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Biomedical subjects

P F Coville

Publications and source records attributed to P F Coville.

At least 19 recordsLinked to original sources
PubMed2002

Decreased hepatic drug metabolising enzyme activity in rats with nitrosamine-induced tumours.

N-Methyl N-benzyl nitrosamine (MBNA), which requires P450-dependant activation to be mutagenic, has been shown to produce squamous cell carcinoma of rat oesophagus. The aim of this study was to determine the effects of tumour induction on hepatic cytochrome P450 (CYP) and phase II enzyme activity. Female Wistar rats were given MBNA (2.5 mg/kg) by gavage, twice weekly for 12 weeks. At the end of 12 weeks they were sacrificed; livers and oesophagi were removed. The activity of hepatic CYP and phase II enzymes was determined by incubation of liver microsomes with appropriate CYP substrates. All rats receiving MBNA developed oesophageal lesions. Hepatic CYP1A2 activity (phenacetin 5 microM) in tumour-bearing rats was significantly decreased to 53% of the controls (p <0.05). CYP2E1 (p-nitrophenol hydroxylase), CYP2D (debrisoquine hydroxylase) and CYP3A (quinine hydroxylase) activity was significantly (p <0.05) reduced. Microsomal UDP-glucuronosyl transferase activity was also found to be markedly decreased while glutathione-S-transferase activity remained almost unchanged. Alteration of the activities of drug metabolising enzymes in rats with chemically induced tumours could be an important factor in determining resistance or susceptibility to xenobiotics and antitumour drugs.

Animals↗
PubMed2001

Tea consumption modulates hepatic drug metabolizing enzymes in Wistar rats.

The antioxidant, antimutagenic and anticarcinogenic activities of green tea and its polyphenols have been reported. As bioactivation of the precarcinogens and detoxification of ultimate carcinogens are mainly carried out by hepatic metabolizing enzymes, we have investigated the modulation of these enzyme activities subsequent to tea consumption in rats. Female Wistar rats were divided into eight groups (n = 5). Six groups were given aqueous solutions (2%, w/v) of six different teas (New Zealand green tea, Australian green tea, Java green tea, Dragon green tea, Gunpowder green tea or English Breakfast black tea) as the sole source of fluid. One group was given a standard green tea extract (0.5%, w/v) while the control group had free access to water. At the end of four-weeks treatment, different cytochrome P450 (CYP) isoform and phase II enzyme activities were determined by incubation of the liver microsomes or cytosols with appropriate substrates. CYP 1A2 activity was markedly increased in all the tea treatment groups (P < 0.05). CYP 1A1 activity was increased significantly in most of the groups except for the Madura, Gunpowder, and Java green tea-treatment groups. Cytosolic glutathione-S-transferase activity was significantly increased (P< 0.05) in the New Zealand, Gunpowder, and Java green tea-treatment groups. The microsomal UDP-glucuronosyl transferase activity remained unchanged or was moderately increased in most of the groups. The balance between the phase I carcinogen-activating enzymes and the phase II detoxifying enzymes could be important in determining the risk of developing chemically-induced cancer.

Administration, Oral↗
PubMed2000

Content of CYP3A4 inhibitors, naringin, naringenin and bergapten in grapefruit and grapefruit juice products.

The flavonoids, naringin and naringenin and the furanocoumarin, bergapten (5-methoxypsoralen), were detected in some fresh grapefruit and commercial grapefruit juices but were not detected in other fruit juices tested (orange; orange with apple base; dark grape; orange and mango with apple base; orange, peach, passion fruit juice). The contents of these three grapefruit constituents in commercial juice and fresh grapefruit varied from brand to brand and also from lot to lot. Juice was prepared from the fresh fruit via different methods (by hand, squeezer or blender). The naringin content, after hand-squeeze, ranged from 115 to 384 mg/l. With hand-squeeze juice production, bergapten was not detected (less than 0.5 mg/l) in two varieties of grapefruit, and naringenin was usually not in detectable levels (less than 2 mg/l) in three varieties. All three constituents were present in New Zealand grapefruit preparations (including juice by hand-squeeze) and different lots showed variation in content (1.5-, 2.3- and 4.7-fold for naringin, naringenin and bergapten, respectively). Differences in the concentrations of these three constituents, which have potential for drug interaction, may contribute to the variability in pharmacokinetics of CYP3A4 drugs and some contradictory results of drug interaction studies with grapefruit juice.

