Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model

The pharmacokinetics and time course of blood–brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04?mg?kg^?1 BUP or 0.6?mg?kg^?1 norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20?min) between brain and blood due to intermediate permeability (47?ml?min^?1) and a large cerebral distribution volume (595?ml). Significant limitation in permeability (6?ml?min^?1) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157?ml) giving a blood–brain equilibration half-life (21?min) similar to that for BUP. The logD of BUP and norBUP were 3.93?±?0.08 and 1.18?±?0.04 (mean?±?SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.     

Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model

The pharmacokinetics and time course of blood-brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04 mg kg(-1) BUP or 0.6 mg kg(-1) norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20 min) between brain and blood due to intermediate permeability (47 ml min(-1)) and a large cerebral distribution volume (595 ml). Significant limitation in permeability (6 ml min(-1)) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157 ml) giving a blood-brain equilibration half-life (21 min) similar to that for BUP. The logD of BUP and norBUP were 3.93 +/- 0.08 and 1.18 +/- 0.04 (mean +/- SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.     

Low levels of tenofovir in breast milk support breastfeeding in HBV-infected mothers treated with tenofovir disoproxil fumarate

ObjectiveTenofovir disoproxil fumarate (TDF) is recommended for the prevention of mother-to-infant transmission of the hepatitis B virus (HBV). This study investigated the safety of infants whose mothers continued to receive TDF while breastfeeding.Patients and methodThirty women taking TDF daily from the second or third trimester of pregnancy to three months postpartum were enrolled. Tenofovir (TFV) concentrations in breast milk were determined and compared with those in umbilical cord (UC) blood and amniotic fluid. Infant growth parameters were assessed at birth, and at 3, 6, and 12 months. TFV uptake experiments were conducted in vitro to elucidate the mechanisms of TFV exposure via breast milk.ResultsTFV concentrations in breast milk ranged from 1.4 to 11.7 ng/mL within 24 h after dosing in the third month postpartum. The median trough concentration of TFV in breast milk was 3.7 (interquartile range, 2.6–6.2) ng/mL, which is lower than that in UC blood (median = 53.5 ng/mL) and amniotic fluid (median = 531.0 ng/mL). The low permeability of TFV in MCF-10A cells may explain the minimal exposure to TFV in breast milk. Body weights, body lengths, and head circumferences of the breastfed infants were comparable to the national standards for physical development.ConclusionInfant exposure to TFV from breast milk is much lower than the exposure from placental transfer and swallowing from amniotic fluid. The physical growth parameters of all infants in this study were normal. The findings indicate that breastfeeding is safe for infants of HBV-infected mothers who continue to receive TDF through three months postpartum.     

Secretion of dilevalol in breast milk

The pharmacokinetics of unchanged and total (unchanged plus Glusulase [Biotechnology Systems, Boston, MA]) released dilevalol and secretion into human breast milk was studied in six healthy breast-feeding female volunteers administered a single 400-mg dilevalol hydrochloride capsule. In plasma, the mean Cmax for unchanged dilevalol, 485 ng/mL was reached at 0.8 hour (tmax) and the AUC(48 hours) was 1435 hr X ng/mL. Pharmacokinetic analysis of unchanged dilevalol in plasma showed that dilevalol was distributed and eliminated with half-lives of 0.9 and 8.2 hours, respectively. Breast milk concentrations of unchanged dilevalol as a function of time, paralleled those of plasma but were consistently lower. The milk Cmax, 149 ng/mL, occurred during the 0 to 2 hour collection interval; the AUC(42 hours) for unchanged dilevalol in milk was 663 hr X ng/mL. The mean milk to plasma concentration ratio was 0.46. The unchanged dilevalol plasma concentrations were 12 to 18% those of total drug suggesting that the drug is extensively conjugated. By contrast, the concentrations of unchanged dilevalol in breast milk, based on Cmax and AUC data were 63 to 94% those of total drug, indicating that very little conjugated drug is secreted into breast milk. Through 48 hours, a mean of only 27 micrograms dilevalol or 0.007% of the administered dose was secreted into breast milk, which is much less than that reported for other beta blockers.     

