ArticleDrug design, development and therapy2025
Cyp3a4-Mediated in vitro Metabolism and in vivo Disposition of Lorlatinib in Rats.
Article in Drug design, development and therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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 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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