PubMed Health⌕ Search

Biomedical subjects

W P Gordon

Publications and source records attributed to W P Gordon.

At least 19 recordsLinked to original sources
PubMed1992

Disposition of 8-methyl-8-azabicyclo[3,2,1]octan-3-yl 3,5-dichlorobenzoate, a potent 5-hydroxytryptamine antagonist, and two metabolites in dogs and monkeys.

The disposition of 8-methyl-8-azabicyclo[3,2,1]octan-3-yl 3,5-dichlorobenzoate (MDL 72,222; 1), a potent 5-hydroxytryptamine antagonist, and its N-demethylated and N-oxide metabolites was studied in dogs and monkeys. After single, intravenous doses of 1 at 5 mg/kg, the mean terminal half-lives of 1 in plasma were 2.6 h in the dog and 3.8 h in the monkey. The mean half-life of the N-demethylated metabolite in dogs (approximately 20 h) was very similar to that in monkeys. However, the mean half-life of the N-oxide metabolite in dogs (10.8 h) was different from that in monkeys (3.9 h). The steady-state volume of distribution of 1 was 16 L/kg in dogs and 8.9 L/kg in monkeys. Examination of the mean residence times revealed that 1, in both species, and the N-oxide metabolite, in dogs, distributed to the peripheral tissue, whereas the distribution of the N-demethylated metabolite in both species and the N-oxide metabolite in monkeys was limited mainly to the systemic circulation. Compound 1 was metabolized extensively in both species. In dogs, 0.7, 2.5 and 40.6% of the administered dose were excreted in 0-120-h urine samples as 1 and its N-demethylated and N-oxide metabolites, respectively. In monkeys, however, the corresponding percentages were 0.8, 0.7, and 1.8%. Most of the administered dose in monkeys was excreted in urine as 3,5-dichlorobenzoic acid and its glycine conjugate.

Animals↗
PubMed1989

Quantitative metabolic profiling of valproic acid in humans using automated gas chromatographic/mass spectrometric techniques.

An automated gas chromatographic/mass spectrometric assay is described for the antiepileptic drug valproic acid (VPA) and 14 of its metabolites in plasma or urine. Quantitative analysis of the parent drug and its biotransformation products was carried out with the aid of trimethylsilyl derivatives, and was performed by selected ion monitoring gas chromatography/mass spectrometry (normally of [M-CH3]+ species) using an HP 5790 mass selective detector (MSD) quadrupole mass spectrometer. The analysis was fully automated, in that simple injection, data acquisition, integration, quantification and report functions were carried out during unattended operation by an HP 59970C ChemStation computer system. The method exhibits good accuracy and high precision, with correlation coefficients greater than 0.990 for all standard curves. Replicate analyses of pooled plasma samples over a 4 month period exhibited an inter-day variation of less than 15% for the parent drug and ten of its metabolites. Moreover, the high dynamic range of the MSD instrument permitted quantification of VPA and minor metabolites thereof (e.g. the hepatotoxic terminal olefin, delta 4-VPA) at levels as disparate as 260 micrograms ml-1 (VPA) and 14 ng ml-1 (delta 4-VPA) in a single analysis. The high stability and sensitivity of the assay, combined with the fully automated features of the instrumentation, make the method ideally suited to expanded clinical studies and for the routine monitoring of potentially high-risk patients on VPA therapy.

Gas Chromatography-Mass Spectrometry↗
PubMed1988

Carcinogenicity of deuterium-labeled 1,2-dimethylhydrazine in mice.

To study the effect of deuterium substitution on the carcinogenicity of 1,2-dimethylhydrazine (DMH) in mice, two comparisons were made between DMH and its fully methyl-deuterated analogue, [2H6]DMH. In a lifetime study with the CBA strain, groups of 19-30 animals of each sex were dosed s.c. weekly with 8 mg/kg of either DMH or [2H6]DMH for 8, 16, or 32 weeks. In the second study, female CF-1 mice were given DMH or [2H6]DMH in 10 weekly s.c. doses of 12 mg/kg each (13.2 mg/kg for [2H6]DMH) and examined for colon tumors 36 weeks after the first dose. Deuteration significantly decreased tumor incidence in the colon of males (P less than 0.01) and the anal tissue of both sexes (P less than 0.05) but increased that of hepatomas and lung tumors in males (P less than 0.01). Substrate deuteration did not significantly affect overall incidence of any other tumor type, however, including hemangioendotheliomas and kidney tumors in both sexes, as well as colon, uterine, ovarian, liver, and lung tumors in females. The results indicate that C--H bond breakage is kinetically important in the activation of DMH to its ultimately carcinogenic form in organs such as the male colon (relative risk in DMH-versus [2H6]DMH-treated animals approximately equal to 6), and that inhibition of this process by substrate deuteration allows a diversionary mechanism having a smaller isotope effect to become relatively more extensive. The qualitatively different effect in other organs (e.g., kidney, relative risk approximately equal to 1) supports recent suggestions that the net mechanism of activation can differ from one target tissue to another, possibly by striking a different balance between parallel metabolic pathways. The lack of a significant isotope effect on overall colon tumor incidence in females of either strain suggests that differences in relative importance among competing enzymes may also be responsible for sexual dimorphism in tumor induction by DMH.

1,2-Dimethylhydrazine↗
PubMed1987

Neurolinguistic characteristics of language production in Huntington's disease: a preliminary report.

Samples of spontaneous and descriptive speech were obtained from 12 patients with Huntington's disease (HD) and 24 at risk (AR) controls. The data were assessed according to a neurolinguistic protocol. HD was identified with a significant reduction in number of words produced, a diminished level of syntactic complexity, reductions of melodic line, phrase length, articulatory agility, and grammatical form, and increases in paraphasic errors and word-finding difficulty. The data were interpreted in support of the hypothesis that neostriatal pathology affects linguistic processing.

Aphasia↗
PubMed1987

Studies on the mechanism of acetamide hepatocarcinogenicity.

The hepatocarcinogen acetamide, in single doses of 100 and 400 mg/kg b.wt., was shown to act as an initiator in a dose-dependent fashion in rat liver using the Solt-Farber method. Acetamide and its putative metabolite N-hydroxy-acetamide did not cause liver necrosis in single dose experiments. Acetamide showed no evidence for genotoxicity in tests for mutations in Salmonella typhimurium, for DNA damage in rat hepatoma cells or for DNA repair in isolated rat hepatocytes. In contrast, N-hydroxy-acetamide displayed genotoxic activity in all 3 test systems. Neither acetamide nor N-hydroxy-acetamide induced transformation of primary Syrian hamster embryo cells or gave evidence of inhibition of metabolic cooperation in V79 cells. Radiolabelled acetamide and N-hydroxy-acetamide were not bound covalently to proteins in the presence of various metabolic activation systems (microsomes plus NADPH or xanthine/xanthine oxidase, cytosol or cytosol plus acetyl CoA or proline plus ATP). N-Hydroxy-acetamide was cytotoxic to monolayers of isolated hepatocytes at concentrations above 2.5 mM. This cytotoxicity was increased after diethyl maleate treatment, but N-hydroxy-acetamide did not deplete cellular glutathione. A HPLC system was developed for the separation and quantification of acetamide, N-hydroxy-acetamide and acetic acid. No significant excretion of N-hydroxy-acetamide or acetic acid in the urine could be demonstrated after treatment of rats with 100 or 1,000 mg/kg b.wt. of acetamide. The underlying mechanism for the observed initiating effect of acetamide is obscure.

Acetamides↗
PubMed1987

Studies on the metabolic fate of valproic acid in the rat using stable isotope techniques.

1. The metabolic fate of two specifically deuterated analogues of valproic acid (VPA), [2-2H1]VPA and [3,3-2H2]VPA, was studied in the rat following i.p. injection. 2. A total of 11 urinary metabolites of each labelled substrate were detected by g.l.c.-mass spectrometry. Those metabolites which resulted from oxidation of the drug at C-4 and/or C-5 retained the deuterium label(s), whereas products of oxidation at C-2 and/or C-3 exhibited varying degrees of deuterium loss. 3. The deuterium content of 3-hydroxy-VPA indicated that this metabolite has a dual origin, and arises in part by beta-oxidation of VPA and in part by direct hydroxylation at C-3. An apparent intramolecular isotope effect (kH/kD) of ca. 8 was associated with the latter process. 3-Oxo-VPA appeared to be formed mainly by oxidation of delta 2-VPA, rather than by oxidation of 3-hydroxy-VPA. 4. Evidence was obtained that delta 3-VPA is formed reversibly from delta 2-VPA, and that further desaturation of delta 3-VPA gives rise to a metabolite believed to have a 2,3'-diene structure. 5. The stable isotope method employed in this investigation represents a powerful technique for studies on the origin of drug metabolites and for the elucidation of complex metabolic inter-relationships in vivo.

Animals↗
PubMed1985

Procarbazine spermatogenesis toxicity: deuterium isotope effects point to regioselective metabolism in mice.

Procarbazine was shown to decrease spermatogenesis in male mice in a dose-dependent manner. Significant decreases (44% of controls) in spermatogenesis were observed when a dose of 400 mg/kg was administered 18 days prior to determination of sperm count. Procarbazine caused no significant acute spermatocidal activity in vivo. Procarbazine-associated decreases in spermatogenesis were thus used as an index of toxicity to developing spermatid cells. Procarbazine analogs were synthesized that had deuterium substituted for hydrogen at the benzylic position, N-isopropyl-alpha-(2-methylhydrazino)-p-[alpha, alpha-2H2]toluamide (d2-procarbazine), or at the methyl position, N-isopropyl-alpha-(2-[alpha, alpha, alpha-2H3]methylhydrazino)-p-toluamide (d3-procarbazine). Spermatogenesis decreases caused by d3-procarbazine were essentially the same as with procarbazine in mice (66% of controls at a dose of 200 mg/kg), but d2-procarbazine was nontoxic to developing sperm cells (99% of control at a dose of 200 mg/kg). The decrease in toxicity caused by deuterium substitution at the benzylic position, coupled with the absence of an effect with the methyl-labeled analog, indicate the requirement for regioselective oxidative metabolism of procarbazine at the benzylic position prior to the toxic event.

Animals↗
PubMed1985

The genotoxicity of 2-bromoacrolein and 2,3-dibromopropanal.

2-Bromoacrolein (2-BA) and 2,3-dibromopropanal (2,3-DBPA), an identified and a postulated reactive metabolite of tris(2,3-dibromopropyl)phosphate (Tris-BP), respectively, were found to cause mutations in Salmonella typhimurium TA 100 both in the absence and presence of a metabolic system. 2-BA, as well as 2,3-DBPA, caused extensive DNA single-stranded breaks as evidenced by alkaline elution of DNA from exposed Reuber hepatoma cells in culture. The data with Syrian hamster embryo cells suggest that both 2-BA and 2,3-DBPA were more potent than Tris-BP in transforming these cells in culture. On the other hand, neither 2-BA, nor 2,3-DBPA, was found to cause increased unscheduled DNA repair synthesis in isolated rat hepatocytes in monolayer cultures, whereas Tris-BP had a significant effect at low concentrations (10-50 microM). There was no correlation between the observed mutagenic effects of 2-BA and 2,3-DBPA and their alkylating activities using the nitrobenzyl-pyridine test. The genotoxic effects associated with 2-BA and its detection in microsomal incubations makes it a likely candidate for a role in the mutagenicity of Tris-BP.

Acrolein↗
PubMed1984

Metabolism in vitro of tris(2,3-dibromopropyl)-phosphate: oxidative debromination and bis(2,3-dibromopropyl)phosphate formation as correlates of mutagenicity and covalent protein binding.

Tris(2,3-dibromopropyl)phosphate (Tris-BP) was found to be metabolized by liver microsomes obtained from untreated and phenobarbital-pretreated rats. Metabolites of Tris-BP, whose formation was dependent on NADPH and oxygen, included bromide ion and bis(2,3-dibromopropyl)phosphate (Bis-BP). The rates of formation of these metabolites were markedly increased in liver microsomes isolated from phenobarbital-pretreated rats compared to microsomes from untreated rats. In the presence of either SKF 525-A or metyrapone, the formation rates of bromide ion and Bis-BP were decreased, whereas alpha-naphthoflavone had no effect. The effects of the various treatments on bromide release and Bis-BP formation paralleled those that have been previously observed with respect to the activation of Tris-BP to mutagenic and covalently protein bound metabolites. Furthermore, rates of oxidative debromination of several Tris-BP analogs directly correlated with their respective mutagenicities. Addition of glutathione (GSH) to microsomal incubations of Tris-BP increased bromide release substantially over control, values but had no effect on Bis-BP formation. On the other hand, the addition of GSH to microsomes decreased covalent binding and mutagenicity of Tris-BP with increased formation of water soluble metabolites. GC/MS analysis of ethyl acetate extracts from incubations of rat liver microsomes with Tris-BP identified 2-bromoacrolein (2-BA) as a metabolite. Introducing deuterium at the carbon atom number 1 of the propyl moiety of Tris-BP had no effect on either bromide release or mutagenicity, whereas the analog labelled at carbon atom 3 showed significant isotope effects on both activities. In contrast, deuterium substitution at carbon atom 2 gave a significant isotope effect on bromide release, but not on mutagenicity. The data indicate that Tris-BP can be metabolized by rat liver microsomes to Bis-BP and 2-bromoacrolein catalyzed by cytochrome P-450 in a process liberating bromide ions. Further, the results are consistent with oxidation at the terminal carbon atom of Tris-BP thereby forming 2-bromoacrolein, which is postulated to be the metabolite mainly responsible for Tris-BP mutagenicity.

Animals↗
PubMed1984

Activation mechanism of tris(2,3-dibromopropyl)phosphate to the potent mutagen, 2-bromoacrolein.

The potent mutagen 2- bromoacrolein is formed from the carcinogenic flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) on incubation with hepatic microsomes. Substitution of deuterium for hydrogen at the terminal carbon atoms (C-3) of Tris-BP significantly decreased both the mutagenic response and the formation rate of 2- bromoacrolein . Mass spectral analysis of the 2- bromoacrolein that was formed from the selectively deuterated analogs of Tris-BP revealed that the primary mechanism for the formation of 2- bromoacrolein involves an initial oxidative dehalogenation at C-3 followed by a beta-elimination reaction.

Acrolein↗
PubMed1984

Genotoxicity studies with paracetamol.

Paracetamol and its major ultimate reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) were studied for their genotoxic potential. Neither paracetamol nor NAPQI were found to cause mutations in Salmonella typhimurium, whereas NAPQI was severely cytotoxic to the bacteria. Radiolabelled paracetamol was found to bind covalently to DNA added to mouse-liver microsomal incubations at a rate of 2.6 pmoles/mg DNA/min. Paracetamol also bound covalently to hepatic DNA at a level of 15 pmoles/mg DNA after a hepatotoxic dose of paracetamol to mice. NAPQI caused extensive DNA single-strand breaks as evidenced by alkaline elution of DNA from treated Reuber hepatoma cells. This effect occurred at concentrations which later resulted in cytotoxicity. Paracetamol was shown to induce increased DNA-repair synthesis in isolated mouse-liver cells in monolayer culture, at concentrations where also cytotoxicity was evident. Increased DNA-repair synthesis occurred at lower paracetamol concentrations in cells isolated from mice pretreated with phenobarbital. Taken together, these data show that paracetamol can cause DNA interaction leading to damage at levels which are cytotoxic.

Acetaminophen↗
PubMed1983

Memory disorders in aphasia--I. Auditory immediate recall.

Vascular lesions within the territory of the left middle cerebral artery were identified by CT scans for 28 aphasic adults. When damage involved parts of Heschl's, middle temporal and superior temporal gyri or the inferior parietal lobule, immediate recall of binary sequences of either digits or tones was only 3 +/- 1 bits. Lesions to various loci were identified with primacy, recency, transposition, and isolated errors. The discussion considers various neural mechanisms subserving auditory immediate recall.

Acoustic Stimulation↗
PubMed1983

Mammalian drug metabolism.

Drugs and other chemicals that do not occur in mammalian systems are metabolized by a wide variety of enzymes. Reactions catalyzed by these enzymes have been classified into two general phases. Phase I reactions include oxidations, reductions, and hydrolyses, whereas Phase II reactions are broadly defined as conjugation reactions and include glucuronidation, sulfation, acylation, methylation, and conjugation with glutathione. The mechanisms of these biotransformations are outlined to demonstrate how both non-toxic and toxic metabolites are produced. The mammalian metabolism of acetaminophen, a widely used mild analgesic, and R-(+)-pulegone, the major constituent terpene of pennyroyal oil, will be discussed to illustrate specific features of mammalian drug metabolism.

Abortifacient Agents↗