Development of CT-guided biopsy sampling for time-dependent postmortem redistribution investigations in blood and alternative matrices--proof of concept and application on two cases.

The postmortem redistribution (PMR) phenomenon complicates interpretation in forensic toxicology. Human data on time-dependent PMR are rare and only exist for blood so far. A new method for investigation of time-dependent PMR in blood as well as in alternative body fluids and tissues was developed and evaluated using automated biopsy sampling. At admission of the bodies, introducer needles were placed in liver, lung, kidney, muscle, spleen, adipose tissue, heart, femoral vein, and lumbar spine using a robotic arm guided by a computed tomography scanner (CT). Needle placement accuracy was analyzed and found to be acceptable for the study purpose. Tissue biopsies and small volume body fluid samples were collected in triplicate through the introducer needles. At autopsy (around 24 h after admission), samples from the same body regions were collected. After mastering of the technical challenges, two authentic cases were analyzed as a proof of concept. Drug concentrations of venlafaxine, O-desmethylvenlafaxine, bromazepam, flupentixol, paroxetine, and lorazepam were determined by LC-MS/MS, and the percentage concentration changes between the two time points were calculated. Concentration changes were observed with both increases and decreases depending on analyte and matrix. While venlafaxine, flupentixol, paroxetine, and lorazepam generally showed changes above 30% and more, O-desmethylvenlafaxine and bromazepam did not undergo extensive PMR. The presented study shows that CT-controlled biopsy collection provides a valuable tool for systematic time-dependent PMR investigation, demanding only minimal sample amount and causing minimal damage to the body.

New validated HPLC methodology for the determination of (-)-trans-paroxetine and its enantiomer in pharmaceutical formulations with use of ovomucoid chiral stationary phase.

A new chromatographic method for the enantioseparation and the determination of (-)-trans-paroxetine and (+)-trans-paroxetine has been developed with the aid of amylose ovomucoid-based chiral stationary phase. The method is faster and five times more sensitive than procedures recommended previously: limit of detection and limit of quantification are 5 and 16 ng/mL, respectively [modified (Ferretti et al. in J Chromatogr B 710:157-164, 1998): 20 and 60 ng/mL]. It was carefully validated and applied for the determination of (-)-trans-paroxetine and (+)-trans-paroxetine in Parogen (Mc Dermott Laboratories Ltd.) and Xetanor (Actavis) coated tablets.

Development and validation of a method for the analysis of paroxetine HCl by circular dichroism.

A simple, rapid, and sensitive method for the analysis of paroxetine, in tablets as well as the pure drug, by circular dichroism is described. The method was validated for repeatability, linearity, limit of detection, limit of quantification, and recovery according to the International Conference on Harmonization guidelines. Excellent results were obtained, within the globally accepted validation reference values, particularly taking into account the low concentration levels investigated. This is the first report of the quantitation of paroxetine, a chiral drug, without previous separation of the analyte. Additionally, the solid state CD spectrum of PXT was obtained.

Comparison of two extraction methods for the determination of selective serotonin reuptake inhibitors in sewage sludge by hollow fiber liquid-phase microextraction.

This paper presents two procedures for the determination of four selective serotonin reuptake inhibitors (citalopram, paroxetine, fluoxetine, and sertraline) and one metabolite (norfluoxetine) in sewage sludge utilizing three-phase hollow fiber liquid-phase microextraction (HF-LPME). First, direct HF-LPME was used for extraction, clean-up, and preconcentration. The pharmaceuticals were extracted from slurry samples into an organic phase and then back-extracted into an aqueous phase in the lumen of the hollow fiber. Second, a procedure combining pressurized hot water extraction and HF-LPME for clean-up and preconcentration was developed for the same analytes and matrix. The extracts were subsequently analyzed by liquid chromatography-mass spectrometry. For direct HF-LPME, limits of detection were between 1 and 12 ng g(-1) (dry weight) and the relative standard deviation (RSD) values were 3-12%. For the second method, limits of detection were approximately 6 ng g(-1) for all the compounds and RSD values were 8-12%. The methods were validated by comparison of results for the same samples. Sewage sludge from a Swedish wastewater treatment plant was analyzed by both methods; average concentrations were similar for citalopram, paroxetine, and fluoxetine with values of approximately 530, 40, and 200 ng g(-1) , respectively.

A simple HPLC method for the simultaneous determination of two selective serotonin reuptake inhibitors and two serotonin-norepinephrine reuptake inhibitors in hair, nail clippings, and cerebrospinal fluid.

