYP3A4 to exert its biological effects. This study evaluated the effects of calcium channel blockers nimodipine, nitrendipine and felodipine on tamoxifen metabolism by studying their interactions with tamoxifen in vitro and in vivo . Rat liver microsomes (RLM) and human liver microsomes (HLM) were used in this study to evaluate the inhibitory potential of nimodipine, nitrendipine and felodipine on tamoxifen metabolism in vitro . A total of 28 cardiovascular drugs, including calcium channel blockers, were screened in an RLM incubation system in vitro . In RLM, nimodipine, nitrendipine and felodipine had half-maximum inhibitory concentration (IC 50 ) values of 5.55 µM, 11.86 µM and 7.71 µM, respectively. In HLM, the IC 50 values were increased to 20.38 µM, 30.06 µM, and 44.45 µM for nimodipine, nitrendipine and felodipine, respectively. The kinetic assays indicated that nimodipine and felodipine inhibited the metabolism of tamoxifen in a competitive way, whereas nitrendipine showed non-competitive inhibition in RLM. However, felodipine exhibited non-competitive inhibition, and nimodipine and nitrendipine showed competitive inhibition in HLM. Pharmacokinetic studies in rats revealed that pretreatment with nimodipine and nitrendipine significantly increased the systemic exposure of tamoxifen, as demonstrated by increasing the area under the curve (AUC), the maximum concentration (C max ) and decreasing the clearance (CL z/F ). Finally, molecular docking studies supported these findings, showing potential interactions at the active site of CYP3A4. These results suggested the necessity for careful monitoring and possible dose adjustments of tamoxifen when co-administered with calcium channel blockers in clinic.
研究领域:
药理学
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肿瘤学
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分子生物学
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Frontiers in Pharmacology
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2024
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IF 4.4
Xia Hailun,Xu Xinhao,Chen Jie,Wu Hualu,Shen Yuxin,Chen Xiaohai,Xu Ren-ai,Wu Wenzhi
Ivacaftor is the first potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein approved for use alone in the treatment of cystic fibrosis (CF). Ivacaftor is primarily metabolized by CYP3A4 and therefore may interact with drugs that are CYP3A4 substrates, resulting in changes in plasma exposure to ivacaftor. The study determined the levels of ivacaftor and its active metabolite M1 by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We screened 79 drugs and 19 severely inhibited ivacaftor metabolism, particularly two cardiovascular drugs (nisoldipine and nimodipine). In rat liver microsomes (RLM) and human liver microsomes (HLM), the half-maximal inhibitory concentrations (IC50) of nisoldipine on ivacaftor metabolism were 6.55 μM and 9.10 μM, respectively, and the inhibitory mechanism of nisoldipine on ivacaftor metabolism was mixed inhibition; the IC50 of nimodipine on ivacaftor metabolism in RLM and HLM were 4.57 μM and 7.15 μM, respectively, and the inhibitory mechanism of nimodipine on ivacaftor was competitive inhibition. In pharmacokinetic experiments in rats, it was observed that both nisoldipine and nimodipine significantly altered the pharmacokinetic parameters of ivacaftor, such as AUC(0-t) and CLz/F. However, this difference may not be clinically relevant. In conclusion, this paper presented the results of studies investigating the interaction between these drugs and ivacaftor in vitro and in vivo. The objective is to provide a rationale for the safety of ivacaftor in combination with other drugs.
研究领域:
药理学
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临床医学
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生物化学
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高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Jiaxing Yang,Shouchun Xiao,Pengxi Li,Bingxue Li,Bingying He,Xueke Liu,Donghui Liu,Zhiqiang Zhou,Peng Wang
Penthiopyrad, a chiral fungicide with a riskier S-enantiomer, exhibited poorly understood stereoselective behaviors in mammals. This study investigated the enantioselective accumulation and metabolism of penthiopyrad enantiomers in mammals using in vivo, in vitro, and in silico approaches. Penthiopyrad accumulated in the liver and kidneys at concentrations over 10-fold higher than those in the blood. S-penthiopyrad showed preferential absorption with 1.6-fold higher bioavailability than the R-enantiomer. Twenty-three metabolites (12 novel) were identified, with CYP-mediated N-demethylation as the dominant pathway. S-penthiopyrad was preferentially metabolized in mouse liver microsomes with a 1.5-fold shorter half-life, while human liver microsomes favored the R-enantiomer. CYP2E1, CYP2C (mouse), and CYP3A4 (human) mediated stereoselective metabolism, with the preferential metabolism of the R-enantiomer by human CYP3A4 attributed to its low binding energy and favorable conformation. This study comprehensively clarified the stereoselective behavior and metabolic pathway of penthiopyrad in mammals, providing valuable metabolic insights for further toxicological evaluation of penthiopyrad.
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BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2017
·Vol. 122
·期 3
·331-340
·
IF 3.176
Hongyan Zhang,Fengjiao Bu,Lei Li,Zheng Jiao,Guo Ma,Weimin Cai,Xiaomei Zhuang,Hai-Shu Lin,Jae-Gook Shin,Xiaoqiang Xiang
Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug–drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.
研究领域:
药理学
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临床药学
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中药学
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XENOBIOTICA
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2023
·
IF 1.8
Fengping Chen,Haizhu Zou,Ping Zhang,Yuqi Yan
In vitro metabolism of bicyclol was studied using liver microsomes, hepatocytes and human recombinant cytochrome P450 enzymes. Liquid chromatography-benchtop orbitrap mass spectrometry technique was utilised to identify the metabolites.A total of 19 metabolites, including 5 new metabolites (M2, M3, M4, M5 and M16) were tentatively identified. Among these metabolites, M6&M8 (demethylenation), M9&M10 (demethylation) and M19 (glucuronidation) were the major metabolites.In glutathione (GSH)-supplemented liver microsomes, 5 new GSH conjugates were found and tentatively identified. The formation was assumed to be through demethylenation of methylenedioxyphenyl to form catechol derivatives, which further underwent oxidation to form ortho-quinone intermediates, reacting with GSH to form stable adducts.CYP3A4 and 2C19 were demonstrated to be the major enzymes responsible for the bioactivation of bicyclol.This study provided valuable information on the metabolic fate of bicyclol in liver microsomes and hepatocytes, and the bioactivation pathways were reported for the first time, which would be helpful for us to understand the potential drug-drug interactions and the possible side effect of this drug.
研究领域:
药理学
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毒理学
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肝脏病学
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高影响因子
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