Pharmacokinetic interaction between evodiamine and doxofylline in rats

Background: Doxofylline (DFL) is a medication widely employed in the management of asthma and chronic obstructive pulmonary disease. Evodiamine (EVO), a bioactive alkaloid from traditional Chinese medicine (TCM), is commonly utilized for treating hypertension, gastropathy, and eczema. Cytochrome P450 enzymes primarily mediate the metabolism of both pharmaceuticals and TCMs in-vivo, which potentially lead to drug-drug interactions. Objectives: This study aimed to investigate the effects of oral EVO on the pharmacokinetics (PK) of DFL and its metabolite, theophylline (TPL), in rats. Methods: Twelve rats were randomly assigned to control and experimental groups. The experimental group received 50 mg/kg EVO orally once daily for one week, while the control group received 0.5% sodium carboxymethyl cellulose. On day 7, DFL (80 mg/kg) was administered 2 h post-treatment. Venous blood specimens were collected from the retro-orbital venous plexus at 0.1667, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 h post-dose. Plasma concentrations of DFL and TPL were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Compared with the control group, the experimental group showed significant alterations in several PK parameters for both DFL and TPL. The administration of EVO markedly increased MRT(0-?), MRT(0-t), VRT(0-?), VRT(0-t), t1/2z, and Vz/F for DFL while also enhancing CLz/F and Vz/F for TPL. Conversely, EVO notably decreased AUC(0-?), AUC(0-t), and MRT(0-t) values associated with TPL. Conclusion: Concomitant administration of EVO alongside DFL resulted in substantial modifications to key PK parameters concerning both DFL and its metabolite TPL in rats. Specifically, EVO prolonged the retention time and increased the volume of distribution of DFL, while simultaneously reducing the bioavailability and accelerating the clearance of TPL (P<0.05). Therefore, it is imperative to closely monitor the impact of TCM EVO on the PKs of DFL and TPL in experimental animals, necessitating further research and clinical observation.