A novel and simple high-performance liquid chromatography method has been developed for the simultaneous determination of two selective serotonin reuptake inhibitors (fluoxetine and paroxetine) and two serotonin-norepinephrine reuptake inhibitors (venlafaxine and duloxetine) in alternative samples of toxicological interest such as hair, nail clippings, and cerebrospinal fluid (CSF). The separation was achieved on a Hichrom Kromasil 100-5C(18) (250 × 4.6 mm) 5 µm column by using ammonium acetate (0.05 M)-acetonitrile (59:41% v/v) as the mobile phase, delivered isocratically at a flow rate of 1.3 mL/min, within ca. 10 min. Ultraviolet detection at 235 nm was used for monitoring the eluting analytes. Validation was performed in terms of linearity, selectivity, accuracy, precision, and stability. Correlation coefficients were greater than 0.9954. The limits of quantitation ranged between 0.3 and 2.1 ng/µL for all analytes in the liquid matrix (CSF), while the respective values were in the range of 0.3-3.6 ng/mg for solid matrices (hair and nail clippings), with an injection volume of 20 µL. Repeatability and intermediate precision (relative standard deviation, RSD%) were less than 16.6%. The method was successfully applied to actual hair and nail samples from a patient under fluoxetine treatment.

Spectrofluorimetric determination of paroxetine HCl in pharmaceuticals via derivatization with 4-chloro-7- nitrobenzo-2-oxa-1,3-diazole (NBD-Cl).

A sensitive and simple spectrofluorimetric method has been developed and validated for the determination of the antidepressant paroxetine HCl (PXT) in its dosage forms. The method was based on coupling reaction of PXT with 4-chloro-7-nitrobenzo-2- oxa-1,3-diazole (NBD-Cl) in an alkaline medium (pH 8) to form a highly fluorescent derivative that was measured at 530 nm after excitation at 460 nm. The factors affecting the formation and stability of the reaction product were carefully studied and optimized. The fluorescence-concentration plot is rectilinear over the range 0.2-6 µg/mL with LOD of 0.08 µg/mL and LOQ of 0.24 µg/mL respectively. The method was applied to the analysis of commercial tablets and the results were in good agreement with those obtained using the reference method. The mean percentage recoveries for paxetin and xandol tablets were 101.27 ± 1.79 and 101.33 ± 1.19 respectively. A proposal of the reaction pathway was postulated.

Modification of the association between paroxetine serum concentration and SERT-occupancy by ABCB1 (P-glycoprotein) polymorphisms in major depressive disorder.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) exert substantial variability in effectiveness in patients with major depressive disorder (MDD), with up to 50-60% not achieving adequate response. Elucidating pharmacokinetic factors that explain this variability is important to increase treatment effectiveness. OBJECTIVES: To examine potential modification of the relationship between paroxetine serum concentration (PSC) and serotonin transporter (SERT)-occupancy by single nucleotide polymorphisms (SNPs) of the ABCB1 gene, coding for the P-glycoprotein (P-gp) pump, in MDD patients. To investigate the relationship between ABCB1 SNPs and clinical response. METHODS: Patients had MDD and received paroxetine 20 mg/day. We measured PSC after 6 weeks. We quantified SERT-occupancy with SPECT imaging (n = 38) and measured 17-item Hamilton Depression Rating Scale (HDRS17)-scores at baseline and after 6 weeks (n = 81). We genotyped ABCB1 at rs1045642 [3435C>T], rs1128503 [1236C>T], rs2032582 [2677G>T/A] and rs2235040 [2505G>A]. For our primary aim, we modeled mean SERT-occupancy in an Emax nonlinear regression model with PSC and assessed whether the model improved by genetic subgrouping. For our secondary aim, we used multivariate linear regression analysis. RESULTS: The rs1128503 and rs2032582 SNPs modified the relationship between PSC and SERT-occupancy in both our intention-to-treat and sensitivity analyses at the carriership level. However, we could not detect significant differences in clinical response between any of the genetic subgroups. CONCLUSION: Pharmacokinetic influences of the ABCB1 rs1128503 and rs2032582 represent a potentially relevant pharmacogenetic mechanism to consider when evaluating paroxetine efficacy. Future studies are needed to support the role of ABCB1 genotyping for individualizing SSRI pharmacotherapy.

New nonextractive and highly sensitive high-performance liquid chromatographic method for determination of paroxetine in plasma after offline precolumn derivatization with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole.