5-Methoxypsoralen↗
PubMed2000

Toxicological evaluation of New Zealand deer velvet powder. Part I: acute and subchronic oral toxicity studies in rats.

Potential toxic effects of acute and subchronic dosage regimens of deer velvet powder have been assessed in rats following OECD guidelines. In the acute study, rats of both sexes were exposed to a single dose of 2 g/kg body weight. There was no mortality or other signs of toxicity during 14 days' observation. Furthermore, no significant alteration either in relative organ weights or their histology was discernible at terminal autopsy. In the 90-day subchronic study, deer velvet was administered in 1 g/kg daily doses by gavage to rats. A control group of rats received water only. There was no effect on body weight, food consumption, clinical signs, haematology and most parameters of blood chemistry including carbohydrate metabolism, liver and kidney function. No significant differences were seen between the mean organ weights of the adrenal, kidney and brain in rats treated with deer velvet and control rats. However, there was a significant difference (P<0.05) in the group mean relative liver weight (3.52 +/- 0.30 vs 3.81 +/- 0.26 g/100 g body weight) of deer velvet-treated and control male rats. The gross necropsy and pathological examination of rats treated with deer velvet did not reveal any abnormalities in tissue morphology. Based on these results, it may be concluded that rats had no deer velvet treatment-related toxicological and histopathological abnormalities at the doses administered, despite the observed minor changes in liver weight.

Administration, Oral↗
PubMed2000

Effect of the grapefruit flavonoid naringin on pharmacokinetics of quinine in rats.

The effect of the grapefruit flavonoid naringin, an inhibitor of CYP3A4, on the pharmacokinetics of quinine in rats after oral or intravenous (i.v.) dosing of quinine was investigated. Female Wistar rats (wt 190-220 g) were used in two separate studies, i.e. oral and i.v. administration of quinine. The animals were divided into two groups, one served as control and the other group was pretreated with 25 mg/kg naringin once a day for 7 consecutive days before the pharmacokinetic study. On the study day, quinine (25 mg/kg) was administered to the rats by either the oral or i.v. route. Blood samples were collected at different times, up to 6 h after quinine administration. Plasma quinine concentration was assayed by HPLC. Pretreatment with naringin did not cause any significant change in the pharmacokinetics of quinine after the i.v. dose. However pretreatment with naringin led to a 208% increase in peak plasma concentration (Cmax), a 93% increase in time to reach Cmax (tmax), and a 152% increase in the area under the plasma concentration-time curve (AUC) of quinine after oral administration. Consequently, the oral bioavailability of quinine was significantly increased (p < 0.05) from 17% (control) to 42% after pretreatment with naringin. There was no significant difference in the elimination half-life (t(1/2)beta) of quinine between the two groups. These results suggest that pretreatment with the grapefruit flavonoid naringin is associated with increased oral bioavailability of quinine in rats.

Administration, Oral↗
PubMed1999

Grapefruit juice has no effect on quinine pharmacokinetics.

OBJECTIVE: As quinine is mainly metabolised by human liver CYP3A4 and grapefruit juice inhibits CYP3A4, the effect of grapefruit juice on the pharmacokinetics of quinine following a single oral dose of 600 mg quinine sulphate was investigated. METHODS: The study was carried out in ten healthy volunteers using a randomised cross-over design. Subjects were studied on three occasions, with a washout period of 2 weeks. During each period, subjects received a pretreatment of 200 ml orange juice (control), full-strength grapefruit juice or half-strength grapefruit juice twice daily for 5 days. On day 6, the subjects were given a single oral dose of 600 mg quinine sulphate with 200 ml of one of the juices. Plasma and urine samples for measurement of quinine and its major metabolite, 3-hydroxyquinine, were collected over a 48-h period and analysed by means of a high-performance liquid chromatography method. RESULTS: The intake of grapefruit juice did not significantly alter the oral pharmacokinetics of quinine. There were no significant differences among the three treatment periods with regard to pharmacokinetic parameters of quinine, including the peak plasma drug concentration (Cmax), the time to reach Cmax (tmax), the terminal elimination half-life (t1/2), the area under the concentration-time curve and the apparent oral clearance. The pharmacokinetics of the 3-hydroxyquinine metabolite were slightly changed when volunteers received grapefruit juice. The mean Cmax of the metabolite (0.25+/-0.09 mg l(-1), mean +/- SD) while subjects received full-strength grapefruit juice was significantly less than during the control period (0.31+/-0.06 mg l(-1), P < 0.05) and during the intake of half-strength grapefruit juice (0.31+/-0.07 mg l(-1), P < 0.05). CONCLUSION: These results suggest that there is no significant interaction between the parent compound quinine and grapefruit juice, so it is not necessary to advise patients against ingesting grapefruit juice at the same time that they take quinine. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut.

