Pharmacokinetics Of Fluoxetine Research Articles

Pharmacogenetic Variants Associated with Fluoxetine Pharmacokinetics from a Bioequivalence Study in Healthy Subjects.

Fluoxetine is one of the most prescribed antidepressants, yet it still faces challenges due to high intersubject variability in patient response. Mainly metabolized by the highly polymorphic gene CYP2D6, important differences in plasma concentrations after the same doses are found among individuals. This study investigated the association of fluoxetine pharmacokinetics (PK) with pharmacogenetic variants. A bioequivalence crossover trial (two sequences, two periods) was conducted with fluoxetine 20 mg capsules, in 24 healthy subjects. Blood samples for fluoxetine determination were collected up to 72 h post-dose. Subjects were genotyped and single nucleotide variants (SNV) were selected using a candidate gene approach, and then associated with the PK parameters. Bioequivalence was confirmed for the test formulation. We found 34 SNV on 10 genes with a quantifiable impact on the PK of fluoxetine in the randomized controlled trial. Out of those, 29 SNVs belong to 7 CYPs (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5), and 5 SNVs to 3 genes impacting the pharmacodynamics and efficacy of fluoxetine (SLC6A4, TPH1, ABCB1). Moreover, decreased/no function SNVs of CYP2D6 (rs1065852, rs28371703, rs1135840) and CYP2C19 (rs12769205) were confirmed phenotypically. Our research contributes to deepening the catalog of genotype-phenotype associations in pharmacokinetics, aiming to increase pharmacogenomics knowledge for rational treatment schemes of antidepressants.

Effect of Food on the Pharmacokinetics of Fluoxetine in Healthy Male Adult Volunteers(Conference Paper )#

Fluoxetine (FX) is an antidepressant drug administered only orally in humans. Despite the wide use of FX, until now, there is only limited literature concerning the pharmacokinetics (PK) of FX and the effect of food on its PK. Thus, the objective of this investigation was to study the PK of FX in Arabic healthy male adult volunteers under fasting and fed conditions. In the fasting study, FX 20 mg capsules (Prozac®, Eli Lilly, Canada) were administered to 41 volunteers after overnight fasting of 12 hours, followed by blood sampling from each volunteer immediately before dosing (zero time) and then at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 36, 48, 60, 72, 96, 120, and eventually at 144 hours after FX dosing. The fed study was conducted after 90 days wash-out period following the completion of the fasting study. The same subjects who received FX in the fasting study were administered the drug directly after a fatty breakfast (fed study), followed by blood sampling intervals similar to the schedule mentioned above for the fasting study. The current investigation demonstrated no statistical differences in the FX pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Kel, T1/2, MRT, Cl/F, and Vd/F after fasting compared to the fed conditions, whereas there was statistically significant elongation in the Tmax values after food intake. Therefore, this study concludes the absence of food effect on the PK of FX (except Tmax) in the Arabic population and confirms the method of administration mentioned in the product information but also concludes high interindividual variation in FX exposure (AUC), which suggest that therapeutic drug monitoring (TDM) might be advisable when feasible.

Fluoxetine pharmacokinetics and tissue distribution quantitatively supports a therapeutic role in COVID-19 at a minimum dose of 20 mg per day

Background. Various in vitro studies have shown fluoxetine inhibits multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen causing the coronavirus disease 2019 (COVID-19) worldwide pandemic and multiple observational clinical studies have shown that patients receiving fluoxetine experienced clinical benefit by lowering the risk of intubation and death. The aim of this study is to conduct population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 50% (EC50) and 90% (EC90) inhibition of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods. Pharmacometric parameter estimates used in this study were obtained from the U.S. FDA website from a new drug application for fluoxetine hydrochloride. A population of 1,000 individuals were simulated at standard fluoxetine antidepressant doses (20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC50 and EC90 SARS-CoV-2 inhibition. All analyses were conducted in R. Results. By day-10 at 20 mg/day, 93.2% and 47% of the population will achieve the trough target plasma EC50 and EC90 concentrations, respectively, which translates to a lung tissue distribution coefficient of 60-times higher EC50 (283.6 ng/ml [0.82 mM]) and EC90 (1390.1 ng/ml [4.02 mM]). Further, by day-10 at an ideal dose of 40 mg/day, 99% and 93% of patients will reach the trough EC50 and EC90 concentrations, respectfully. Lastly, only a dose of 60 mg/day will reach the SARS-CoV-2 EC90 inhibitory concentration in the brain at pharmacokinetic steady-state. Conclusion. Overall, with a minimum treatment period of 10-days and a minimum dose of 20 mg/day, this study corroborates in vitro studies reporting fluoxetine inhibiting SARS-CoV-2 titers and also multiple observational clinical studies showing therapeutic benefit of fluoxetine in COVID-19 patients.