New nonextractive and simple offline precolumn derivatization procedures have been proposed, for the first time, for the trace determination of paroxetine (PXT) in human plasma by HPLC with fluorescence detection. Trimetazidine (TMZ) was used as an internal standard. Plasma samples were treated with acetonitrile for protein precipitation and then derivatized with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole in borate buffer of pH 8 at 70 degrees C for 30 min. Separations of the derivatized PXT and TMZ were performed on a Nucleosil CN column using a mobile phase consisting of acetonitrile-10 mM sodium acetate buffer (pH 3.5)-methanol (47 + 47 + 6, v/v) at a flow rate of 1.0 mL/min. The derivatized samples were excited at 470 nm and monitored at an emission wavelength of 530 nm. Under the optimum chromatographic conditions, a linear relationship with good correlation coefficient (r = 0.9998, n = 7) was found between the peak area ratio and PXT concentrations in the range of 5-600 ng/mL. The LOD and LOQ were 1.37 and 4.14 ng/mL, respectively. The intraday and interassay precisions were satisfactory; the RSD did not exceed 4.2%. The accuracy of the method was proved by recovery of PXT from spiked human plasma at levels of 97.28-104.38 +/- 0.41-3.62%. The proposed method had high throughput, as the analysis involved a simple sample pretreatment procedure and short run time (< 10 min). The results demonstrated that the method would have a great value when it is applied in the therapeutic monitoring of PXT.

Obtaining granular activated carbon from paper mill sludge - A challenge for application in the removal of pharmaceuticals from wastewater.

In this work, a granular activated carbon (GAC) was produced using primary paper mill sludge (PS) as raw material and ammonium lignosulfonate (AL) as binder agent. PS is a residue from the pulp and paper industry and AL is a by-product of the cellulose pulp manufacture and the proposed production scheme contributes for their valorisation together with important savings in GAC precursors. The produced GAC (named PSA-PA) and a commercially available GAC (GACN), used as reference material, were physically and chemically characterized. Then, these materials were tested in batch experiments for the adsorption of carbamazepine (CBZ), sulfamethoxazole (SMX), and paroxetine (PAR) from ultra-pure water and wastewater. Even though GACN and PSA-PA possess very similar specific surface areas (SBET) (629 and 671 m2 g-1, respectively), PSA-PA displayed lower maximum adsorption capacities (qm) than GACN for the pharmaceuticals here studied (6 ±â€¯1-44 ±â€¯5 mg g-1 and 49 ±â€¯6-106 ±â€¯40 mg g-1, respectively). This may be related to the comparatively higher incidence of mesopores in GACN, which might have positively influenced its adsorptive performance. Moreover, the highest hydrophobic character and degree of aromaticity of GACN could also have contributed to its adsorption capacity. On the other hand, the performance of both GACs was significantly affected by the matrix in the case of CBZ and SMX, with lower qm in wastewater than in ultra-pure water. However, the adsorption of PAR was not affected by the matrix. Electrostatic interactions and pH effects might also have influenced the adsorption of the pharmaceutical compounds in wastewater.

Analysis of paroxetine, fluoxetine and norfluoxetine in fish tissues using pressurized liquid extraction, mixed mode solid phase extraction cleanup and liquid chromatography-tandem mass spectrometry.

Recent studies have shown that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are accumulated in the tissues of fish as a result of discharges of pharmaceuticals into surface waters from municipal wastewater treatment plants. In this study, an analytical method based on liquid chromatography with atmospheric pressure chemical ionization and tandem mass spectrometry (LC-APCI-MS/MS) was developed and validated for the determination of residues of paroxetine, fluoxetine and its active metabolite, norfluoxetine, in fish tissue. The procedure for sample preparation includes extraction of tissue by pressurized liquid extraction (PLE), followed by cleanup on a mixed-mode solid phase extraction (SPE) cartridge, Oasis MCX. With the optimized method, matrix interferences were reduced and recoveries >85% were obtained. The limits of quantitation (LOQ) determined by analysis of spiked fish tissue were 0.24, 0.07, and 0.14 ng/g wet weight for paroxetine, fluoxetine and norfluoxetine, respectively. This method was successfully applied to the analysis of samples of fish collected from Hamilton Harbour in Ontario, Canada, which is an urbanized and industrialized embayment of Lake Ontario. These analyses showed that the three analytes were present in fish tissues at concentrations up to approximately 1 microg/kg wet weight.