Quantification of lorazepam and lormetazepam in human breast milk using GC-MS in the negative chemical ionization mode

Lormetazepam (Loramet is a benzodiazepine mainly used as an hypnotic to treat insomnia. Lorazepam (Temesta) is used as an anxiolytic, tranquilizer, sedative, and anticonvulsant, and it is the major metabolite of lormetazepam. In this study, we designed a method to simultaneously detect and quantify these substances in human breast milk. Solid-phase extraction of 2 mL of milk was followed by derivatization with a trimethylsilyl reagent. Separation and detection was performed using gas chromatography coupled to mass spectrometry in the negative chemical ionization mode. Calibration curves were linear in the ranges of 10-200 and 1-20 ng/mL for lorazepam and lormetazepam, respectively. Limits of detection were estimated at 0.016 ng/mL for lormetazepam and 0.100 ng/mL for lorazepam. Our method was applied to real case samples from a woman receiving both benzodiazepines. Lorazepam concentrations varied from 55.3 to 123.1 ng/mL, and lormetazepam concentrations varied from 1.7 to 7.3 ng/mL.     

The effect of methadone and buprenorphine on human placental aromatase

Methadone and buprenorphine (BUP) are used for treatment of the pregnant opiate addict. CYP19/aromatase is the major placental enzyme responsible for the metabolism of methadone to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and BUP to norbuprenorphine (norBUP). The aim of this investigation was to determine the effects of methadone and BUP on the activity of placental microsomal aromatase in the conversion of its endogenous substrates testosterone to 17beta-estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)). The conversion of testosterone and 16-OHT by human placental microsomes exhibited saturation kinetics, and the apparent K(m) values were 0.2 +/- 1 and 6 +/- 3 microM, respectively. V(max) values for E(2) and E(3) formation were 70 +/- 16 and 28 +/- 10 pmol/mg proteinmin, respectively. Also, data obtained revealed that methadone and BUP are competitive inhibitors of testosterone conversion to E(2) and 16-OHT to E(3). The K(i) for methadone inhibition of E(2) and E(3) formation were 393 +/-144 and 53 +/- 28 microM, respectively, and for BUP the K(i) was 36 +/- 9 and 6 +/- 1 microM. The higher potency of the two opiates and their metabolites in inhibiting E(3) formation is in agreement with the lower affinity of 16-OHT than testosterone to aromatase. Moreover, the metabolites EDDP and norBUP were weaker inhibitors of aromatase than their parent compounds. The determined inhibition constants of methadone and BUP for E(3) formation by a cDNA-expressed CYP19 preparation were similar to those for placental microsomes. Therefore, data reported here suggest that methadone, BUP, and their metabolites are inhibitors of androgen aromatization in the placental biosynthesis of estrogens.     

Buprenorphine assay and plasma concentration monitoring in HIV-infected substance users

The availability of buprenorphine (BUP) provides an alternative approach to the treatment of opioid addiction with methadone, an agent that has many drug-drug interactions when combined with antiretroviral therapy (ART). However, due to limited long-term pharmacokinetic studies in HIV-infected patients, the clinical use of BUP, a CYP450-3A4 substrate, will require that studies be conducted to examine safety, tolerability and pharmacokinetics when these drugs are taken for chronic treatment. One clinical approach could include plasma concentration monitoring to avoid under- or overdosing BUP secondary to drug interactions with ART. The measurement of BUP and its active metabolite, norbuprenorphine (NBUP) facilitates the addition of BUP to ART in an attempt to avoid drug toxicity as described in a recent report by Bruce et al. Therefore, our objective was to validate a BUP assay and integrate its application into an ongoing antiretroviral (ARV) plasma concentration monitoring program. A chromatographic method for monitoring BUP and its active metabolite, NBUP was investigated. An assay was developed that would facilitate BUP and ARV measurement from a single 3 mL blood sample (0.75 mL plasma required) in conjunction with a previously validated multiple ARV HPLC method. The method measures BUP and NBUP over the range from 0.25 to 50 ng/mL with mass spectrometry detection. Inter- and intra-assay variation was 相似文献   

Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows

Antidepressant pharmaceuticals have been reported in wastewater effluent at the nanogram to low microgram-per-liter range, and include bupropion (BUP), fluoxetine (FLX), sertraline (SER), and venlafaxine (VEN). To assess the effects of antidepressants on reproductive anatomy, physiology, and behavior, adult male fathead minnows (Pimephales promelas) were exposed for 21 days either to a single concentration of the antidepressants FLX, SER, VEN, or BUP, or to an antidepressant mixture. The data demonstrated that exposure to VEN (305 ng/L and 1104 ng/L) and SER (5.2 ng/L) resulted in mortality. Anatomical alterations were noted within the testes of fish exposed to SER and FLX, both modulators of the neurotransmitter serotonin. Additionally, FLX at 28 ng/L induced vitellogenin in male fish--a common endpoint for estrogenic endocrine disruption. Significant alterations in male secondary sex characteristics were noted with single exposures. Effects of single compound exposures neither carried over, nor became additive in the antidepressant mixtures, and reproductive behavior was not affected. Analysis of brain tissues from the exposed fish suggested increased uptake of FLX, SER and BUP and minimal uptake of VEN when compared to exposure water concentrations. Furthermore, the only metabolite detected consistently in the brain tissues was norfluoxetine. Similar trends of uptake by brain tissue were observed when fish were exposed to antidepressant mixtures. The present study demonstrates that anatomy and physiology, but not reproductive behavior, can be disrupted by exposure to environmental concentrations of some antidepressants. The observation that antidepressant uptake into fish tissues is selective may have consequences on assessing the mode-of-action and effects of these compounds in future studies.     

Excretion of ketoprofen and nalbuphine in human milk during treatment of maternal pain after delivery

Analgesics are required to prevent and treat postpartum pain, but breast-feeding may be contraindicated, because data on milk transfer are very limited. The present study was undertaken to quantify the transfer of ketoprofen and nalbuphine in milk. Eighteen patients gave their informed consent to participate and completed the study. Following delivery, they received ketoprofen (100 mg/12 hours) and nalbuphine (0.2 mg/kg/4 hours) as an intravenous bolus over 2 to 3 days for postpartum pain. Milk samples were collected during the 12 hours between the third and fourth ketoprofen administrations. Ketoprofen and nalbuphine concentrations were determined with high-performance liquid chromatography. The mean and maximum ketoprofen milk concentrations were 57+/-37 and 91+/-51 ng/mL, respectively. Assuming a milk volume of 150 mL/kg/day, the mean and maximum doses that a breast-fed neonate would ingest during one day are 8.5+/-5.5 and 13.6+/-7.6 microg/kg/day, respectively, and the relative infant dose is 0.31+/-0.17% of the weight-adjusted maternal daily dose. The mean and maximum nalbuphine milk concentrations were 42+/-26 and 61+/-26 ng/mL, respectively. Assuming a milk volume of 150 mL/kg/day, the mean and maximum doses that a breast-fed neonate would ingest during one day is 7.0+/-3.2 and 9.0+/-3.8 microg/kg/day, and the relative infant dose is 0.59+/-0.27% of the weight-adjusted maternal daily dose. Therefore, breast-feeding is permissible when ketoprofen and/or nalbuphine are administered to the mother to treat postpartum pain.     

Olanzapine treatment during breast feeding: a case report

Postpartum psychosis constitutes a severe complication that entails risk for both mother and child. Little is known about the use of olanzapine in the treatment of postpartum psychosis. In previous studies, it has been reported on mothers receiving relatively low doses of olanzapine. We report a 38-year-old patient who was admitted to the hospital for an acute psychotic exacerbation. She was breast feeding her 5-month-old child, and she wished to continue breast feeding. Olanzapine treatment was started with a daily dosage of 15 mg. The weight-corrected maternal dose was 270 mug/kg. The olanzapine concentration in the mother's plasma was 24 ng/mL. The analysis of olanzapine in breast milk applying two different high-performance liquid chromatography procedures revealed similar results: 12.2 ng/g without and 11.5 ng/g with additional hydrochloric acid extraction, respectively. In addition, breast milk of an unmedicated mother was used for establishing the analytical procedure so that the validity of the results was better confirmed. The milk-plasma ratio arising from our data was 0.5, and the relative infant dose was 0.3%. The olanzapine concentration was below the limit of detection (<5 ng/mL) in the infant's plasma sample. No adverse effects were noticed, and the mother experienced a rapid improvement in her psychopathology during her hospital stay. In future studies, long-term follow-up of both mother and child would be useful.     

Implications of nicotine detected in autopsy cases of newborn babies and infants from the perspective of social medicine

