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Pharmacokinetics and Pharmacodynamics of the Selective Serotonin Reuptake Inhibitors, Fluoxetinean D Paroxetine, During Pregnancy and the Nursing Period

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Pharmacokinetics and Pharmacodynamics of the Selective Serotonin Reuptake Inhibitors, Fluoxetinean D Paroxetine, During Pregnancy and the Nursing Period Pharmacokinetics and Pharmacodynamics of the selective serotonin reuptake inhibitors, fluoxetine and paroxetine, during pregnancy and the nursing period. by John Kim M.Sc.(Pharm.), The University of British Columbia, Vancouver, Canada, 1995 B.Sc. (Biochem), Simon Fraser University, Burnaby, Canada, 1991 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Faculty of Pharmaceutical Sciences) (Division of Pharmaceutics and Biopharmaceutics) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA November, 2000 ©John Kim, 2000 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of r^hfartrMMJ-ioHsf (SdU^j The University of British Columbia Vancouver, Canada Date 2T) fJl>S p p DE-6 (2/88) 11 Abstract The prevalence of depressive disorders during pregnancy and the postpartum period and the need for continuous pharmacological intervention necessitate a better understanding of antidepressant disposition via placental transfer and breast-feeding. However, there is relatively limited information available for pharmacokinetics of these drugs. In the present studies, the pharmacokinetics of fluoxetine and paroxetine were examined and compared in humans and sheep. In order to characterize drug disposition, several sensitive analytical methods for quantitative determination of fluoxetine and norfluoxetine isomers and paroxetine were developed using GC/MS and LC/MS/MS. In humans and sheep, fluoxetine and norfluoxetine cross the placenta extensively. A relatively lower fetal-to-maternal ratio of paroxetine compared to fluoxetine was observed in humans. In adults, fluoxetine is extensively metabolized; however, minimal metabolic capacity was observed in human and ovine fetus. In the fetal lamb, no detectable concentrations of norfluoxetine isomers were observed in fetal plasma and amniotic fluid following fetal fluoxetine administration. Limited accumulation of fluoxetine in amniotic fluids was observed in fetal lamb unlike other basic amine drugs. In humans, serum neonatal fluoxetine and norfluoxetine concentrations were remained elevated following birth and slowly declined. These data were consistent with an in vitro metabolism study in sheep, which indicated lack of fetal N-demethylation in contrast to adult microsomes. In contrast, neonatal paroxetine concentration declined rapidly following birth. In fetal lambs, moderate transient changes in blood gas status were observed following fluoxetine administration. However, in both fluoxetine- and paroxetine-exposed human gravida, neither significant changes in birth-outcome nor perinatal complications were observed. Ill Fluoxetine, norfluoxetine and paroxetine are excreted in human breast milk with the milk-to- serum ratio higher for fluoxetine compared to paroxetine, which resulted in relatively higher exposure to fluoxetine in combination with relatively lower metabolic capacity in the neonate. Serum drug concentrations were also measured in nursing infants, and detectable levels of fluoxetine and norfluoxetine were observed in infants younger than 2 months. Compared to adult ewes, significant changes in total body clearance, half-life and steady- state volume of distribution were observed in pregnant ewes. In addition, the stereoselective disposition of fluoxetine isomers was observed in both humans and sheep. In sheep, stereoselective pharmacokinetics following a single dose are mainly mediated by stereoselective plasma protein binding. However, during chronic therapy, stereoselective drug metabolism along with fluoxetine-mediated inhibition of hepatic enzymes is responsible for stereoselectivity. Clearance- and exposure time-dependency of stereoselective disposition was observed in both species. Therefore, stereoselectivity during chronic dosing may be mediated by the inhibition of CYP2D6 by fluoxetine and norfluoxetine and stereoselective metabolism of fluoxetine by CYP2C9/19. In conclusion, the present studies present the first detailed pharmacokinetics of fluoxetine and paroxetine during pregnancy and the nursing period, which suggest relatively lower exposure of paroxetine compared to fluoxetine. Furthermore, stereoselective disposition of fluoxetine was examined during both acute and chronic administration, and potential mechanisms were proposed. iv Table of Contents Abstract ii Table of Contents iv