Antimalarials↗
PubMed1999

In vitro hepatic metabolism of a CYP3A-mediated drug, quinine, in Adélie penguins.

Very little is known about Antarctic animals' ability to metabolise or detoxify xenobiotics. The activity of cytochromes P450 subfamily 3A (CYP3A) in Adélie penguin liver was studied by incubating penguin liver microsomes with a human CYP3A substrate, quinine, and results were compared with those from human liver microsomes. The mean maximum rate of metabolism (Vmax) for quinine in penguin livers was approximately five times less (160+/-72 versus 574+/-416 pmol/mg/min; P<0.01), and the mean Km (substrate affinity) for the formation of quinine's major metabolite (3-hydroxyquinine) was significantly greater than that observed in human livers (160+/-73 versus 83+/-19 microM; P<0.01). The mean intrinsic clearance (Vmax/Km) was 1.1+/-0.4 microl/min (penguin), i.e. sevenfold less than in human livers (7.4+/-5.9 microl/min, P<0.005), suggesting that penguins have much less ability than humans to eliminate xenobiotics having a similar metabolic nature to quinine (i.e. CYP3A substrates). 3-Hydroxyquinine formation in penguin liver was inhibited by specific CYP3A inhibitors, midazolam and troleandomycin, but not by other CYP inhibitors, indicating that quinine metabolism to 3-hydroxyquinine in Adélie penguin liver is likely to be catalysed by a CYP isoform resembling human CYP3A. Adélie penguin liver CYP isoforms could serve as biomarkers for the impact of environmental pollution.

Animals↗
PubMed1998

Genetic polymorphism of debrisoquine (CYP2D6) and proguanil (CYP2C19) in South Pacific Polynesian populations.

OBJECTIVE: Genetic oxidation polymorphisms of debrisoquine (CYP2D6) and proguanil (CYP2C19) were studied in unrelated healthy South Pacific Polynesian volunteers recruited in the South Island of New Zealand. METHODS: Phenotyping for CYP2D6 and CYP2C19 activities was determined using debrisoquine and proguanil, respectively, as probe drugs by measuring the urinary metabolic ratio of parent drug and its metabolite. RESULTS: Of 100 Polynesian subjects phenotyped, the metabolic ratio of debrisoquine ranged from 0.01 to 9.94. Therefore, all South Pacific Polynesians were classified as extensive metabolizers of debrisoquine according to previously established criteria of the antimode. The prevalence of poor metabolizers of debrisoquine (CYP2D6) in this Polynesian population is 0% (95% confidence interval of 0-3.6%). Oxidation polymorphism of CYP2C19 using proguanil as a probe was also studied in 59 Polynesian volunteers. The frequency distribution of the proguanil/cycloguanil ratio was bimodal. The proguanil/cycloguanil ratios for these subjects ranged from 0.09 to 34.4. Using a recommended proguanil/cycloguanil ratio cut-off point of 10 established in Caucasian populations, eight Polynesian subjects were identified as poor metabolizers of proguanil (CYP2C19), which corresponds to a poor metabolizer phenotype frequency of 13.6% (a 95% confidence interval of 5.9-24.6%). CONCLUSION: The incidence of poor metabolizer phenotypes for debrisoquine (CYP2D6) in South Pacific Polynesians appears to lower than in Caucasian populations, while the prevalence of poor metabolizers for proguanil (CYP2C19) in this ethnic population is higher. The frequencies of the poor metabolizer phenotype for debrisoquine and also for proguanil in South Pacific Polynesians are similar to those reported in Asian populations.

Adolescent↗
PubMed1997

Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine.

