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Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers

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dc.contributor.authorChung, Jae-Yong-
dc.contributor.authorCho, Joo-Youn-
dc.contributor.authorYu, Kyung-Sang-
dc.contributor.authorKim, Jung-Ryul-
dc.contributor.authorJung, Hye-Ryung-
dc.contributor.authorLim, Kyoung-Soo-
dc.contributor.authorJang, In-Jin-
dc.contributor.authorShin, Sang-Goo-
dc.date.accessioned2009-12-29T01:15:04Z-
dc.date.available2009-12-29T01:15:04Z-
dc.date.issued2005-06-18-
dc.identifier.citationClin Pharmacol Ther. 2005 Jun;77(6):486-94.en
dc.identifier.issn0009-9236 (Print)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15961980-
dc.identifier.urihttp://hdl.handle.net/10371/22928-
dc.description.abstractOBJECTIVE: Our objective was to investigate the effect of the uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B15 genetic polymorphism on the pharmacokinetics and pharmacodynamics of lorazepam in basal, inhibited, and induced metabolic states in healthy normal volunteers. METHODS: Twenty-four healthy subjects were enrolled and grouped into UGT2B15*1/*1 or UGT2B15*2/*2 genotype groups. The pharmacokinetic and pharmacodynamic profiles of intravenous lorazepam were characterized before and after inhibition with 600 mg valproate once daily for 4 days and after induction with rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 10 days between. The plasma concentrations of lorazepam and lorazepam glucuronide were analyzed before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 hours after lorazepam administration by liquid chromatography-tandem mass spectrometry. Visual analog scale assessments and psychomotor coordination tests were administered before and up to 12 hours after drug administration. RESULTS: The UGT2B15*2/*2 group showed 0.58-fold (95% confidence interval, 0.43-0.72; P < .0001) lower systemic clearance during the basal state and 1.37-fold (95% confidence interval, 1.05-1.88; P = .037) higher area under the visual analog scale-time curve during the induced state compared with the UGT2B15*1/*1 group. The mean systemic clearance of lorazepam decreased by 20% in the inhibited state and increased by 140% in the induced state. During the inhibited or induced state, absolute values of clearance were consistently lower in the *2/*2 group, but the percent changes from baseline did not differ significantly by genotype. CONCLUSIONS: Our results suggest that the UGT2B15*2 polymorphism is a major determinant of interindividual variability with respect to the pharmacokinetics and pharmacodynamics of lorazepam.en
dc.language.isoen-
dc.publisherElsevieren
dc.subjectAdulten
dc.subjectDrug Interactions/geneticsen
dc.subjectEnzyme Inhibitors/pharmacokinetics/pharmacologyen
dc.subjectFemaleen
dc.subjectGenotypeen
dc.subjectGlucuronosyltransferase/*geneticsen
dc.subjectHumansen
dc.subjectHypnotics and Sedatives/*pharmacokinetics/pharmacologyen
dc.subjectInfusions, Intravenousen
dc.subjectLorazepam/*pharmacokinetics/pharmacologyen
dc.subjectMaleen
dc.subjectPolymorphism, Geneticen
dc.subjectRifampin/pharmacokinetics/pharmacologyen
dc.subjectValproic Acid/pharmacokinetics/pharmacologyen
dc.titleEffect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteersen
dc.typeArticleen
dc.contributor.AlternativeAuthor정재용-
dc.contributor.AlternativeAuthor조주연-
dc.contributor.AlternativeAuthor유경상-
dc.contributor.AlternativeAuthor김정렬-
dc.contributor.AlternativeAuthor정혜령-
dc.contributor.AlternativeAuthor임경수-
dc.contributor.AlternativeAuthor장인진-
dc.contributor.AlternativeAuthor신상구-
dc.identifier.doi10.1016/j.clpt.2005.02.006-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Pharmacology (약리학전공)Journal Papers (저널논문_약리학전공)
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