Smoking by pregnant and parturient women is generally suspected to increase nicotine levels in fetal and infant blood. Supportive data of nicotine levels in infants is, however, inadequate. We investigated blood and muscle nicotine and cotinine levels in 14 autopsy cases of newborn babies and infants using gas chromatography. Among the 14 cases investigated, nicotine or cotinine was detected in six cases (42.9%). In each of these six cases, the mother was a smoker. Route of exposure to nicotine originating from smoking was transplacental in three cases, via breast milk in one case and secondhand smoke in two cases. Nicotine and cotinine levels in blood from the two cases with placental exposure were 10.6-84.4 ng/ml and 20.3-183 ng/ml, and levels in muscle from one case were 43.9 ng/g and 308 ng/g, respectively. Nicotine and cotinine levels in blood from exposure via breast milk were 19.1 ng/ml and 87.1 ng/ml, and from secondhand smoke were 0 ng/ml and 14.6-20.1 ng/ml. Mean concentrations of blood nicotine and cotinine in 68 autopsy cases of adult habitual smokers were 30.0 ng/ml and 247 ng/ml. Our data for nicotine and cotinine levels in infant blood seem to indicate that some infants who are born and develop under exposure to smoking by family members, particularly the mother, may show high nicotine levels in blood and experience possible health risks.     

Exposure of infants to ochratoxin A with breast milk

The nephrotoxic and carcinogenic mycotoxin ochratoxin A (OTA) is a worldwide contaminant in food commodities and also found frequently in human biological fluids. Dietary contaminants ingested by nursing mothers can appear in breast milk. But the rate of lactational transfer of OTA has not been investigated so far at various stages of breastfeeding. Therefore, and to investigate OTA exposure of Chilean infants, we conducted a longitudinally designed study in mother–child pairs (n = 21) with parallel collection of maternal blood, milk and of infant urine samples over a period of up to 6 months. Validated analytical methods were applied to determine OTA concentrations in all biological samples (n = 134). OTA was detected in almost all maternal blood plasma, at concentrations ranging between 72 and 639 ng/L. The OTA concentrations in breast milk were on average one quarter of those measured in plasma (M/P ratio 0.25). Interestingly, a higher fraction of circulating OTA was excreted in colostrum (M/P 0.4) than with mature milk (M/P ≤ 0.2). Infants exposure was calculated as daily intake from our new data for OTA levels in breast milk, and taking into account milk consumption and body weight as additional variables: Chilean infants have an average intake of 12.7 ± 9.1 ng/kg bw during the first 6 days after delivery while intake with mature milk results in average values close to 5.0 ng/kg bw/day. Their OTA exposure is discussed in the context of tolerable intake values suggested by different scientific bodies. Moreover, the study design enabled a comparison of OTA intake and infant urine concentrations over the breastfeeding period. The statistical analysis of n = 27 paired values showed a good correlation (r = 0.57) for this type of studies and thereby confirms that urinary OTA analysis in infants is a valid biomarker of exposure.     

Transdermal delivery of bupropion and its active metabolite, hydroxybupropion: a prodrug strategy as an alternative approach

This investigation includes an evaluation of the percutaneous absorption of bupropion (BUP) and hydroxybupropion (BUPOH) in vitro and in vivo. In addition, a carbamate prodrug of BUPOH (But-BUPOH) was evaluated in vitro. In vitro diffusion studies were conducted in a flow-through diffusion cell system. The in vitro mean steady-state flux of BUP was significantly higher (p < 0.001) compared to BUPOH (320 +/- 16 nmol cm(-2) h(-1) vs. 27 +/- 4 nmol cm(-2) h(-1)). Additionally, a good correlation existed between in vitro and in vivo results. Mean steady-state plasma concentrations of 442 +/- 32 ng/mL and125 +/- 18 ng/mL were maintained over 48 h after topical application of BUP and BUPOH in hairless guinea pigs in vivo, respectively. Although BUP traversed human skin at rates sufficient to achieve required plasma levels, it is chemically unstable and hygroscopic, and unsuitable for transdermal formulation. On the other hand, BUPOH is stable but its transport across skin is much slower. Alternatively, the prodrug But-BUPOH was found to be stable, and also provided a 2.7-fold increase in the transdermal flux of BUPOH across human skin in vitro. Thus, But-BUPOH provides a viable option for the transdermal delivery of BUPOH.     

The in vivo glucuronidation of buprenorphine and norbuprenorphine determined by liquid chromatography-electrospray ionization-tandem mass spectrometry