AIMS: Our previous studies using in vitro hepatic microsomal preparations suggested that the hepatic metabolism of quinine to form the major metabolite 3-hydroxyquinine is most likely catalysed by human P450 3A (CYP3A). The present study was carried out to investigate the kinetics and to identify and further characterise the human liver CYP isoforms involved in the metabolism of quinine. METHODS: In vitro human microsomal techniques were employed. RESULTS: The mean apparent Km value for 3-hydroxyquinine formation was 83 +/- 19 (s.d.) microM, ranging from 57 microM to 123 microM in microsomes from ten human livers. There was a 6.7-fold variation in Vmax values (mean 547 +/- 416 pmol min-1 mg-1). Quinine 3-hydroxylation was inhibited by the specific CYP3A inhibitors, troleandomycin, midazolam and erythromycin. Inhibitors selective for CYP1A1/2, CYP2D6, CYP2E1, CYP2C9/10 or CYP2C19 had little or no effect on quinine 3-hydroxylation. Using microsomes from a panel of livers, significant correlations were found only between 3-hydroxyquinine activity and other CYP3A activities (caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) and immunoreactive CYP3A content. There were no statistically significant correlation with activities selective for CYP1A2, CYP2C9 and CYP2E1. Competitive inhibition of quinine 3-hydroxylation was observed with a substrate known to be specifically metabolized by human CYP3A, i.e. midazolam, with an apparent Ki value of 11.0 microM. CONCLUSIONS: The present results strongly indicate that the conversion of quinine to 3-hydroxyquinine is the major metabolic pathway in human liver in vitro and that the reaction is catalysed by CYP3A isoforms.

Antimalarials↗
PubMed1995

Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man.

The effect of rifampicin and isoniazid pretreatment on the pharmacokinetics of quinine after a single oral dose (600 mg quinine sulphate) was studied in nine healthy young Thai male volunteers using a three-way randomized crossover design. Subjects were studied over three 2 day periods, during which they received no pretreatment, or pretreatment with daily 600 mg p.o. rifampicin for 2 weeks, or isoniazid 300 mg p.o. daily for 1 week, prior to quinine administration. The mean (+/- s.d.) clearance (CL/F) of quinine coadministered with rifampicin (0.87 +/- 0.35 1 h-1 kg-1) was significantly greater than that of quinine alone (0.14 +/- 0.05 1 h-1 kg-1). The mean difference in clearance from the control treatment was 0.73 1 h-1 kg-1, with 95% confidence interval (C.I.) of 0.48 to 0.98. The unbound clearance (CLu/F) of quinine, which reflects the activity of the drug-metabolizing enzymes, was considerably greater (6.9-fold) in subjects when rifampicin was coadministered with quinine than that of quinine alone (6.9 +/- 3.6 vs 1.0 +/- 0.5 1 h-1 kg-1; the 95% C.I. for the mean difference was 3.3 to 8.5). The mean elimination half-life of quinine when coadministered with rifampicin (5.5 +/- 3.0 h) was significantly shorter than when quinine was given alone (11.1 +/- 3.0 h; the 95% C.I. for the mean difference was -8.6 to -2.6). In contrast to rifampicin, pretreatment for 1 week with 300 mg oral isoniazid had no significant effects on the pharmacokinetics of quinine.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Metabolism of quinine in man: identification of a major metabolite, and effects of smoking and rifampicin pretreatment.

Our previous studies have shown that cigarette smoking and rifampicin pretreatment enhance the elimination of quinine, metabolism assumed, by analogy with quinidine, to be carried out by CYP3A (P450IIIA). This finding is unexpected since it has been shown that smoking induces the CYP1A rather than the CYP3A enzyme family, suggesting that the metabolism of quinine may be catalysed by CYP1A. Therefore, we conducted this study to identify possible quinine metabolites in human urine and to determine which metabolic pathway is induced by cigarette smoking and rifampicin pretreatment. A specific HPLC procedure was employed to identify metabolites of quinine in urine samples collected from healthy volunteers after an oral dose of 600 mg quinine sulphate. The results showed that there were at least seven possible metabolites of quinine detected in human urine. Three of these were identified as 2'-oxoquininone, quinine glucuronide and 3-hydroxyquinine. The 3-hydroxyquinine appeared to be a major metabolite of quinine in urine samples from every subject who took an oral dose of quinine. Although cigarette smoking and rifampicin pretreatment were shown to cause a marked increase in the elimination of quinine there were no significant changes in the formation of 3-hydroxyquinine as measured in the urine samples. This suggests that the effects of smoking and rifampicin are more complicated than we expected and require further investigation.

