109451
论文已发表
注册即可获取德孚的最新动态
IF 收录期刊
- 3.4 Breast Cancer (Dove Med Press)
- 3.2 Clin Epidemiol
- 2.6 Cancer Manag Res
- 2.9 Infect Drug Resist
- 3.7 Clin Interv Aging
- 5.1 Drug Des Dev Ther
- 3.1 Int J Chronic Obstr
- 6.6 Int J Nanomed
- 2.6 Int J Women's Health
- 2.9 Neuropsych Dis Treat
- 2.8 OncoTargets Ther
- 2.0 Patient Prefer Adher
- 2.2 Ther Clin Risk Manag
- 2.5 J Pain Res
- 3.0 Diabet Metab Synd Ob
- 3.2 Psychol Res Behav Ma
- 3.4 Nat Sci Sleep
- 1.8 Pharmgenomics Pers Med
- 2.0 Risk Manag Healthc Policy
- 4.1 J Inflamm Res
- 2.0 Int J Gen Med
- 3.4 J Hepatocell Carcinoma
- 3.0 J Asthma Allergy
- 2.2 Clin Cosmet Investig Dermatol
- 2.4 J Multidiscip Healthc
已发表论文
洛拉替尼在大鼠体内经 CYP3A4 介导的体外代谢及体内处置情况
Authors Xie C, Guan T, Huang J, Chen J, Li Y, Zheng P
Received 4 September 2025
Accepted for publication 17 October 2025
Published 25 October 2025 Volume 2025:19 Pages 9627—9645
DOI https://doi.org/10.2147/DDDT.S565228
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Solomon Tadesse Zeleke
Cong Xie,1,2,* Tongshu Guan,1,2,* Jin Huang,1,2 Jiayu Chen,1,2 Yilei Li,1,2 Ping Zheng1,2
1Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yilei Li; Ping Zheng, Email lei@smu.edu.cn; zpm321@126.com
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.
Keywords: lorlatinib, CYP3A4 metabolism, enzyme kinetics, pharmacokinetics, tissue distribution
1Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Yilei Li; Ping Zheng, Email lei@smu.edu.cn; zpm321@126.com
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.
Keywords: lorlatinib, CYP3A4 metabolism, enzyme kinetics, pharmacokinetics, tissue distribution