Objectives To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo , when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.
Dongmei Cui,Li Mi,Xuan Xu,Jusheng Lu,Jing Qian,Songqin Liu
Cytochrome P450 enzymes (cyt P450s) with an active center of iron protoheme are involved in most clinical drugs metabolism process. Herein, an electrochemical platform for the investigation of drug metabolism in vitro was constructed by immobilizing cytochrome P450 2D6 (CYP2D6) with cyt P450 reductase (CPR) on graphene modified glass carbon electrode. Direct and reversible electron transfer of the immobilized CYP2D6 with the direct electron transfer constant of 0.47 s–1 and midpoint potential of -0.483 V was obtained. In the presence of substrate tramadol, the electrochemical-driven CYP2D6 mediated catalytic behavior toward the conversion of tramadol to o-demethyl-tramadol was confirmed. The Michaelis–Menten constant (Kmapp) and heterogeneous reaction rate constant during the metabolism of tramadol were calculated to be 23.85 μM and 1.96 cm s–1, respectively. The inhibition effect of quinidine on CYP2D6 catalyze-cycle was also investigated. Furthermore, this system was applied to studying the metabolism of other drugs.
The integration of noble metals onto semiconductor surfaces has become a key focus in advancing surface-enhanced Raman spectroscopy (SERS) research. Two-dimensional materials such as MoS 2 are valued for their exceptional thermal and chemical stability, making them promising candidates for advanced SERS sensor development. In this study, we synthesized flower-like MoS 2 microspheres (~380 nm in diameter) through a facile hydrothermal method and functionalized their surfaces with gold nanoparticles (AuNPs) to produce MoS 2 @Au composites. Rhodamine 6G, used as a Raman probe, revealed that the enhancement factor of the MoS 2 @Au system increased substantially from 2.78 × 10 5 to 3.79 × 10 7 , and the detection limit improved to an impressive 3.13 × 10 −10 mol/L—exhibiting a two-order-of-magnitude improvement in sensitivity compared with pristine MoS 2 . Detecting trace tramadol hydrochloride holds immense significance. It enables the precise identification of minuscule drug quantities, facilitating early detection of abuse. This provides crucial support for clinical treatment, rehabilitation interventions, and holds vital importance in judicial appraisal and related fields. The composite demonstrated exceptional proficiency in detecting tramadol hydrochloride, achieving an unprecedented detection limit of 10 −10 mol/L, well below clinically relevant thresholds. Finite-difference time-domain simulations revealed the spatial distribution of the electromagnetic field, while density functional theory calculations elucidated the intricacies of charge transfer and bandgap modulation upon tramadol adsorption. These theoretical insights uncovered the fundamental mechanisms driving the observed SERS enhancement. Experimental validation confirmed that AuNP modification substantially enhanced charge transfer efficiency, highlighting the synergistic contributions of electromagnetic and chemical enhancement effects in improving SERS sensitivity. This work not only deepens our understanding of SERS phenomena but also broadens its potential applications in biomedical sensing.
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