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Effects of multiple dosing of dexamethasone on the pharmacokinetics of oseltamivir through carboxylesterase 1 modulation in healthy volunteers : 건강 자원자에서 덱사메타손 반복투여에 의한 carboxylesterase 1 조절을 통한 오셀타미비어의 약동학 변화에 관한 연구

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dc.contributor.advisor유경상-
dc.contributor.author장경호-
dc.date.accessioned2017-07-14T01:47:09Z-
dc.date.available2017-07-14T01:47:09Z-
dc.date.issued2017-02-
dc.identifier.other000000142117-
dc.identifier.urihttps://hdl.handle.net/10371/122346-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2017. 2. 유경상.-
dc.description.abstractIntroduction: Oseltamivir is widely used in the treatment and prophylaxis of influenza A and B viral infections. Dexamethasone may have beneficial effects in the treatment of acute respiratory distress syndrome, a severe complication of influenza. Carboxylesterase (CES) 1 predominantly converts oseltamivir into its active metabolite, oseltamivir carboxylate, in the liver, and dexamethasone modulates the expression of CES1. However, the effects of dexamethasone on the pharmacokinetics (PK) of oseltamivir remain unclear. The aim of this study was to investigate the effects of co-administration of oseltamivir and dexamethasone on the PK of oseltamivir in healthy volunteers.
Methods: An open-label, two-period, one-sequence, multiple-dose study was conducted in 19 healthy male volunteers. Oseltamivir (75 mg) was orally administered on Day 1 and Day 8, and dexamethasone (1.5 mg) was administered once daily from Day 3 to Day 8. Serial blood and urine samples were collected for PK analysis of oseltamivir and oseltamivir carboxylate on Day 1 and Day 8. In addition, a genotype test was performed on Day 1 to identify the CES1 genotype. Oseltamivir and oseltamivir carboxylate concentrations in plasma and urine were determined using liquid chromatography–tandem mass spectrometry.
Results: After dexamethasone treatment for 6 days, the area under the plasma concentration–time curve (AUC) of oseltamivir and oseltamivir carboxylate decreased by 4% (P = 0.21) and 12% (P < 0.0001), respectively. The geometric mean ratio (90% confidence interval) of the metabolic ratio (oseltamivir carboxylate AUC0–48h/oseltamivir AUC0–48h) was 0.92 (0.87–0.97
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dc.description.abstractP = 0.02). The amount of unchanged oseltamivir excreted in urine increased by 14% after dexamethasone treatment (P = 0.08).
Conclusions: These findings suggest that the co-administration of low-dose dexamethasone and oseltamivir may decrease the systemic exposure to oseltamivir and oseltamivir carboxylate by the inhibition of CES1. However, the co-administration does not appear to have a clinically relevant effect on the PK of oseltamivir. Therefore, low-dose dexamethasone can be co-administered with oseltamivir without dose adjustment.
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dc.description.tableofcontentsI. INTRODUCTION 1
II. MATERIALS AND METHODS 5
1.1 Subjects 5
1.2 Study Design 6
1.3 Determination of oseltamivir and oseltamivir carboxylate concentration 9
1.4 Pharmacokinetics data analysis 9
1.5 Genotyping of CES1 c.662A>G SNP 11
1.6 Statistical analysis 11
III. RESULTS 13
1.1 Study population 13
1.2 Plasma oseltamivir and oseltamivir carboxylate concentration profiles 15
1.3 Effects of dexamethasone on oseltamivir PK 16
1.4 Effects of dexamethasone on oseltamivir carboxylate PK 21
1.5 Tolerability 29
IV. DISCUSSION 30
V. REFERENCES 36
VI. APPENDIX 42
VII. ABSTRACT IN KOREAN 56
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dc.formatapplication/pdf-
dc.format.extent3504323 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectOseltamivir-
dc.subjectDexamethasone-
dc.subjectCarboxylesterase-
dc.subjectDrug-drug interaction-
dc.subject.ddc610-
dc.titleEffects of multiple dosing of dexamethasone on the pharmacokinetics of oseltamivir through carboxylesterase 1 modulation in healthy volunteers-
dc.title.alternative건강 자원자에서 덱사메타손 반복투여에 의한 carboxylesterase 1 조절을 통한 오셀타미비어의 약동학 변화에 관한 연구-
dc.typeThesis-
dc.contributor.AlternativeAuthorKYUNGHO JANG-
dc.description.degreeDoctor-
dc.citation.pages58-
dc.contributor.affiliation의과대학 의과학과-
dc.date.awarded2017-02-
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