Fluoxetine pharmacokinetics and tissue distribution quantitatively supports a therapeutic role in COVID-19 at a minimum dose of 20 mg per day

Background. Various in vitro studies have shown fluoxetine inhibits multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen causing the coronavirus disease 2019 (COVID-19) worldwide pandemic and multiple observational clinical studies have shown that patients receiving fluoxetine experienced clinical benefit by lowering the risk of intubation and death. The aim of this study is to conduct population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 50% (EC50) and 90% (EC90) inhibition of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods. Pharmacometric parameter estimates used in this study were obtained from the U.S. FDA website from a new drug application for fluoxetine hydrochloride. A population of 1,000 individuals were simulated at standard fluoxetine antidepressant doses (20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC50 and EC90 SARS-CoV-2 inhibition. All analyses and graphing were conducted in R. Results. By day-10 at 20 mg/day 93.2% and 47% of the population will achieve the trough target plasma EC50 and EC90 concentrations, respectively, which translates to a lung tissue distribution coefficient of 60-times higher EC50 (283.6 ng/ml [0.82 mM]) and EC90 (1390.1 ng/ml [4.02 mM]). Further, by day-10 at an ideal dose of 40 mg/day, 99% and 93% of patients will reach the trough EC50 and EC90 concentrations, respectfully. Lastly, only a dose of 60 mg/day will reach the SARS-CoV-2 EC90 inhibitory concentration in the brain. Conclusion. Overall, with a minimum treatment period of 10-days and a minimum dose of 20 mg/day, this study corroborates in vitro studies reporting fluoxetine inhibiting SARS-CoV-2 titers and also multiple observational clinical studies showing therapeutic benefit of fluoxetine in COVID-19 patients.

Pharmacokinetics of fluoxetine in horses following oral administration.

This study aimed to investigate pharmacokinetics of fluoxetine in horses and validate a method for liquid chromatography mass spectrometry analysis of serum levels. Fluoxetine pharmacokinetics were determined using 10healthy, adult horses. Fluoxetine pharmacokinetics following a single oral dose (0.25mg/kg) were determined using blood samples collected prior to and at several time points over 7days following administration. Serum concentrations of fluoxetine and its bioactive metabolite norfluoxetine were measured using liquid chromatography coupled to an accurate mass/high-resolution mass spectrometer. Pharmacokinetic parameters were estimated using a noncompartmental model. Time to maximum serum concentration and serum half-life of fluoxetine was 1.5 and 15.6h, respectively. Steady-state serum concentrations were evaluated using five horses each receiving fluoxetine (0.25mg/kg, PO, q24hrs) for 8weeks and were found to be 62.9±25.5ng/ml on average. Norfluoxetine was not detected in any sample.

Fluoxetine pharmacokinetics and tissue distribution quantitatively supports a therapeutic role in COVID-19 at a minimum dose of 20 mg per day

Background. Various in vitro studies have shown fluoxetine inhibits multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen causing the coronavirus disease 2019 (COVID-19) worldwide pandemic and multiple observational clinical studies have shown that patients receiving fluoxetine experienced clinical benefit by lowering the risk of intubation and death. The aim of this study is to conduct population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 50% (EC50) and 90% (EC90) inhibition of SARS-CoV-2 as reported in Calu-3 human lung cells. Methods. Pharmacometric parameter estimates used in this study were obtained from the U.S. FDA website from a new drug application for fluoxetine hydrochloride. A population of 1,000 individuals were simulated at standard fluoxetine antidepressant doses (20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC50 and EC90 SARS-CoV-2 inhibition. All analyses were conducted in R. Results. By day-10 at 20 mg/day, 93.2% and 47% of the population will achieve the trough target plasma EC50 and EC90 concentrations, respectively, which translates to a lung tissue distribution coefficient of 60-times higher EC50 (283.6 ng/ml [0.82 mM]) and EC90 (1390.1 ng/ml [4.02 mM]). Further, by day-10 at an ideal dose of 40 mg/day, 99% and 93% of patients will reach the trough EC50 and EC90 concentrations, respectfully. Lastly, only a dose of 60 mg/day will reach the SARS-CoV-2 EC90 inhibitory concentration in the brain at pharmacokinetic steady-state. Conclusion. Overall, with a minimum treatment period of 10-days and a minimum dose of 20 mg/day, this study corroborates in vitro studies reporting fluoxetine inhibiting SARS-CoV-2 titers and also multiple observational clinical studies showing therapeutic benefit of fluoxetine in COVID-19 patients.

Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers.

Background.Recentin vitrostudies have shown fluoxetineinhibitsthe severe acute respiratory syndrome coronavirus2 (SARS-CoV-2)pathogen, including variants B.1.1.7 and B.1.351, SARS-CoV-2 spike mutations (E484K,K417N,N501Y),and oneretrospectiveclinical study reported fluoxetine exposureat a median dose of 20mgin patientswith theSARS-CoV-2coronavirus disease 2019 (COVID-19) had asignificantlylower risk of intubation and death. The aim of this study is to conductin silicopopulationpharmacokineticdosing simulations to quantify the percentage of patientsachieving atroughlevelforthe effective concentration resulting in 90% inhibition(EC90)of SARS-CoV-2as reportedinCalu-3human lungcells. Methods.Population pharmacokineticparameterestimates fora structural one-compartmentmodel with first-order absorption wereused to simulate fluoxetinepharmacokineticdata.Apopulationof1,000 individualswere simulatedat standard fluoxetinedoses(20mg/day, 40mg/day, and 60mg/day)to estimate the percentage ofthe patientsachieving atroughplasmalevel forthe EC90SARS-CoV-2inhibitory concentrationfora10daytreatment period. All analyseswereconductedvia statistical programming inR. Results.Standard fluoxetineantidepressantdoses resulted ina range of81% to 97%of thepatientpopulationachieving atroughtargetplasma concentration of23.2ng/mlat day10 andtranslates toalung-tissuedistribution coefficient of 60-times higher(EC90 of 4.02mM).At adose of 40mg per day, at least 87% of patients will reach thetroughtarget EC90 concentrationwithinthreedays. Conclusion.Overall, the findings of this population pharmacokineticdosing studycorroborates in vitroandobservationalclinicalstudies reportingthe first selective serotonin reuptake inhibitor fluoxetineinhibits theSARS-CoV-2pathogenat commonly treated doses in the practice of psychiatry.

The Herb-Drug Pharmacokinetic Interaction of Fluoxetine and Its Metabolite Norfluoxetine with a Traditional Chinese Medicine in Rats by LC-MS/MS.

Background Fluoxetine (FLU) is the first-line and widely used medication for depression. The combination of Chaihu Shugan san (CSGS) and FLU is commonly used to enhance antidepressant effects and reduce side effects. Objective The primary objective of this study was to investigate the potential pharmacokinetic effect of CSGS on FLU. Materials and Methods Thirty-two healthy adult male Sprague-Dawley (SD) rats were randomly divided into four groups, the fluoxetine group and multiple dose groups A, B, and C. The rats in the different groups were orally administered with a combination of FLU and different doses of CSGS for 14 d. On the fifteenth day, serial blood samples were taken from the caudal vein before the administration and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 h after the administration. A liquid-liquid extraction method was applied to extract the analytes from serum. Then, the concentrations of FLU and its metabolite, norfluoxetine (NOF), were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by DAS 3.2.8 program and compared by statistic analysis. Results Compared with the FLU group, the FLU and NOF area under the plasma concentration-time curve (AUC) (0–∞) in multiple dose group C was significantly increased, while the NOF AUCs (0–∞) in multiple dose group A and multiple dose group B were decreased. Compared with the FLU group, the NOF clearance (CL) in multiple dose group C was decreased, while the CL in multiple dose groups A and B was increased. Discussion and Conclusion There were some differences in pharmacokinetic parameters between the FLU group and multiple dose groups, and CSGS can affect the pharmacokinetics of fluoxetine.

Pharmacogenetic study focused on fluoxetine pharmacodynamics in children and adolescent patients: impact of the serotonin pathway.

Pharmacogenetic studies of fluoxetine in children and adolescents are scarce. After reporting the effect of genetic variants in genes related to the fluoxetine pharmacokinetics on clinical response in a pediatric population, we now evaluate the impact of genetic markers involved in its pharmacodynamics. The assessment was performed in 83 patients after 12 weeks of fluoxetine treatment. The genetic association analysis included a total of 316 validated single nucleotide polymorphisms in 45 candidate genes involved in six different pathways. Clinical improvement after treatment with fluoxetine in our pediatric population was associated significantly with two polymorphisms located in genes related to the serotonergic system: the 5-hydroxytryptamine receptor 1B (HTR1B) and the tryptophan 5-hydroxylase 2 (TPH2). Although a wide range of candidate genes related to different pathways were assessed, the results show that genetic markers directly related to serotonin have an important effect on fluoxetine response.

