Effect of the genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers

• DOI: 10.1016/j.clpt.2005.02.006
• Publication Date: 2005-05-08T00:47:38Z
• Authors: J CHUNG; J CHO; K YU; J KIM; H JUNG; K LIM; I JANG; S SHIN
• Keywords: Lorazepam; Pharmacodynamics

Our objective was to investigate the effect of uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B15 genetic polymorphism on pharmacokinetics and pharmacodynamics lorazepam in basal, inhibited, induced metabolic states healthy normal volunteers.Twenty-four subjects were enrolled grouped into UGT2B15*1/*1 or UGT2B15*2/*2 genotype groups. The pharmacokinetic pharmacodynamic profiles intravenous characterized before after inhibition with 600 mg valproate once daily for 4 days induction rifampin (INN, rifampicin) pretreatment (600 10 days), a washout period between. plasma concentrations glucuronide analyzed at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48 hours administration by liquid chromatography-tandem mass spectrometry. Visual analog scale assessments psychomotor coordination tests administered up 12 drug administration.The group showed 0.58-fold (95% confidence interval, 0.43-0.72; P < .0001) lower systemic clearance during basal state 1.37-fold 1.05-1.88; = .037) higher area under visual scale-time curve compared group. mean decreased 20% inhibited increased 140% state. During state, absolute values consistently *2/*2 group, but percent changes from baseline did not differ significantly genotype.Our results suggest that UGT2B15*2 is major determinant interindividual variability respect lorazepam.