A sensitive HPLC-FL method to simultaneously determine febuxostat and diclofenac in rat plasma: assessment of metabolic drug interactionsin vitroandin vivo

摘要

Febuxostat (FEB) is a selective xanthine oxidase (XO) inhibitor approved for chronic management of hyperuricemia (HU) in patients with gout. Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DIC) are the first choice for the prevention and treatment of gouty inflammation and flare. In this study, a sensitive and simple bioanalytical method using HPLC coupled with a fluorescence detector (HPLC-FL) was developed for the simultaneous determination of FEB and DIC. The linearity (1-1500 ng mL(-1)for FEB and 5-1500 ng mL(-1)for DIC), precision, accuracy, recovery, matrix effect, and stability of the newly developed method were validated as per the US Food and Drug Administration (FDA) guidelines. Next, thein vivoandin vitrometabolic interactions between FEB and DIC were comprehensively examined. Thein vivopharmacokinetics of FEB were found to be significantly altered by the co-administration of DIC in rats. Further, thein vitromicrosomal metabolism study revealed that the altered pharmacokinetics of FEB could be attributed primarily to the competitive inhibition of FEB metabolism by DIC. To our knowledge, this is the first systematic study showing thein vivopharmacokinetic interaction of FEB with DIC following intravenous and oral administration in rats and the associated metabolic inhibition mechanism together with a new HPLC-FL method to simultaneously determine FEB and DIC in biological matrices.