Effect of CYP2D6, CYP2C9 and ABCB1 genotypes on fluoxetine plasma concentrations and clinical improvement in children and adolescent patients

There is little known about pharmacogenetic of fluoxetine in children and adolescents. In this study, we evaluate, for the first time, the influence of CYP2D6, CYP2C9 and ABCB1 genotypes on the steady-state plasma concentrations of fluoxetine and its active metabolite (S)-norfluoxetine, and on the clinical improvement in children and adolescent patients receiving fluoxetine treatment. The assessment was performed in 83 patients after 8 and 12 weeks of treatment. Fluoxetine/(S)-norfluoxetine ratio was negatively correlated with the number of active CYP2D6 alleles (r: -0.450; P<0.001). Regarding the G2677T ABCB1 polymorphism, T allele carriers showed significantly higher improvements on the majority of scales including the Clinical Global Impression-Improvement scale (P<0.001). Our results confirm the influence of CYP2D6 genetic variants in fluoxetine pharmacokinetics and provide evidence for the potential effect of the ABCB1 genotype on the clinical improvement in children and adolescent patients treated with fluoxetine.

Juvenile pharmacokinetics of fluoxetine in rhesus monkeys

Juvenile pharmacokinetics of fluoxetine in rhesus monkeys

Studies impacting the clinical world in the European Child and Adolescent Psychiatry

One of the most promising areas in medicine is the so called personalized medicine where pharmacogenetic approach has a clear role [4]. However, the developments in the pharmacogenetic field of psychiatric disorders have not been as quick as in other areas of medicine. This scenario is even slower for child and adolescents mental disorders. In this issue of the journal, Blazquez et al. [1] present an extensive review of the literature describing how certain genes are involved in the pharmacodynamics and pharmacokinetics of fluoxetine in children and adolescents. Initial exciting findings seem to suggest a potential role for polymorphisms in several genes like SLC6A4, HTR1A and MAO-A as moderators of response to fluoxetine in depression. Nevertheless, the authors clearly document the scarcity of studies and the diversity of methodology in the investigations hampering any chance of a major step in defining a more personalized treatment for this disorder at the present moment. Other relevant research areas in child mental health with impact on clinical work are: (1) the role of environmental factors in child mental disorders, specially smoking during pregnancy in ADHD; and (2) the need of developing friendly non-pharmacological interventions that can help individuals with mental disorders dealing with the impact of symptoms in their daily lives. There is an unresolved debate in the literature on the real role of smoking during pregnancy in the etiology of ADHD with several authors suggesting that the association found might be solely a product of not controlled confounding variables like the genetic predisposition for ADHD (see Motlagh et al. [6] and Thapar et al. [7]). In this issue of the journal, Ellis et al. [5] add interesting findings for this discussion. In a community sample of 995 4-year olds from Norway, they found increased odds for both ADHD and ODD in offspring of mothers that smoked during pregnancy, even after adjusting for potential confounding variables by using the propensity score. Obviously, if a real association exists between smoking during pregnancy and externalizing disorders in children, the implications for public mental health are enormous. Developmental psychopathology has emphasized the intimate relation between child and adult mental disorders. Pharmacological interventions are key tools for treating core symptoms of some mental disorders like ADHD [2]. However, clinicians are left without many evidence-based options for helping their patients to deal with increasing environmental demands, even more when they grow up entering adulthood. Thus, there is a clear need to test potential interventions in the real world addressing this shortcoming. In this context, Wentz et al. [9] applied a user-centered design to develop a model for internet-based support and coaching for adolescents and adults with ADHD and ASD. The intervention is a mix of support sessions via internet (chat) and two additional in-person meetings. It was designed to last 8 weeks and the model was validated in a pilot study with ten individuals with ASD and/or ADHD. Since quality of life seems to be seriously impaired by ADHD (see Danckaerts et al. [3]), one reassuring finding was an improvement in subjective quality of life at follow-up. Although replication is needed before any firm conclusion on the efficacy of the intervention might be defined, the field certainly welcomes this kind of initiatives. Finally, but yet in the context of developmental psychopathology, roads from certain temperamental aspects L. A. Rohde (&) Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil e-mail: lrohde@terra.com.br