List of Tables xii List of Figures xv List of Abbreviations xix Acknowledgments xxiii Chapter 1 Introduction 1 1.1 Depression during pregnancy and the postpartum period 1 1.2 Association and impact of maternal depression on infant/child development 2 1.3 Pharmacotherapy during pregnancy and the postpartum period 3 1.4 Pharmacological management of depression during pregnancy and the nursing period 6 1.5 Teratogenicity of SSRIs in experimental animals 7 1.6 Teratogenicity and perinatal complications of SSRIs in humans 9 1.7 Clinical use of SSRIs 14 1.8 Pharmacology of fluoxetine, norfluoxetine and paroxetine 15 1.9 Pharmacokinetics of fluoxetine and norfluoxetine 18 1.10 Pharmacokinetics of paroxetine 25 1.11 Placental transfer of the therapeutic agents 27 1.12 Methods of studying placental transfer and fetal exposure 28 1.13 Pharmacokinetics of fluoxetine and paroxetine during pregnancy 31 1.14 Breast-feeding and pharmacotherapy 32 1.15 Lactation and excretion of medication in breast milk 34 1.16 Excretion of fluoxetine, norfluoxetine and paroxetine in breast milk 35 1.17 Neonatal drug disposition 36 V 1.18 Rationales 39 1.19 Objectives and specific aims 41 Chapter 2 Analytical Method Development 43 2.1 Materials 45 2.2 Instrumentation 48 2.2.1 Gas chromatograph-mass selective detector (GC/MSD) 48 2.2.2 Gas chromatograph-mass spectrometer (GC/MS) 49 2.2.3 Liquid chromatograph-tandem mass spectrometer (LC/MS/MS) 49 2.2.4 Other equipment 50 2.3 Stereoselective GC/MS/EI method for fluoxetine and norfluoxetine isomers 50 2.3.1 Methods 50 2.3.1.1 Separation of fluoxetine and norfluoxetine using differential re-crystallization 50 2.3.1.2 Standard stock solution preparation 52 2.3.1.3 Sample extraction 53 2.3.1.4 Gas chromatography/mass spectrometry in electron impact mode 55 2.3.1.5 Calibration curve and regression model 55 2.3.1.6 Extraction recovery 5 6 2.3.1.7 Method validation 56 2.3.1.8 Analyte stability 5 7 2.3.2 Results and discussion 59 2.3.2.1 Mass spectrometric detection 59 2.3.2.2 Chiral separation of fluoxetine and norfluoxetine isomers 61 2.3.2.3 Extraction, recovery and stability 65 vi 2.3.2.4 Method validation 66 2.4 Synthesis and purification of deuterium-labeled fluoxetine hydrochloride 70 2.4.1 The synthesis of 2-benzoyl-l-(N-benzyl-N-methyl)-ethyl-ethylamine hydrochloride: B-acetylation 70 2.4.2 The synthesis of 1 -D5-phenyl-3-(N-methyl)aminopropan-1 -ol: hydrogenation 71 2.4.3 The synthesis of deuterium-labeled fluoxetine 72 2.5 Stereoselective LC/MS/MS method for fluoxetine and norfluoxetine isomers 73 2.5.1 Methods 74 2.5.1.1 Standard stock solution preparation 74 2.5.1.2 Sample extraction 74 2.5.1.3 Liquid chromatography/electrospray tandem mass spectrometry 75 2.5.1.4 Calibration curve and regression model 75 2.5.1.5 Extraction recovery 76 2.5.1.6 Method validation 77 2.5.1.7 Analyte stability 78 2.5.2 Results and Discussion 78 2.5.2.1 Mass spectrometric detection 78 2.5.2.2 Chiral separation of fluoxetine and norfluoxetine isomers 81 2.5.2.3 Extraction, recovery and stability 83 2.5.2.4 Method validation 83 2.6 GC/MS/EI method for paroxetine 88 2.6.1 Methods 88 2.6.1.1 Standard stock solution preparation 8 8 vu 2.6.1.2 Sample extraction 89 2.6.1.3 Gas chromatography/mass spectrometry 91 2.6.1.4 Calibration curve and regression model 92 2.6.1.5 Extraction recovery 92 2.6.1.6 Method validation 93 2.6.1.7 Analyte stability 93 2.6.2 Results and Discussion 94 2.6.2.1 Mass spectrometric detection and chromatograms 94 2.6.2.2 Extraction, recovery and stability 98 2.6.2.3 Method validation 100 2.7 GC/MS/NCI method for paroxetine 102 2.7.1 Methods 102 2.7.1.1 Standard stock solution preparation 102 2.7.1.2 Sample extraction 102 2.7.1.3 Gas chromatography/mass spectrometry 102 2.7.1.4 Calibration curve and regression model 103 2.7.1.5 Method validation 104 2.7.1.6 Recovery and analyte stability 105 2.7.2 Results and Discussion 105 2.7.2.1 Mass spectrometric detection and chromatograms 105 2.7.2.2 Method validation 108 Chapter 3 Stereoselective pharmacokinetics of fluoxetine and norfluoxetine in non-pregnant and pregnant ewes 112 Vlll 3.1 Materials and supplies 112 3.2 Study methods 113 3.2.1 Animals and surgical preparation 113 3.2.1.1 Adult (non-pregnant) sheep 113 3.2.1.2 Pregnant sheep 115 3.2.2 Pharmacokinetic experimental protocols 117 3.2.2.1 Intravenous administration of racemic fluoxetine for characterization of stereoselective pharmacokinetics in non-pregnant sheep 117 3.2.2.2 Paired intravenous administration of racemic fluoxetine for characterization of stereoselective maternal and fetal pharmacokinetics 118 3.2.3 Physiological monitoring 119 3.2.4 Plasma protein binding studies
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