Einar Solheim

DISTRIBUTION OF TAMOXIFEN AND METABOLITES INTO BRAIN TISSUE AND BRAIN METASTASES IN BREAST CANCER PATIENTS

We determined the amount of tamoxifen, N-desmethyltamoxifen (metabolite X), N-desdimethyltamoxifen (metabolite Z), and hydroxylated metabolites (Y, B, BX) in brain metastases from breast cancer and in the surrounding brain tissues. Specimens were collected from the breast cancer patients who received tamoxifen for 7-180 days and with the last dose taken within 28 h before surgical removal of the tumour. The concentrations of tamoxifen and its metabolites were up to 46-fold higher in the brain metastatic tumour and brain tissue than in serum. Metabolite X was the most abundant species followed by tamoxifen and metabolite Z. Small but significant amounts of the hydroxylated metabolites, trans-1(4-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene (metabolite Y), 4-hydroxytamoxifen (metabolite B) and 4-hydroxy-N-desmethyltamoxifen (metabolite BX) were detected in most specimens. The ratios between the concentrations of tamoxifen and various metabolites were similar in tumour, brain and serum. This is the first report on the distribution of tamoxifen and metabolites into human brain and brain tumour, and the data form a basis for further investigation into the therapeutic effects of tamoxifen on brain metastases from breast cancer.

Metabolism of Alkenebenzene Derivatives in the Rat. II. Eugenol and Isoeugenol Methyl Ethers

1. The metabolites of 3,4-dimethoxyallylbenzene (eugenol methyl ether) and 3,4-dimethoxypropenylbenzene (isoeugenol methyl ether) in the rat were identified and quantitatively determined by g.l.c. and g.l.c.-mass spectrometry. 2. The major metabolic reactions of 3,4-dimethoxyallylbenzene were oxidation of the allylic side chain to 2-hydroxy-3-(3,4-dimethoxyphenyl)-propionic acid, 3,4-dimethoxybenzoic acid and 3,4-dimethoxycinnamic acid, the two latter being largely excreted as their glycine conjugates. The formation of the hydroxy acid presumably involved epoxidation of the double bond and subsequent hydration to the diol whereas the formation of 3,4-dimethoxycinnamic acid and 3,4-dimethoxybenzoic acid involved migration of the double bond and the formation of cinnamoyl intermediates. Other reactions were O-demethylation to 4-hydroxy-3-methoxyallylbenzene (eugenol) and 3-hydroxy-4-methoxyallylbenzene in equal amounts, oxidation to 1-(3,4-dimethoxyphenyl)-2-propen-1-ol, hydroxylation of the benzene ring to a hydroxy-3,4-dimethoxyallylbenzene and oxidation to 3,4-dimethoxyphenylacetic acid. The formation of 1-(3,4-dihydroxyphenyl)propane was found to be carried out by the rat intestinal micro-organisms. A total of at least 63% but as much as 95% dose was accounted for. 3. The major metabolic pathway of 3,4-dimethoxypropenylbenzene was via the cinnamoyl derivatives, leading to the formation of 4-hydroxy-3-methoxycinnamic acid (ferulic acid), 3,4-dimethoxycinnamic acid and 3,4-dimethoxybenzoic acid, the two latter being excreted largely as their glycine conjugates. Other reactions were O-demethylation to 4-hydroxy-3-methoxypropenylbenzene (isoeugenol) and 3-hydroxy-4-methoxypropenylbenzene in equal amounts, and oxidation to 3,4-dimethoxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetone. Epoxidation of the side chain appeared to be a minor metabolic reaction with the propenyl derivative. 4. The biliary metabolites of 3,4-dimethoxyallylbenzene and 3,4-dimethoxypropenylbenzene were identified and most of the urinary metabolites were also found in the bile.

Metabolism of Alkenebenzene Derivatives in the Rat I. p-Methoxyallylbenzene (Estragole) and p-Methoxypropenylbenzene (Anethole)

Abstract1. The metabolism of p-methoxyallylbenzene (estragole) and p-methoxy-propenylbenzene (anethole) in the rat has been investigated. The metabolites were identified and quantitatively determined mainly by g.l.c. and by combined g.l.c.-mass spectrometry.2. The major metabolic reactions of p-methoxyallylbenzene were found to be O-demethylation to p-hydroxyallylbenzene and oxidation of the allylic side chain to p-hydroxy-3-(p-methoxyphenyl)propionic acid or to p-methoxybenzoic acid (anisic acid) which was largely excreted as p-methoxyhippuric acid. The former oxidative pathway involved epoxidation of the double bond and subsequent hydration to the diol whereas the latter pathway involved migration of the double bond and the formation of cinnamoyl intermediates. Other reactions gave rise to 1-(p-methoxyphenyl)allyl alcohol and to p-methoxyphenylacetic acid and its glycine conjugate. A total of at least 60–65% but as much as 90% dose was accounted for.3. A major metabolic reaction of p-methoxypropenylbenz...

Transplacental Passage of Ketamine after Intravenous Administration

This study was designed to measure how fast and at what concentrations ketamine would enter the foeto‐placental circulation, when administered intravenously to 10 healthy mothers immediately before forceps delivery, which was indicated by a delayed second stage of labour. It is shown that ketamine very rapidly passes the placenta, and that ketamine levels in cord blood exceed the levels in the maternal venous blood as early as 1 min 37 s after the injection. The ketamine levels in cord blood reach a maximum in the period 1 min 37 s to 2 min 5 s after the injection. Later they show a tendency to decline. A short‐lasting, marked elevation of blood pressure was produced by the ketamine anaesthesia. Two of the newborn showed low Apgar scores at 1 min. In one of them this was probably attributable to the anaesthesia.

