Apatinib Inhibits the Metabolic Clearance of Ropivacaine: An in vitro and in vivo Evaluation.

BACKGROUND: Ropivacaine, a local anesthetic, is commonly used for surgical local anesthesia and labor analgesia. PURPOSE: This study aimed to investigate the effect of apatinib on ropivacaine metabolism in vitro and in vivo, and to elucidate its inhibitory mechanism. METHODS: Following preliminary screening of 18 candidate drugs, apatinib was selected for further evaluation. An enzymatic reaction system was established using rat liver microsomes (RLM), human liver microsomes (HLM), and recombinant human CYP1A2 (rCYP1A2). The ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous quantification of ropivacaine and its metabolite, 3-hydroxy ropivacaine. RESULTS: The UPLC-MS/MS method showed good linearity over 2-250 ng/mL for ropivacaine and 1-25 ng/mL for 3-hydroxy ropivacaine, respectively. Both showed intra- and inter-day precision (RSD%) below 15% and accuracy (RE%) within ± 15%. Apatinib inhibited ropivacaine metabolism in RLM, HLM, and rCYP1A2, with half-maximal inhibitory concentration (IC50) values of 0.29, 9.12, and 2.49 μM, respectively. In the RLM metabolic stability assay, apatinib slowed ropivacaine metabolism and reduced its intrinsic clearance (CLint) from 0.14 to 0.04 mL/min/mg. Enzyme kinetic analysis indicated non-competitive inhibition in all systems. In rats, co-administration with apatinib increased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of ropivacaine by 0.83- and 0.71-fold, respectively, decreased the clearance (CLz/F) by 47.17%. CONCLUSION: Both in vitro and in vivo results indicated that apatinib inhibited the metabolism of ropivacaine. These findings provided essential reference data for the rational application of ropivacaine in clinical precision dosing regimens.