Evaluation of the Effects of Apatinib on the Pharmacokinetics of
Tramadol and O-desmethyltramadol
Abstract
Since the combination of anticancer drugs and opioids is very common,
apatinib and tramadol are likely to be used in combination clinically.
Based on this, it is particularly important to explore the effect of
apatinib on the metabolism of tramadol. This study evaluated the effects
of apatinib on the pharmacokinetics of tramadol and its main metabolite
o-desmethyltramadol in SD rats and the inhibitory effects of apatinib on
tramadol in rat liver microsomes (RLMs), human liver microsomes (HLMs)
and recombinant human CYP2D6.1. The samples were determined by
ultra-performance liquid chromatography-tandem mass spectrometry
(UPLC-MS/MS). The in vivo results showed that compared with the control
group, apatinib increased the AUC(0-t), AUC(0-∞) and Cmax values of
tramadol and O-desmethyltramadol, and decreased the values of VZ/F and
CLz/F. In addition, the MRT(0-t), MRT(0-∞) values of O-desmethyltramadol
were increased. In vitro, apatinib inhibited the metabolism of tramadol
by a mixed way with IC50 of 1.927µM in RLMs, 2.039µM in HLMs and 15.32µM
in CYP2D6.1.