Fate and microbiological effects of furazolidone in a marine aquaculture sediment

Furazolidone is used in the treatment of bacterial diseases in farmed fish. During application a large proportion of the administered drug reaches the environment directly or via feces. The persistence and metabolism of furazolidone in sediment from a Norwegian salmon farm is described. Furazolidone, in contrast to oxytetracycline and oxolinic acid, is actively metabolized by microorganisms in the sediment. The main metabolite is 3-(4-cyano-2-oxobutylidene-amino)-2-oxazolidone. This is a well known metabolite of the degradation of furazolidone in mammals, fish and Escherichia coli. 3-(4-Cyano-2-oxobutylideneamino)-2- oxazolidone had no detectable antibacterial activity. The half-life of furazolidone in the sediment at 4 degrees C was calculated to be 18 h.

Metabolism of Some Kava Pyrones in the Rat

1. The metabolism in rats of several kava pyrones from Piper methysticum Forst. was studied. The compounds were the 5,6-dihydro-alpha-pyrones, dihydrokawain, kawain and methysticin, and the alpha-pyrones, 7,8-dihyroyangonin and yangonin. 2. Approx. half the dose (400 mg/kg, p.o.) of dihydrokawain was found in the urine in 48 h. About two-thirds of this was hydroxylated metabolites (three mono- and three di-hydroxylated derivatives), of which p-hydroxydihydrokawain was the most abundant. The remaining third consisted of metabolites formed by scission of the 5,6-dihydro-alpha-pyrone ring and included hippuric acid (9--13% dose). 3. Lower amounts of urinary metabolites were excreted when kawain was given, but both hydroxylated and ring-opened products were formed. 4. Methysticin gave rise to only small amounts of two urinary metabolites formed by demethylenation of the methylenedioxyphenyl moiety. 5. Urinary metabolites of the alpha-pyrones, 7,8-dihydroxyangonin and yangonin, were formed via omicron-demethylation. No ring-opened products were detected. 6. These lipophilic kava pyrones have extremely low solubility in water, which would be expected to reduce their absorption rates and appears to be responsible for the variable and low extent of metabolism observed.

Leaching of organic additives from dentures in vivo

Samples of saliva were collected from subjects with dentures. These samples were collected both before the dentures were replaced and 1 week after the subjects had received their new dentures. Dibutylphthalate and phenyl benzoate were detected in the saliva samples with a gas-chromatography and a gas-chromatography/mass-spectrometry technique. We also quantified the dibutylphthalate in the saliva. In addition, in an in vitro study, we identified biphenyl leached from heat-cured denture base polymer plates. Our study suggests that subjects with dentures have higher contents of the above organic substances in saliva than subjects without dentures and that organic additives leach from new heat-cured dentures.

The Metabolism of Zingerone, a Pungent Principle of Ginger

1. The metabolism of 4-(4-hydroxy-3-methoxyphenyl)butan-2-one (zingerone), a pungent principle of ginger, has been investigated in rats. 2. Oral or intraperitoneal dosage (100mg/kg) of zingerone resulted in the urinary excretion of most metabolites within 24 h, mainly as glucuronide and/or sulphate conjugates. While zingerone itself accounted for roughly 50-55% of the dose, reduction to the corresponding carbinol (11-13%) also occurred. Side chain oxidation took place at all three available sites and oxidation at the 3-position, giving rise to C6-C2 metabolites, predominated. About 95-97% of the dose was accounted for. 3. Appreciable (40% in 12 h) biliary excretion occurred. Biliary studies and studies in vitro using caecal micro-organisms indicated that several O-demethylated metabolites found in the urine are of bacterial origin.

A qualitative and quantitative analysis of the sediment gas and diethylether extract of the sediment from salmon farms

Abstract A quantitative glc/ms analysis of the diethylether extract of the sediment under Norwegian salmon farms showed that in addition to numerous fatty acids, metabolites typical of anaerobic microbiological activity ( p -cresol, benzoic acid, 3-phenylpropionic acid, phenylacetic acid and methylindole) are present in large amounts. The gas developed in the sediment consisted of methane (70–90%), carbon dioxide (10–30%) and hydrogen sulfide (1–2%), when sampled just above the sediment. Even though H 2 S and CO 2 are very soluble in seawater, both were still present in the gas sampled 9 m above the bottom.

Leaching from denture base materials in vitro

Specimens made from denture base materials were leached in Ringer solution and in ethanol. The specimens comprised a heat-cured product processed in two different ways and two cold-cured materials. The organic compounds leaching from the specimens to the solutions were separated, identified, and quantified by a combined gas-chromatography and gas-chromatography/mass-spectrometry technique. Additives and degradation products, possibly made by free radical reactions, were released from the denture base materials. In Ringer solution only phthalates could be quantified. In ethanol solvent, biphenyl, dibutyl phthalate, dicyclohexyl phthalate, phenyl benzoate, and phenyl salicylate were quantified. In addition, copper was found in the ethanol solvent from one of the denture base materials. The amount of leachable organic compounds varies among different materials. Processing temperature influences the initial amount of leachable compounds.