Determination of paroxetine in human saliva by reversed-phase high-performance liquid chromatography with UV detection.

A rapid and sensitive high-performance liquid chromatographic method was validated and described for determination of paroxetine in human saliva. Following liquid-liquid extraction of the drug and an internal standard (dibucaine), chromatographic separation was accomplished using a C18 analytical column with a mobile phase consisting of 0.05 mol/L sodium phosphate buffer, pH 5.0, and acetonitrile (A 30:70, v/v; B 60:40, v/v). Paroxetine and the internal standard were detected by ultraviolet absorbance at 205 nm. The average recoveries of the drug and internal standard were 92.5% and 89%, respectively. The lower limits of detection and quantification were 1 and 4 ng/ml, respectively, and the calibration curve was linear over a concentration range of 4 ng/ml. The saliva level of paroxetine in patients with depression taking 10 to 40 mg/day of the drug was significantly correlated with the plasma level of paroxetine in each patient (r = 0.617, P < 0.004, n = 19). These data indicate that the saliva level of paroxetine could be a useful marker to predict the plasma level of the drug.

Selective serotonin reuptake inhibitors in sewage influents and effluents from Tromsø, Norway.

An analytical method for quantification of the selective serotonin reuptake inhibitors (SSRIs) citalopram, sertraline, paroxetine, fluoxetine and fluvoxamine in sewage influents and effluents from selected sewage treatment plants (STPs) has been developed and validated. This quantification method is based on solid phase extraction of 2.5L samples, followed by liquid-liquid extraction for further sample clean up in order to minimize matrix effects during subsequent quantification. The samples were analysed on a high performance liquid chromatograph coupled to a triple quadrupole mass spectrometric detector using 0.1% ammonia in acetonitrile/water as mobile phase, with positive electrospray ionisation and multiple reaction monitoring for detection and quantification. 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-pyrrolidine (N-7084) was used as internal standard for quantification. The recovery rates of the SSRIs ranged between 54 and 84%, and the method limit of quantification (MLQ) was between 120 and 290 pg/L for the target compounds. Samples were collected in July 2005 from three different STPs and a pump station in Tromsø, Northern Norway. Two of the STPs serve the University hospital and its psychiatric department, respectively, in addition to domestic sewage. SSRIs were detected in all samples collected. The concentrations varied greatly from below the MLQ to several hundreds ng/L. Concentrations in influents were higher compared to filtered effluents, indicating that SSRIs adsorb to particulate matter, are degraded by microorganisms, or degraded in other ways during the filtration process. However, more samples should be analysed before general conclusions can be drawn.

Electroanalytical determination of paroxetine in pharmaceuticals.

Electroanalytical methods based on square-wave adsorptive-stripping voltammetry (SWAdSV) and flow-injection analysis with SWAdSV detection (FIA-SWAdSV) were developed for the determination of paroxetine (PRX). The methods were based on the reduction of PRX at a mercury drop electrode at -1.55V versus Ag/AgCl, in a borate buffer of pH 8.8, and the possibility of accumulating the compound at the electrode surface. Because the presence of dissolved oxygen did not interfere significantly with the analysis, it was also possible to determine PRX using FIA-SWAdSV. This method enables analysis of up to 120 samples per hour at reduced costs. Both methods developed were validated and successfully applied to the quantification of PRX in pharmaceutical products.

An HPLC method for the indirect quantification of a quinone adduct of the drug paroxetine.

An HPLC method has been developed which enables the quantification of low levels of a catechol derivative and a quinone adduct of paroxetine in the presence of excess drug substance. Due to its inherent instability, the paroxetine quinone adduct is not available as a pure compound so that an indirect method was developed for its quantification. This procedure is based on the assumption that one molecule of the catechol (or more precisely the corresponding 1,2-benzoquinone) reacts with one molecule of paroxetine to produce one molecule of paroxetine quinone adduct. In the presence of paroxetine excess, pseudo-first-order kinetics was used to study the formation of the unstable product. A detector response factor for the paroxetine quinone adduct was calculated as a function of the response factor for the paroxetine catechol derivative, after considering a mass balance of the reaction. Using the methodology outlined, quantitative analysis was carried out of the paroxetine catechol derivative and the paroxetine quinone adduct in batches of paroxetine drug substance.

Spectrophotometric methods for the determination of the antidepressant drug paroxetine hydrochloride in tablets.