Pharmacokinetics of Fluoxetine in Rhesus Macaques following Multiple Routes of Administration

Background/Aims: Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor currently used to treat depression and mood disorders. It has been widely studied clinically and preclinically, yet there is limited knowledge of its pharmacokinetics in nonhuman primates. Methods: The present study characterized the pharmacokinetics of fluoxetine and its active metabolite norfluoxetine in rhesus macaques following both acute (1, 3, 5.6 and 10 mg/kg) and chronic doses (5.6 and 10 mg/kg/day) via different routes of administration (intravenous, subcutaneous, intramuscular, and oral). Blood samples were collected at multiple time points following administration and analyzed using mass spectrometry. Results: Fluoxetine had a half-life of 11–16 h and norfluoxetine had a half-life of 21–29 h. Potentially functionally significant serum concentrations of norfluoxetine were present at 24 h even after a single administration of fluoxetine. Similar to observations in humans under steady state conditions, norfluoxetine accounted for the greater percentage of active drug in the blood stream. Conclusion: A daily dose of 10 mg/kg administered orally maintained serum concentrations in the human clinical range over the course of 6 weeks. Given the long half-lives of fluoxetine and norfluoxetine observed in this study, precautions should be taken when designing preclinical studies to prevent accumulation of drug serum concentrations.

Sex-Specific Effects of Chronic Fluoxetine Treatment on Neuroplasticity and Pharmacokinetics in Mice

Neurogenesis is a mechanism through which antidepressants may produce therapeutic effects. There is a dearth of information regarding the effects of antidepressants on neurogenesis and neurotrophin mobilization in females. This study examined sex differences in the alteration of cell proliferation and survival in multiple regions of the brain. Additional experiments examined brain-derived neurotrophic factor (BDNF) levels and pharmacokinetics of fluoxetine to determine whether they mediate sex differences. MRL/MpJ mice were treated with fluoxetine (5 and 10 mg/kg b.i.d.) for 21 days and received injections of 5-bromo-2'-deoxyuridine (200 mg/kg) to measure DNA synthesis. In the hippocampus, fluoxetine increased cell proliferation at both doses; females treated with 10 mg/kg produced more new cells than males. Fluoxetine did not alter survival in males, but 10 mg/kg reduced survival in females. In the frontal cortex, fluoxetine increased cell proliferation and survival in males treated with 10 mg/kg. In the cerebellum and amygdala, 10 mg/kg fluoxetine increased cell proliferation in both sexes but did not alter the incorporation of the new cells. Fluoxetine increased BDNF levels in the hippocampus of both sexes. BDNF levels correlated with cell proliferation in males but not females. Brain and plasma levels indicated that females metabolized fluoxetine faster than males and produced more of the metabolite norfluoxetine. These data suggest that fluoxetine acts on multiple areas of the brain to increase cell proliferation, and the pattern of activation differs between males and females. Sex-specific effects of fluoxetine on neurotrophin mobilization and pharmacokinetics may contribute to these differences in neural plasticity.

Pharmacokinetics of Fluoxetine in Elderly Men and Women

Fluoxetine is widely prescribed as an antidepressant for geriatric patients. Despite a large scientific literature describing its efficacy and safety, there are few published data describing the pharmacokinetics of fluoxetine in the elderly. Given the common practice of polypharmacy in this population, additional pharmacokinetic information in elderly men and women is needed so that physicians can better assess potential drug-drug interactions. Twenty-five subjects, men and women between ages 65 and 83, received 20 mg of fluoxetine for 1 week followed by 40 mg for 5 weeks. Serum fluoxetine levels were measured during the period of drug administration and for 8 weeks after. The plasma concentration of fluoxetine and norfluoxetine in our subjects was higher than previously reported in the literature. Elderly women had a significantly higher serum level of norfluoxetine than men. The terminal half-life of norfluoxetine was longer in patients over age 75; elderly women had a significantly slower rate of norfluoxetine elimination than similarly aged men.