The opioid partial agonist medication, buprenorphine (BUP), and its primary metabolite, norbuprenorphine (NBUP), are extensively glucuronidated. Sensitive analytical methods that include determination of buprenorphine-3-glucuronide (BUPG) and norbuprenorphine-3-glucuronide (NBUPG) are needed to more fully understand the metabolism and pharmacokinetics of buprenorphine. A method has now been developed that uses solid-phase extraction followed by liquid chromatography-electrospray ionization-tandem mass spectrometry. BUP-d4, NBUP-d3, and morphine-3-glucuronide-d3 were used as internal standards. The lower limit of quantitation was 0.1 and 0.5 ng/mL for each of the analytes in 1-mL of human plasma and urine, respectively, except for NBUP in urine in which it was 2.5 ng/mL. The analytes were stable under the following conditions: plasma and urine at room temperature, up to 20 hours; plasma and urine at -20 degrees C for 119 and 85 days, respectively; plasma freeze-thaw, up to 3 cycles; processed sample, up to 96 hours at -20 degrees C and up to 48 hours on the autosampler; stock solutions at room temperature and at -20 degrees C, up to 6 hours and 128 days, respectively. In plasma collected from 5 subjects on maintenance daily sublingual doses of 16 mg BUP and 4 mg naloxone, respective 0- to 24-hour areas under the curve were 32, 88, 26, and 316 ng/mL x h for BUP, NBUP, BUPG, and NBUPG. In urine samples respective percent of daily dose excreted in the 24-hour urine were 0.014%, 1.89%, 1.01%, and 7.76%. This method allowed us to determine that NBUPG is a major metabolite present in plasma and urine of BUP. Because urinary elimination is limited ( approximately 11% of daily dose), the role of NBUPG in total clearance of buprenorphine is not yet known.     

Development of a highly efficient extraction technique and specific multiplex assay for measuring antiretroviral drug concentrations in breast milk

Understanding the pharmacology of drugs in breast milk is important for the health of both mother and baby. Current methods to measure drug concentrations in breast milk are not easily validated for precision or accuracy, primarily because of suboptimal sample clean-up. We report here an optimized clean-up method to remove both proteins and fat from milk, thereby enhancing the extraction efficiency of antiretroviral drugs. Recoveries were consistently above 91% for all drugs, demonstrating that this method successfully and reliably released drugs from fat globules. With use of 200 muL of human breast milk, an high-performance liquid chromatography/ultraviolet method for simultaneously detecting lamivudine, stavudine, zidovudine, and nevirapine was validated over the range of 20 to 20,000 ng/mL. Intra- and interday precision (average percent relative standard deviation) and accuracy (average percent deviation from nominal) was less than 3.6% and 7.5%, respectively. Intra- and interday accuracy (average percent deviation from nominal) was less than 0.25% and 1.3%, respectively. This novel method efficiently, reliably, and accurately measured antiretroviral drugs in breast milk and can be applied to any matrix containing fat and protein.     

Stability of bupropion and its major metabolites in human plasma

Bupropion (BUP) is a new, monocyclic, second-generation antidepressant with efficacy comparable with that of the tricyclics but possessing a more favorable side-effect profile. Therapeutic drug monitoring services are expected to be widely available following the marketing of BUP, yet relatively little has been published on its clinical pharmacokinetics. The purpose of this study was to assess the drug's plasma stability and to determine the best storage conditions for conducting pharmacokinetic studies of BUP and its major metabolites. Human plasma was spiked with known concentrations of BUP and its major basic metabolites, threo-amino alcohol (TB), erythro-amino alcohol (EB), and hydroxy metabolite (HB), and incubated under varying conditions of temperature and pH. BUP showed a log linear degradation that was both temperature and pH dependent. BUP half-life in pH 7.4 plasma stored at 22 and 37 degrees C was 54.2 and 11.4 h, respectively. Incubation at 37 degrees C, pH 2.5 to 10, for 48 h had minimal effect on metabolite concentrations. These results indicate that drug degradation must be considered in studies involving the incubation of plasma for protein binding determinations and the collection and storage of plasma samples for drug concentration analysis during therapeutic drug monitoring.     

Passive cannabis smoke exposure and oral fluid testing. II. Two studies of extreme cannabis smoke exposure in a motor vehicle

Two studies were conducted to determine if extreme passive exposure to cannabis smoke in a motor vehicle would produce positive results for delta-tetrahydrocannabinol (THC) in oral fluid. Passive exposure to cannabis smoke in an unventilated room has been shown to produce a transient appearance of THC in oral fluid for up to 30 min. However, it is well known that such factors as room size and extent of smoke exposure can affect results. Questions have also been raised concerning the effects of tobacco when mixed with marijuana and THC content. We conducted two passive cannabis studies under severe passive smoke exposure conditions in an unventilated eight-passenger van. Four passive subjects sat alongside four active cannabis smokers who each smoked a single cannabis cigarette containing either 5.4%, 39.5 mg THC (Study 1) or 10.4%, 83.2 mg THC (Study 2). The cigarettes in Study 1 contained tobacco mixed with cannabis; cigarettes in Study 2 contained only cannabis. Oral fluid specimens were collected from passive and active subjects with the Intercept Oral Specimen Collection Device for 1 h after smoking cessation while inside the van (Study 1) and up to 72 h (passive) or 8 h (active) outside the van. Additionally in Study 1, Intercept collectors were exposed to smoke in the van to assess environmental contamination during collection procedures. For Study 2, all oral fluid collections were outside the van following smoking cessation to minimize environmental contamination. Oral samples were analyzed with the Cannabinoids Intercept MICRO-PLATE EIA and quantitatively by gas chromatography-tandem mass spectrometry (GC-MS-MS). THC concentrations were adjusted for dilution (x 3). The screening and confirmation cutoff concentrations for THC in neat oral fluid were 3 ng/mL and 1.5 ng/mL, respectively. The limits of detection (LOD) and quantitation (LOQ) for THC in the GC-MS-MS assay were 0.3 and 0.75 ng/mL, respectively. Urine specimens were collected, screened (EMIT, 50 ng/mL cutoff), and analyzed by GC-MS-MS for THCCOOH (LOD/LOQ = 1.0 ng/mL). Peak oral fluid THC concentrations in passive subjects recorded at the end of cannabis smoke exposure were up to 7.5 ng/mL (Study 1) and 1.2 ng/mL (Study 2). Thereafter, THC concentrations quickly declined to negative levels within 30-45 min in Study 1. It was found that environmentally exposed Collectors contained 3-14 ng/mL in Study 1. When potential contamination during collection was eliminated in Study 2, all passive subjects were negative at screening/confirmation cutoff concentrations throughout the study. Oral fluid specimens from active smokers had peak concentrations of THC approximately 100-fold greater than passive subjects in both studies. Positive oral fluid results were observed for active smokers 0-8 h. Urine analysis confirmed oral fluid results. These studies clarify earlier findings on the effects of passive cannabis smoke on oral fluid results. Oral fluid specimens collected in the presence of cannabis smoke appear to have been contaminated, thereby falsely elevating THC concentrations in oral fluid. The risk of a positive test for THC was virtually eliminated when specimens were collected in the absence of THC smoke.     

Excretion of loratadine in human breast milk

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40-mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration-time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration-time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and 4.2 micrograms of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8-hour collection interval. Through 48 hours, the mean milk-plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 micrograms of descarboethoxyloratadine (7.5 micrograms loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 micrograms loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4-kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hplc/electrospray ionization mass spectrometric analysis of the heterocyclic aromatic amine carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in human milk

A new procedure has been developed for the extraction of 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) and other heterocyclic aromatic amines from human breast milk samples. Extracts were analyzed by high-performance liquid chromatography/electrospray ionization/tandem mass spectrometry (HPLC/ESI-MS/MS) with selective reaction monitoring detection. Tandem ESI-MS/MS detection provides much improved sensitivity and specificity, compared with those of a previous method that used selected ion monitoring. Milk samples were collected from 48 healthy volunteers, including five vegetarians. Donors completed a detailed dietary questionnaire. The concentrations of PhIP in the milk samples were low and below the limit of quantification (0.68 pg/mL) for all subjects except one, for whom a concentration of 1.0 pg PhIP/mL was measured. Our results indicate that the levels of PhIP in human milk are substantially lower than what was previously reported.     

Inhaled corticosteroids in asthma: a dose-proportionality study with triamcinolone acetonide aerosol.

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1-week washout period between dosing. Serial blood samples were collected for 10 hours postdosing for the determination of plasma TAA concentrations by using a specific radioimmunoassay. The pharmacokinetic profiles that were obtained showed slow and limited absorption over the first 4 hours after dosing followed by rapid elimination with a half-life of approximately 2 hours (range: 1.8-2.3 hr). Comparison of pharmacokinetic parameters from each dose group showed excellent proportionality and consistent absorption for all patients. Mean Cmax values ranged from 0.51 ng/mL after the 400 mcg dose to 1.01 ng/mL and 1.97 ng/mL after the 800 and 1600 mcg doses, respectively. Mean AUC0-10 values for these same doses were 2.6 ng x hr/mL, 5.3 ng x hr/mL and 10.5 ng x hr/mL, respectively. The results suggest that systemic exposure to TAA is minimal after oral inhalation, occurs in a dose proportional fashion, and produces circulating plasma concentrations which are unlikely to have significant adverse systemic effects.