Simple, sensitive, and accurate visible spectrophotometric methods are described for the determination of paroxetine hydrochloride (PA) in tablets. Among them, the first 3 methods are based on the ion-pair complexes of PA formed with bromothymol blue (BTB), bromophenol blue (BPB), and bromocresol green (BCG) in aqueous acidic buffers. The complex species extracted into chloroform were quantitatively measured at 414 nm with BTB and BCG and at 412 nm with BPB. Beer's law was obeyed over the concentration ranges of 2-20, 2-16, and 2-16 microg/mL, respectively. The fourth method described is based on a coupling reaction between PA and 7-chloro-4-nitrobenzofurazon (NBD-Cl) in borate buffer, pH 8.5, in which a yellow reaction product that was measured at 478 nm was formed. The Beer's law range for this method was 2-10 microg/mL. The last method developed describes the interaction of PA base, as an n-electron donor, with 7,7,8,8-tetracyanoquinodimethane (TCNQ), as a pi-acceptor, in acetonitrile to give blue-colored TCNQ- radical anion with absorption maxima at 750 and 845 nm. Measured at 845 nm, the absorbance-concentration plot was rectilinear over the range of 1.5-15 microg/mL. The new methods developed were successfully applied to the determination of PA in tablets without any interference from common tablet excipients. The results of the methods were in good agreement with those obtained with an official liquid chromatographic method. This report describes first colorimetric methods for the determination of PA.

Development and validation of spectrophotometric methods for determination of fluoxetine, sertraline, and paroxetine in pharmaceutical dosage forms.

Three simple and sensitive spectrophotometric methods were developed and validated for determination of the hydrochloride salts of fluoxetine, sertraline, and paroxetine in their pharmaceutical dosage forms. These methods were based on the reaction of the N-alkylvinylamine formed from the interaction of the free secondary amino group in the investigated drugs and acetaldehyde with each of 3 haloquinones, i.e., chloranil, bromanil, and 2,3-dichloronaphthoquinone, to give colored vinylamino-substituted quinones. The colored products obtained with chloranil, bromanil, and 2,3-dichloronaphthoquinone exhibit absorption maxima at 665, 655, and 580 nm, respectively. The factors affecting the reactions were studied and optimized. Under the optimum reaction conditions, linear relationships with good correlation coefficients (0.9986-0.9999) were found between the absorbances and the concentrations of the investigated drugs in the range of 4-120 microg/mL. The limits of detection for the assays ranged from 1.19 to 2.98 microg/mL. The precision values of the methods were satisfactory; the relative standard deviations were 0.56-1.24%. The proposed methods were successfully applied to the determination of the 3 drugs in pure and pharmaceutical dosage forms with good accuracy; the recoveries ranged from 99.1 to 101.3% with standard deviations of 1.15-1.92%. The results compared favorably with those of reported methods.

Paroxetine in Postmortem Fluids and Tissues from Nine Aviation Accident Victims.

Paroxetine is a selective serotonin reuptake inhibitor commonly prescribed for the treatment of depression, obsessive-compulsive disorder, panic disorder, social anxiety disorder and post-traumatic stress disorder. While the use of paroxetine is considered relatively safe, negative side effects, including nausea, drowsiness, insomnia and dizziness, can adversely affect a pilot's ability to safely operate an aircraft. The use of paroxetine may increase suicidal behavior and suicidal ideation. When relying on postmortem specimens for toxicological evaluation, a general understanding of drug distribution throughout postmortem specimens is important. This laboratory has determined the distribution of paroxetine in postmortem tissues and fluids from nine aviation accident fatalities. Specimens were processed using an n-butyl chloride liquid/liquid extraction followed by gas chromatographic/mass spectrometeric analysis. Blood paroxetine concentrations obtained from these cases ranged from 0.019 to 0.865 µg/mL. The distribution of paroxetine, expressed as mean specimen/blood ratio, was 1.67 ± 1.16 urine (n = 4), 0.08 ± 0.04 vitreous humor (n = 6), 5.77 ± 1.37 liver (n = 8), 9.66 ± 2.58 lung (n = 9), 1.44 ± 0.57 kidney (n = 8), 3.80 ± 0.69 spleen (n = 8), 0.15 ± 0.04 muscle (n = 8), 4.27 ± 2.64 brain (n = 7) and 1.05 ± 0.43 heart (n = 8). The large standard deviations associated with the paroxetine distribution coefficients suggest that paroxetine can experience significant postmortem concentration changes.

Paroxetine in human breast milk and nursing infants.

