Åke Norström

Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms

Objective: The purpose of this study was to investigate whether the disposition of fluvoxamine is associated with the CYP2D6 and CYP2C19 phenotype polymorphisms. Methods: The serum concentration of fluvoxamine was followed for 48 h after oral administration of a single dose of 50 mg fluvoxamine to five poor metabolizers of the CYP2D6 test drug dextromethorphan, five poor metabolizers of the CYP2C19 test drug mephenytoin, and five extensive metabolizers of both test drugs. Results: Poor metabolizers of dextromethorphan had significantly higher areas under the serum concentration-time curve than extensive metabolizers of dextromethorphan (mean 1.31 vs 1.00 μmol · h · l−1). There were no differences between poor and extensive metabolizers of mephenytoin (mean, 1.00 vs 1.15 μmol · h · l−1). Conclusion: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism.

Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion

Some data indicate that bupropion inhibits the cytochrome P-450 enzyme CYP2D6, but very little published data is available on the extent of this inhibition. The objective of the present study was to quantify this inhibition in a subject treated with bupropion for smoking cessation. Genotypically, the patient was a CYP2D6 homozygous extensive metabolizer (EM). His CYP2D6 phenotype was assessed using the test drug dextromethorphan before, during, and after treatment with bupropion. During treatment with bupropion, he clearly changed from the EM to the poor metabolizer (PM) phenotype. Although the results from a single patient should be interpreted with great caution, the extent of the interaction indicates that bupropion might be a CYP2D6 inhibitor as potent as the most powerful CYP2D6 inhibitors known, such as quinidine and paroxetine.

Impurities in Commercial Products Related to Pentachlorophenol

When discussing the effects of pentachlorophenol (PCP) on the environment one should have in mind that PCP itself is just a part of the problem. Most commercial chlorophenol formulations contain other chlorophenols, in PCP mainly tetrachlorophenol. In one PCP formulation sold in Sweden the PCP can be regarded as an impurity as the main constituent is tetrachlorophenol (80%). In addition to other chlorophenols, technical chlorophenols have been shown to contain a variety of dimeric impurities. Although present only in minor amounts most of the interest has been devoted to the chlorinated dioxins due to their exceptionally high toxicity. However, chlorinated phenoxyphenols, which can act as precursors of dioxins, are often present in 1–5%. Other dimeric impurities found are chlorinated diphenyl ethers, dibenzofurans and dihydroxybiphenyls. Considerable effort has been made in a number of laboratories to prepare some of these impurities for use as analytical standards and for evaluation of their biological effects. Different methods of synthesizing chlorinated dioxins, dibenzofurans, diphenyl ethers and phenoxyphenols are reviewed.

Analysis of some older Scandinavian formulations of 2,4-dichlorophenoxy acetic acid and 2,4,5-trichlorophenoxy acetic acid for contents of chlorinated dibenzo-p-dioxins and dibenzofurans.

Ten samples of older formulations of 2,4,5-trichlorophenoxy acetic acid and 2,4-dichlorophenoxy acetic acid used in Sweden were analyzed for chlorinated dibenzo-p-dioxins and dibenzofurans. The analyses were performed with gas chromatography/mass spectrometry with a high resolution glass capillary column for maximum isomeric separation and sensitivity. The detection limit was 0.01-0.05 ppm. The amounts of contaminants were of the same order of magnitude as that found earlier in European samples with later production dates (late 1960s and 1970s).

Synthesis of halogenated diphenyl ethers and dibenzofurans - A discussion of specific isomers available

Abstract Synthetic routes for the preparation of halogenated diphenyl ethers and dibenzofurans are reviewed, and isomers reported in the literature are listed. In addition, the routes preferred for the synthesis of specific chlorinated isomers - especially from the point of view of an unambiguous structural assignment - are discussed in detail. The route recommended for chlorinated diphenyl ethers is the coupling of biaryliodonium salts with phenols, and for chlorinated dibenzofurans the palladium acetate-promoted cyclization of diphenyl ethers. Chlorinated isomers of diphenyl ethers and dibenzofurans which are available via these routes are listed. Furthermore, the synthesis of a new octachlorodiphenyliodonium salt and its coupling with three different chlorophenols are described, and the cyclization of an octachlorodiphenyl ether to octachlorodibenzofuran is shown.

