Impact Of Genetic Polymorphisms On Clinical Pharmacokinetics Of Lornoxicam

Lornoxicam is a nonsteroidal anti-inflammatory drug that decreases prostaglandin synthesis by inhibiting cyclo-oxygenase. It has analgesic, antipyretic and anti-inflammatory effects, and used in the management of painful and inflammatory conditions, such as postoperative pain and rheumatoid arthritis. Unlike other oxicams, lomoxicam has a short elimination half-life of 3-5 hours. 5'-Hydroxylation is the main metabolic pathway, and CYP2C9, a polymorphic enzyme in humans, has been proven to be the primary enzyme involved in the formation of 5'-hydroxy lomoxicam in vitro. Previous studies have shown that lomoxicam has a large inter-individual variability in pharmacokinetics, and this will be significant in the clinical use of lomoxiam. Therefore, it is important to know why there is large variability in lomoxicam pharmacokinetics.The aims of the thesis are to investigate the pharmacokinetics of lomoxicam in healthy Chinese subjects, to reveal the pharmacogenetic mechanism of the polymorphism in pharmacoknetics of lomoxicam. In this paper, the impact of CYP2C9 alleles on the activity of enzyme is also assessed.1 Studies on the pharmacokinetics of lomoxicam in humanThe pharmacokinetics of lomoxicam in Chinese subjects was investigated within a bioequivalence study. Twenty healthy male subjects were enrolled in this clinical trial. Plasma concentrations of lomoxicam were measured using a validated LC/MS/MS method. After a single oral dose of 8 mg of lomoxicam (Xafon, the reference formulation) in 19 subjects, the C_max of lomoxicam was found to be 997 ±211 ng·ml^-1 at 2.2 ± 0.5 h, AUC_{0→∞} was 5.77 ± 2.57 μg·ml^-1 ·h, T_1/2 was 4.80 ± 1.32 h, and the CL/F was 28.2 ± 13.7ml·min^-1 . In this study, one subject (subject No. 14) was found to be a very poor metabolizer of lomoxicam with a long T_1/2 of 105 h, a low CL/F of 0.74 ml·min^-1 , and a high AUC_{0→∞}, of 179.1 μg·ml^-1, and the C_max of lomoxicam was achieved to be 1402 ng·ml^-1 at 2.0 h.Plasma concentrations of 5'-hydroxyIornoxicam in 14 subjects including the poor...