OBJECTIVE: The purpose of this study was to determine the extent of infant medication exposure through breast-feeding during maternal treatment with paroxetine. METHOD: Breast milk and paired maternal and infant sera were collected after 10 days of maternal treatment with paroxetine at a stable daily dose (10-50 mg/day). All samples were analyzed by means of high-performance liquid chromatography with ultraviolet detection and a limit of detection of 2 ng/ml. RESULTS: Breast milk paroxetine concentrations were highly variable (2-101 ng/ml) and were present in all breast milk samples (N=108). A significant gradient effect was observed, with greater paroxetine concentrations found in later portions of breast milk (hind milk) than in early portions (fore milk). No clear time course of paroxetine excretion into breast milk was demonstrated, although maternal paroxetine daily dose reliably predicted both trough and peak breast milk concentrations over a 24-hour period. In 16 mother and infant serum pairs, no detectable concentrations of paroxetine were found in the serum of the nursing infants. CONCLUSIONS: This study extends previous data by demonstrating the presence of paroxetine in the breast milk of nursing women treated with this medication. The low concentrations of paroxetine in infant serum and lack of any observable adverse effects after maternal use of this medication while breast-feeding parallels the available data on other selective serotonin reuptake inhibitors.

Paroxetine levels in postpartum depressed women, breast milk, and infant serum.

BACKGROUND: The purpose of this study was to determine the concentrations of paroxetine in maternal serum, breast milk, and infant serum samples and to estimate infant exposure through breastfeeding. METHOD: A total of 25 sample sets was obtained: I sample set each from 23 mother-infant dyads and 2 sample sets from 1 mother-infant dyad. All mothers met DSM-IV criteria for major depressive disorder. The maternal fixed dosage of paroxetine was 10, 20, or 40 mg/day for a minimum of 30 days before the samples were drawn. Samples were collected 6 hours after dose intake, and the concentration of paroxetine in each sample was determined using gas chromatography/mass spectrometry. The analytic method employed in this study is the most sensitive to date, with the ability to detect drug concentrations as low as 0.1 ng/mL. RESULTS: Detectable levels of paroxetine were present in all maternal serum samples and in 24 of the 25 breast milk samples. In all of the infant serum samples, the paroxetine concentrations were below the lower limit of quantification. No unusual adverse effects were reported in any of the infants. CONCLUSION: The results of this study demonstrate that paroxetine, like the other selective serotonin reuptake inhibitors studied to date, is excreted into the breast milk of nursing mothers. The mean infant dose of paroxetine was 1. 1% of the maternal dose. Although no short-term adverse effects were reported in any of the infants in this study, future studies are needed to address a more systematic method for observing and recording any adverse effects. In addition, future studies should incorporate follow-up studies in order to evaluate possible long-term effects of paroxetine exposure.

Excretion of paroxetine into breast milk.

BACKGROUND: The study was carried out to quantify the excretion of the selective serotonin reuptake inhibitor paroxetine in breast milk. METHOD: In 6 lactating women, the concentrations of paroxetine in breast milk and serum were studied at the times for assumed minimum (24 hours after dose intake) and maximum (4-7 hours after dose intake) drug levels in milk. Moreover, a seventh subject was studied with frequent and regular sampling throughout a dose interval of 24 hours at 2 different dose levels. RESULTS: The mean milk/serum concentration ratios in the first 6 subjects ranged from 0.39 to 1.11 (overall mean +/- SD = 0.69 +/- 0.29), and the mean estimated dose to the infants ranged from 0.7% to 2.9% (overall mean +/- SD = 1.4% +/- 0.79%) of the weight-adjusted maternal dose. Based on area-under-the-curve data from the seventh subject, the milk/serum concentration ratio was 0.69 at a dose of 20 mg/day and 0.72 at a dose of 40 mg/day; the estimated relative doses to the infant were 1.0% and 2.0%, respectively. The mean increase in milk paroxetine concentrations from assumed minimum to assumed maximum was 61% (range, 4%-172%; p < .01). The mean paroxetine concentration in hindmilk was 78% higher than in foremilk (range, 16%-169%; p < .01), an increase that was parallel to the increase in milk triglyceride levels (r = 0.83, p = .005). No adverse drug reactions or unusual behaviors were reported in the infants. CONCLUSION: The study indicates that the relative dose to a suckling infant for paroxetine is lower than that reported for fluoxetine and citalopram and higher than that reported for sertraline and fluvoxamine.