Occupational exposure to chain saw exhausts in logging operations

The composition of exhaust emissions from two-stroke chain saw engines was studied. The emissions of exhaust were sampled and analyzed under controlled laboratory experiments. The compounds sampled were those considered primarily responsible for acute health effects--hydrocarbons, aldehydes, nitrogen oxides and carbon monoxide. Exposure to tetramethyllead, dibromoethane and polycyclic aromatic hydrocarbons also was monitored. The results revealed no significant differences in the exhaust emissions from seven different chain saws. Heavily worn-out chain saws do not emit increased amounts of exhaust. A lean fuel-air mixture increases the emission of aldehydes and nitrogen oxides, whereas a rich mixture increases emission of carbon monoxide and hydrocarbons. Based on these new data on the composition of two-stroke chain saw exhaust emissions, operator exposure to chain saw exhaust was evaluated under various logging situations. Exposure measurements revealed no difference in average levels of exposure between logging in the presence or in the absence of snow. The felling operation, however, results in high exposure levels of short duration--especially when the operation is performed while there is deep snow on the ground. (This operation excludes limbing and bucking into lengths.) This is judged to be the main cause of the discomfort experienced by loggers. Average exposure levels for loggers engaged only in felling are twice those for cutters who also perform limbing, bucking and manual skidding of the timber, since these latter operations involve considerably lower exposure. Typical average levels of exposure are as follows: hydrocarbons, 20 mg/m3; benzene, 0.6 mg/m3; formaldehyde, 0.1 mg/m3; and carbon monoxide, 20 mg/m3.

Determination of dextropropoxyphene and nordextropropoxyphene in urine by liquid chromatography–electrospray ionization mass spectrometry

Dextropropoxyphene and nordextropropoxyphene were extracted from urine samples with mixed mode solid-phase extraction cartridges. After elution and evaporation to dryness, the eluate was dissolved in mobile phase and each sample was injected in a LC-ESI-MS system. Quantification was carried out in the selected ion monitoring mode. This article shows the possibility to analyse drugs of abuse substances in urine with a single quadrupole mass spectrometer if only a thorough work-up procedure and a sufficient chromatographic separation is accomplished. In order to enhance the fragmentation of the analytes, in-source fragmentation was carried out. One fragment and the pseudomolecular ion per analyte together with chromatographic retention times were sufficient to verify that the sought compound was found in the samples. In- and between day variation was lower than 10% and the recovery was well above 90%. The analytes were quantified in the range 100-10000 ng/ml urine.

Sampling and analysis of polycyclic aromatic hydrocarbons (PAH) from two-stroke chain-saw engines

A sampling and analysis method for PAH from two-stroke engines is described. The method, which uses a standard glass fiber filter with a back-up section of Amberlite XAD-2 for sampling and GC or GC-MS for analysis, is suitable for both emission studies and occupational studies during logging. Filters and XAD-2 are desorbed with cyclohexane in an ultrasonic bath. After separation on a silica-gel micro column, the samples are submitted to analyses by capillary GC. The method is simple and covers both gaseous and particulate PAH. Naphthalene and alkyl substituted naphthalenes are also quantified.

A new strategy for monitoring exposure to chain-saw exhaust

Abstract In determining the atmospheric concentration of various components in a complex mixture of organic compounds, substantial problems are often encountered in connection with sampling and analysis. A strategy based on limited sampling of a few compounds, together with a mathematical model (monitor), is proposed as a practical solution to these problems. In this paper such a simplified procedure for monitoring occupational exposure to chain-saw exhaust is reported. The procedure is based on personal monitoring of formaldehyde, benzaldehyde and carbon monoxide and on a mathematical model calculated from emission data. Exposure to hydrocarbons, including benzene, other aldehydes, nitrogen oxides, alkyllead, lead, scavengers and polycyclic aromatic hydrocarbons may be calculated from this monitor with acceptable precision. The use of the monitor greatly simplifies an evaluation of occupational exposure to chain-saw exhaust during logging and it can also be used in emission studies.

[3H]GBR 12935 binding in platelets from poor and extensive cytochrome P-4502D6 metabolizers

Previous studies have indicated that part of the binding of [3H] [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride] ([3H]GBR 12935) to human platelets is to a piperazine acceptor site, which might be associated with cytochrome P-450IID6 (CYP4502D6, debrisoquine-4-hydroxylase). Due to mutant CYP4502D6 alleles, 5-10% of Caucasians are poor metabolizers of CYP4502D6 substrates such as debrisoquine and dextromethorphan. In the present study, possible differences in binding characteristics of [3H]GBR 12935 in platelets from CYP4502D6 poor and extensive metabolizers were investigated. The most prominent finding was a gender difference, with males having significantly higher Kd values than females. There were no differences in Bmax. After correction for gender, there was a tendency towards higher Kd values in poor metabolizers than in extensive metabolizers, although the difference was not statistically significant. Whether this finding corresponds to reduced CYP4502D6 activity is a matter of further investigation.