P.2.c.005 Clinical pharmacokinetics of fluoxetine in depressed Parkinsonian patients on mono and combined therapy

P.2.c.005 Clinical pharmacokinetics of fluoxetine in depressed Parkinsonian patients on mono and combined therapy

Influence of CYP2C9, 2C19 and 2D6 Genetic Polymorphisms on the Steady‐State Plasma Concentrations of the Enantiomers of Fluoxetine and Norfluoxetine

The antidepressant fluoxetine is administered as racemic mixture of two enantiomers (S- and R-fluoxetine). While S- and R-fluoxetine are equipotent in blocking serotonin reuptake, the enantiomers of the demethylated metabolite, norfluoxetine, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times as potent as R- norfluoxetine as a serotonin reuptake inhibitor. In vitro and in vivo data suggest that the metabolism of fluoxetine to norfluoxetine is stereoselective and mediated, at least in part, by the polymorphic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP2C9 and CYP2C19. In the present study, the influence of CYP2D6, CYP2C9 and CYP2C19 polymorphisms on the steady-state plasma concentrations of fluoxetine and norfluoxetine enantiomers was evaluated in 78 patients receiving chronic fluoxetine treatment (10-60 mg/day). The plasma concentrations of fluoxetine and norfluoxetine enantiomers were measured and CYP2D6, CYP2C9 and CYP2C19 genotypes were analyzed. No statistically significant relationship was identified between CYP2D6 or CYP2C19 genotypes and the dose normalised plasma concentrations of any of the enantiomers or the active moiety (i.e. the sum of S-fluoxetine, R-fluoxetine and S-norfluoxetine). However, the plasma concentration of S-norfluoxetine was very low in the only CYP2D6 poor metaboliser. Furthermore, the median S-norfluoxetine/S-fluoxetine ratios were higher in homozygous than in heterozygous extensive metabolisers (P<0.05). Among homozygous extensive metabolizers for CYP2D6, patients homozygous for CYP2C9*1 had lower dose-normalized R-fluoxetine concentrations and lower active moiety levels compared with those carrying detrimental CYP2C9 alleles (P<0.05). These results suggest that CYP2D6 and CYP2C9 polymorphisms contribute to the interindividual variability in fluoxetine pharmacokinetics at steady-state.

Additional comments on pharmacokinetics of fluoxetine

Additional comments on pharmacokinetics of fluoxetine

Pharmacokinetics/Pharmacodynamics of Desloratadine and Fluoxetine in Healthy Volunteers

The authors assessed the potential for a pharmacokinetic/pharmacodynamic interaction between desloratadine and fluoxetine. This randomized, placebo-controlled, open-label study was conducted in 54 healthy volunteers. Subjects received 1 of 3 treatments: desloratadine 5 mg plus fluoxetine 20 mg, desloratadine 5 mg plus placebo, or fluoxetine 20 mg plus placebo. Serial electrocardiograms (ECGs) were performed at baseline and day 35. Treatment effects on C(max) and AUC were assessed. During coadministration of desloratadine with fluoxetine, the ratio of the mean log-transformed C(max) and AUC values for desloratadine following concomitant fluoxetine therapy revealed a small increase in C(max) values of 15% (90% confidence interval [CI], 95%-139%) but no increase for AUC values (90% CI, 82%-123%). Corresponding values for 3-OH desloratadine demonstrated small increases in mean log-transformed C(max) and AUC ratios: 17% (90% CI, 100%-136%) and 13% (90% CI, 96%-132%), respectively. Statistical evaluation of the ratio of the mean C(max) and AUC values for fluoxetine following concomitant desloratadine therapy revealed small decreases of 9% (90% CI, 72%-115%) and 11% (90% CI, 69%-113%), respectively. Corresponding values for norfluoxetine demonstrated modest increases in mean log-transformed C(max) and AUC ratios: 22% (90% CI, 100%-139%) and 18% (90% CI, 101%-136%), respectively. Coadministration of desloratadine with a potent inhibitor of CYP2D6 did not result in clinically relevant changes in its pharmacokinetic parameters. Desloratadine administration was not associated with clinically important changes in the pharmacokinetics of fluoxetine, a drug metabolized by CYP2D6. The most common adverse event in all groups was headache (65%). Desloratadine plus fluoxetine caused no significant changes in ECGs or ventricular rate.

Accelerated Metabolism of Drugs in Late Pregnancy

This new section of TDM aims at critically reviewing breakthrough papers in therapeutic drug monitoring published in other journals. Readers are invited to submit Journal Club papers to Dr. Gideon Koren, MD, Co-Editor-in-Chief. The submission should not exceed 1000 words, and 10 references. Review of (1) Demspey et al. Accelerated metabolism of nicotine and cotinine in pregnant women. J Pharmacol Exp Ther. 2002;301: 594-598 and (2) Heikkinen et al. Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation.