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Biomedical subjects

B C Foster

Publications and source records attributed to B C Foster.

At least 19 recordsLinked to original sources
PubMed2003

Phytochemical and biological analysis of skullcap (Scutellaria lateriflora L.): a medicinal plant with anxiolytic properties.

The phytochemistry and biological activity of Scutellaria lateriflora L. (American skullcap) which has been traditionally used as a sedative and to treat various nervous disorders such as anxiety was studied. In vivo animal behaviour trials were performed to test anxiolytic effects in rats orally administered S. laterifolia extracts. Significant increases in the number of entries into the center of an "open-field arena"; number of unprotected head dips, number of entries and the length of time spent on the open arms of the Elevated Plus-Maze were found. The identification and quantification of the flavonoid, baicalin in a 50% EtOH extract (40 mg/g) and its aglycone baicalein in a 95% EtOH extract (33 mg/g), as well as the amino acids GABA in H2O and EtOH extracts (approximately 1.6 mg/g) and glutamine in a H2O extract (31 mg/g), was performed using HPLC. These compounds may play a role in anxiolytic activity since baicalin and baicalein are known to bind to the benzodiazepine site of the GABAA receptor and since GABA is the main inhibitory neurotransmitter.

Administration, Oral↗
PubMed2003

In vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural products.

Spices, herbal and black teas, and soybean products were analyzed for their capacity to inhibit in vitro metabolism of drug marker substrates by human cytochrome P-450 (CYP) isoforms. Inhibition of drug metabolism was determined using aliquots or infusions from these products in a fluorescence-detection assay. Aliquots and infusions of all natural product categories inhibited 3A4 metabolism to some extent. Of the 26 aliquots from teas and spices further tested with 2C9, 2C19 and 2D6, many demonstrated significant inhibitory activity on the metabolism mediated by these isoforms. Black teas and herbal tea mixtures were generally more inhibitory than single-entity herbal teas. Spices and single-entity herbal teas showed species-specific isoform inhibition with sage, thyme, cloves, St John's Wort and goldenseal having the highest activity against several isoforms. Seven soybean varieties tested, as well as daidzein and genistein isolated from soybean, were found to inhibit 3A4-mediated metabolism. Genistein was found to inhibit 3A7- but not 3A5-mediated metabolism of the marker substrate. Assessment of the in vitro CYP inhibition potential for these natural products has important implications for predicting the likelihood of natural product-drug interactions if these products are taken concomitantly.

Chromatography, High Pressure Liquid↗
PubMed2000

An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures.

Serial dilutions of 21 commercial ethanolic herbal extracts and tinctures, and 13 related pure plant compounds have been analyzed for their in vitro cytochrome P450 3A4 (CYP3A4) inhibitory capability via a fluorometric microtitre plate assay. Roughly 75% of the commercial products and 50% of the pure compounds showed significant inhibition of CYP3A4 metabolite formation. For each herbal product and pure compound exhibiting dose-dependency, the inhibition values were used to generate median inhibitory concentration (IC50) curves using linear regression. Among the commercial extracts, Hydrastis canadensis (goldenseal), Hypericum perforatum (St. John's wort), and Uncaria tomentosa (cat's claw) had the lowest IC50 values at < 1% full strength, followed by Echinacea angustifolia roots, Trifolium pratense (wild cherry), Matricaria chamomilla (chamomile), and Glycyrrhiza glabra (licorice), which had IC50 values ranging from 1%-2% of full strength. Dillapiol, hypericin, and naringenin had the lowest IC50 values among the pure plant compounds at < 0.5 mM; dillapiol was the most potent inhibitor at 23.3 times the concentration of the positive CYP3A4 inhibitor ketoconazole. Utilizing high-throughput screening methodologies for assessing CYP3A4 inhibition by natural products has important implications for predicting the likelihood of potential herbal-drug interactions, as well as determining candidates for further in-depth analyses.

Cytochrome P-450 CYP3A↗
PubMed1999

Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients.

AIMS: The objective of the study was to determine the effect of multiple doses of rifampicin on the steady-state pharmacokinetics of zidovudine and its 5'-glucuronosyl (GZDV) and 3'-amino (AMT) metabolites. METHODS: Eight asymptomatic HIV-infected patients (seven male, one female) participated in this three-period longitudinal study. Each patient received zidovudine (200 mg every 8 h) for 14 days (period 1), followed by rifampicin (600 mg every 24 h) with zidovudine for 14 days (period 2), and then zidovudine alone for a further 14 days (period 3). Blood and urine samples were collected over 6 h on the last day of each period for measurements of zidovudine and GZDV by h.p.l.c.-u.v. and AMT by h.p.l.c.-m.s-m.s. RESULTS: Compared with zidovudine-alone values in period 1, 14 days of coadministration with rifampicin significantly increased zidovudine oral clearance (89%) and formation clearances to GZDV (100%) and AMT (82%). Correspondingly, there were decreases in maximum plasma concentration (43%), AUC (47%) and urine recovery (37%) of zidovudine. GZDV/zidovudine and AMT/zidovudine AUC ratios increased by 99% and 36%, respectively, despite a significant 29% decrease in AMT AUC. After stopping rifampicin for 14 days, values of these pharmacokinetic parameters returned to within 26% of baseline. Over the three periods AMT plasma levels were <18 ng ml-1 (n=6) and <40 ng ml-1 (n=2), and molar AMT/zidovudine AUC ratios ranged from 1.7% to 4.5%. CONCLUSIONS: Rifampicin induced zidovudine glucuronidation and amination pathways resulting in decreased plasma and urine exposures to zidovudine. AMT plasma exposure decreased because induction was more pronounced for the major GZDV metabolite. The magnitude of the residual inductive effect was minimal at 14 days after stopping rifampicin.

Adult↗
PubMed1997

CYP2D6-related oxidation polymorphism in a Canadian Inuit population.

The xenobiotic oxidation polymorphism associated with cytochrome P450 2D6 (CYP2D6) was investigated in 152 genetically related and unrelated healthy Inuit subjects living in the High Arctic of eastern Canada. Phenotyping was based on HPLC determination of the CYP2D6-related dextromethorphan metabolic ratio in overnight urine samples after oral administration of 30 mg dextromethorphan hydrobromide. The log metabolic ratio was bimodally distributed, with three subjects classified as poor metabolizers (PMs). In subjects unrelated in the first degree, the incidence of the PM phenotype was 3 of 90 or 3.3%. PCR-based analyses of DNA for variants of the CYP2D6 gene demonstrated that the PMs of dextromethorphan had the defective allele CYP2D6*4. The estimated frequency of the CYP2D6*4 allele was 0.067-0.083, which is lower than the frequency in Caucasians but higher than the frequency in Oriental populations. The CYP2D6*3 and the CYP2D6*6 alleles were not detected in the Inuit population. The CYP2D6*10 allele was present in only four unrelated subjects, classified as extensive metabolizers (EMs), resulting in an estimated allele frequency of 0.022, which is much lower than in Oriental populations. This study demonstrated the existence of the CYP2D6 polymorphism in Canadian Inuit, while the frequencies of allelic variants of CYP2D6 point to the uniqueness of this population. Several important therapeutic drugs that are being prescribed in Arctic communities will have altered pharmacokinetics in PMs of CYP2D6.

Adolescent↗
PubMed1996

CYP2C19 genotyping and associated mephenytoin hydroxylation polymorphism in a Canadian Inuit population.

The CYP2C19-associated oxidation polymorphism of mephenytoin was investigated in an Inuit population living in the high Arctic of Canada. Results were obtained for 152 subjects, of whom 90 were unrelated to first degree relatives. Phenotyping was based on the capillary gas chromatographic determination of the S/R enantiomeric ratio in overnight urine collected after a dose of 100 mg (R,S)-mephenytoin. The phenotype was confirmed by determining the S/R enantiomeric ratio after acid treatment of urine samples, and for some subjects, by determining urinary recovery of 4'-hydroxymephenytoin using capillary electrophoresis analysis. DNA was analysed for the m1 and m2 mutations of CYP2C19. Three of 152 subjects (2.0%; 95% confidence limits: 0.0-4.2%) were phenotypically classified as poor metabolizers (PMs). Genotype analysis characterized three individuals as homozygous, and 28 individuals as heterozygous for the m1 mutation, the remaining individuals being homozygous for the wild-type allele. The genotype of the three PMs was concordant with that of the phenotype. DNA fingerprinting confirmed that these three individuals were genetically unrelated. The allele frequency of the CYP2C19m1 mutation, determined in unrelated subjects, was 0.12 (95% confidence limits: 0.07-0.17). CYP2C19m2 was not detected in this population. Thus, the Canadian Inuit resemble Caucasian rather than Asian populations in both the incidence of PM phenotype and the molecular basis of the polymorphism.

Adolescent↗
PubMed1995

The influence of pregnancy on the biotransformation and urinary excretion of methoxyphenamine in mice.

(i) The urinary elimination of methoxyphenamine (MPA) and its metabolites in underivatized samples was examined after single and multiple oral administration to pregnant and non-pregnant mice by GLC and GLC-MS. (ii) The major metabolite O-desmethylmethoxyphenamine (ODMP), along with lesser amounts of N-desmethylmethoxyphenamine (NDMP) and 2-hydroxyamphetamine (2OH), were the only metabolites detected in urine extracts of pregnant and non-pregnant mice. 5-Hydroxymethoxyphenamine (5HMP) was not detected. Enzyme hydrolysis did not increase the recovery of either substrate or metabolites in either the pregnant or non-pregnant animals. The results show that MPA metabolism in the Swiss-Webster mouse is distinctly different from that seen in man and other laboratory animals. (iii) The mean MPA:ODMP ratio in day-6 urine from pregnant mice after a single dose was 0.31 +/- 0.04. The NDMP:ODMP ratios were less than 0.10 in all samples. Non-pregnant mice urine had equivalent amounts of MPA, NDMP, ODMP, and 2OH after multiple dosing. (iv) While multiple dosing and pregnancy did not alter either the urinary recovery or profile of the metabolites detected, there was a linear decrease in the MPA:ODMP ratio during gestation. (v) MPA was extensively metabolized to ODMP in the male mice, and the MPA:ODMP ratio of 0.41 was slightly higher than that observed in the pregnant and non-pregnant females.

Animals↗
PubMed1995

Metabolism of methoxyphenamine and 2-methoxyamphetamine in P4502D6-transfected cells and cell preparations.

1. Control and P4502D6-transfected human B-lymphoblastoid cell lines (cHol and h2D6v2 respectively) were used to study 2D6-mediated metabolism of methoxyphenamine (MPA) and 2-methoxyamphetamine (2MA). The main metabolites were products of O-dealkylation and aromatic hydroxylation at the 5-position. In addition, N-desmethyl-methoxyphenamine (NDMP) was also identified as a minor metabolite of MPA in extracts of these cells, confirming previous reports of 2D6-mediated N-demethylation of MPA. 2. An additional ring-hydroxylated metabolite of MPA and 2MA has been tentatively identified as the corresponding 3-hydroxy-2-methoxy derivative. 3. MPA metabolism in whole cells was time dependent, with approximately 30% of the MPA metabolized after 72 h. A 35% conversion of MPA was achieved on average with cell lysates. Only 18% 2MA was metabolized. By contrast, control cells (cHol) showed no evidence of any MPA or 2MA metabolites even after 96-h incubation. 4. Continuous presence of haemin/dimethylsulphoxide (DMSO) throughout the 4-day incubation with MPA resulted in a shift in the metabolite profile towards the production of NDMP at the expense of the other products. 5. In summary, h2D6v2 cells, lysates and microsomes can form all metabolites of MPA and can be used in drug interaction studies.

Amphetamines↗
PubMed1993

Biotransformation and urinary excretion of 4-substituted amphetamines in pregnant mice.

The urinary elimination of 4-hydroxyamphetamine (PHA) and a series of homologous 4-alkoxy-substituted amphetamines and their metabolites was examined after single and multiple oral administration to pregnant and non-pregnant mice. The metabolic profile and extent of biotransformation in a series of alkoxy analogues were affected by the size of the alkoxy side chain, multiple dosing and pregnancy. There were increased recoveries of both the substrate and the conjugated derivative of PHA during gestation. The major metabolic routes observed were O-dealkylation, conjugation, and aliphatic hydroxylation of the propoxy side chain. There was some evidence of oxidative deamination. Pregnancy did not alter the profile of the major metabolites detected by GLC and NMR spectroscopy.

Amphetamines↗
PubMed1992

In vitro assessment of cytotoxicity and biotransformation of propranolol in Cunninghamella echinulata.

1. Biotransformation studies with five concentrations of racemic propranolol were conducted using the filamentous fungus Cunninghamella echinulata ATCC 9244. 2. The rate of formation and subsequent disappearance of a new major metabolite, 8-hydroxypropranolol, was dose-dependent. Desisopropylpropranolol and 4-hydroxypropranolol were also formed. 4-Hydroxypropranolol was the major fungal metabolite in earlier studies. 3. Propranolol exerted a dose-dependent response on biotransformation, fungal growth, dextrose utilization, ammonia formation and incubation broth pH. Determination of dextrose utilization and incubation broth pH would provide reliable, cost-effective and convenient alternative methods for cytotoxicological evaluation.

Ammonia↗
PubMed1992

Biotransformation of tri-substituted methoxyamphetamines by Cunninghamella echinulata.

1. Four trimethoxyamphetamine analogues were incubated with the filamentous fungus Cunninghamella echinulata. 2. 2,4,5-Trimethoxyamphetamine and 2,5-dimethoxy-4-ethoxyamphetamine were poorly metabolized by C. echinulata ATCC 9244 and C. echinulata var. elegans ATCC 9245. 2,5-Dimethoxy-4-(n)-propoxyamphetamine was mainly metabolized through N-acetylation and O-dealkylation with minor amounts of several aliphatic hydroxylation metabolites formed. 2,5-Dimethoxy-4-methylthioamphetamine was extensively metabolized to the corresponding sulphoxide. 3. 2,5-Dimethoxy-4-methylthioamphetamine metabolism was inhibited by ethanol and quinidine. Sparteine did not inhibit the formation of the sulphoxide and may have shunted the substrate through alternate metabolic pathways. 4. Incubation conditions can affect the rate and extent of fungal biotransformation of 2,5-dimethoxy-4-methylthioamphetamine, and influence dextrose utilization, ammonia formation and pH.

Amphetamines↗
PubMed1991

The biotransformation of tranylcypromine by Cunninghamella echinulata.

When incubated alone for 7 days with the fungus Cunninghamella echinulata, tranylcypromine was extensively metabolized. As observed in mammalian systems, N-acetyltranylcypromine was the major metabolite recovered along with lesser amounts of 4-hydroxytranylcypromine, as its N,O-diacetyl derivative. The rate and extent of tranylcypromine biotransformation was affected by whether incubation was on either 30 degrees or flat brackets with a gyratory shaker. There is a strong association between the rate of biotransformation and the utilization of glucose, formation of ammonia, and pH. The slowest rates of biotransformation and metabolic response were observed with the large fungal pellets formed during incubation on flat brackets. These findings raise the possibility that, as in mammalian systems, fungal metabolism of xenobiotics can be affected by nutrient and environmental conditions.

Biotransformation↗
PubMed1991

Biotransformation of 2-, 3-, and 4-methoxy-amphetamines by Cunninghamella echinulata.

1. Three methoxyamphetamine analogues have been incubated with Cunninghamella echinulata under different environmental and nutrient conditions. 2. The biotransformation of 4-methoxyamphetamine was inhibited by cobalt; the carbon source and other trace metals had no effect. The rate of biotransformation of 4-methoxyamphetamine and formation of 4-hydroxyamphetamine was greater in cultures incubated on 30 degrees angle brackets rather than flat. 3. Carbon monoxide, ethanol and quinidine had a significant effect on methoxyamphetamine metabolism. 4. Metabolism was influenced by the position of the methoxy side-chain and substrate concentration. In day 7 samples the relative order for biotransformation was 3- greater than 4- greater than 2-methoxyamphetamine. 5. O-Demethylation was the major metabolic route in the biotransformation of 4-methoxyamphetamine but occurred to a lesser extent with 3-methoxyamphetamine, and was only a trace pathway with 2-methoxyamphetamine. N-acetylation was a trace pathway.

Amphetamines↗
PubMed1990

Dextran sulfate disposition in the rat.

Comparative studies of oral and intravenous administration of tritiated dextran sulfate in rats showed markedly different distribution patterns. Following IV dosing about 50 per cent of the radioactivity was recovered in feces and urine within 24 h. The major portion of the recoverable dose was eliminated in the urine as dextran sulfate within 3 h after administration. In orally treated rats only about 32 per cent of the 3H was recovered in the feces and urine, the major fraction being associated with unabsorbed dextran sulfate in the feces. The remainder of the dose in both treatment groups has apparently distributed throughout the rat body with some accumulation in the liver, kidney and spleen. Consequently, the disposition of about 67 per cent or the oral dose could not be fully accounted for by these excretion routes. However, separation with Sephadex columns showed similarities in the 24 h plasma and urine profiles of the IV and orally dosed rats which suggest that while the oral dose was absorbed as dextran sulfate, it underwent rapid metabolism to small molecular weight products prior to entering the systemic circulation which were then widely distributed within the rat.

Administration, Oral↗
PubMed1990

Fungal metabolism of 4-substituted amphetamines.

1. rac.-4-Ethoxyamphetamine was incubated with 14 different yeast and fungal microorganisms. 4-Hydroxyamphetamine was the major metabolite; traces of N-acetyl-4-ethoxyamphetamine were also detected. 2. The major fungal (Cunninghamella) metabolite of 4-propoxyamphetamine and 4-benzyloxyamphetamine was 4-hydroxyamphetamine. The major metabolites of 4-methoxyamphetamine were N-acetyl-4-methoxyamphetamine and 4-hydroxyamphetamine. 3. Acetoin derivatives were formed when alkoxyamphetamine substrates were incubated in the presence of various fungi and yeasts. 4. The findings indicate that Cunninghamella echinulata may be a useful microbial model for drug disposition and interaction studies.

Amphetamines↗
PubMed1989

Effect of sparteine and quinidine on the metabolism of methoxyphenamine by Cunninghamella bainieri.

1. The fungus C. bainieri, incubated for 7 days with methoxyphenamine alone or in combination with either sparteine or quinidine, gave N-desmethylmethoxyphenamine and its N-acetyl conjugate as major metabolites, while O-desmethylmethoxyphenamine, 5-hydroxymethoxyphenamine and 2-hydroxyamphetamine were produced in lesser amounts. In addition, 1-(2-hydroxyphenyl)-2-aminopropane, 1-hydroxy-1-(2-methoxyphenyl)-2-propanone, beta-hydroxymethoxyphenamine, and 1-(5-hydroxy-2-methoxyphenyl)-2-aminopropane were tentatively identified as minor components of the fungal biotransformation of methoxyphenamine. 2. As observed in mammalian systems, the addition of either sparteine or quinidine decreased the rate and extent of methoxyphenamine biotransformation. 3. C. bainieri may be a useful model for drug interaction studies.

Biotransformation↗
PubMed1989

Biotransformation of aryl alkylamines by Cunninghamella bainieri.

1. Incubations of phenylethylamine and 11 of its analogues with Cunninghamella bainieri have been performed. 2. Products of all major routes of mammalian metabolism including ring and aliphatic hydroxylation, oxidative deamination, N-oxidation, N-dealkylation, and conjugation were found in extracts of the fungal incubation broths. 3. Metabolism was influenced by the nature and degree of substitution.

Biotransformation↗