Antimalarials↗
PubMed1993

Cigarette smoking enhances the elimination of quinine.

The pharmacokinetics of a single dose (600 mg) of quinine sulphate were examined in a group of non-smokers (n = 10) and in heavy cigarette smokers (n = 10). The mean (+/- s.d.) oral clearance of quinine in smokers (0.189 +/- 0.075 1 h(-1) kg(-1)) was significantly greater than in non-smokers (0.107 +/- 0.045 1 h(-1) kg(-1) , P < 0.01). The unbound clearance of quinine which reflects activity of the drug-metabolizing enzyme, was considerably greater (1.5-fold) in the smokers than in the non-smoker subjects. The mean elimination half-life of quinine in smokers was 7.5 +/- 1.4 (s.d.) h, significantly shorter (P < 0.005) than the mean value in non-smokers (12.0 +/- 3.1 h). These results suggest that cigarette smoking enhances the elimination of quinine. The clinical significance of these findings is unknown but they indicate the need for caution in the administration of quinine to patients who are heavy cigarette smokers.

Administration, Oral↗
PubMed1970

Influence of thyroid hormones on the sensitivity of cardiac and smooth muscle to biogenic amines and other drugs.

1. Rats and guinea-pigs were injected with 1-thyroxine or thyroidectomized. Sensitivity of isolated tissues and of the intact cardiovascular system to drugs was investigated.2. Thyroxine increased the sensitivity of the isolated perfused heart to noradrenaline, adrenaline, isoprenaline, acetylcholine and histamine.3. Thyroxine increased the sensitivity of the rat isolated uterus to noradrenaline, adrenaline, isoprenaline, acetylcholine, histamine and 5-hydroxytryptamine.4. In contrast, thyroxine decreased the sensitivity of the isolated ileum to acetylcholine, histamine and 5-hydroxytryptamine, but not to adrenaline.5. Thyroxine also decreased the sensitivity of the isolated aorta to noradrenaline, adrenaline, histamine and 5-hydroxytryptamine.6. In pithed rats, thyroxine potentiated pressor responses to (+)-amphetamine but not to noradrenaline or synephrine.7. In anaesthetized thyroxine-treated rats, blood pressure responses to (+)-amphetamine were potentiated while those to noradrenaline were unaltered. Responses to acetylcholine were increased, and the response to isoprenaline became purely pressor.8. Thyroxine-induced changes in the sensitivity of the isolated uterus and ileum to modification of the concentration of calcium in the physiological salt solution paralleled the changes in drug sensitivity of these tissues.9. In general, thyroidectomy produced the opposite effects to those of thyroxine.10. It is concluded that there is no specific interaction between thyroxine and sympathomimetic amines, the effect of thyroxine on drug sensitivity being non-specific.

Acetylcholine↗
PubMed1970

The effect of thyroid hormones on the action of some centrally acting drugs.

1. The effect of administration of thyroxine or thyroidectomy on the pharmacological action of (+)-amphetamine, caffeine, hexobarbitone and morphine was determined in rats or mice.2. Locomotor activity induced by (+)-amphetamine or caffeine was increased by hyperthyroidism and decreased by hypothyroidism.3. The LD50s of (+)-amphetamine and caffeine in hyperthyroid rats were 1/30 and 2/5 that of control rats. With each drug, the LD50 regression lines in hyperthyroid and control rats were not parallel, suggesting that hyperthyroidism modifies the mechanism of the toxic effects. Hypothyroidism reduced toxicity to (+)-amphetamine.4. Hexobarbitone sleeping time was prolonged in hyperthyroid male rats, but was shortened in hyperthyroid female rats. In control rats, sleeping time was approximately four times as long in females as it was in males. Ethinyloestradiol treatment and castration also prolonged sleeping time in male rats. No further prolongation was produced by combined administration of thyroxine and ethinyloestradiol, but thyroxine further prolonged the sleeping time of castrated rats indicating that its mode of action in producing these changes is not mediated via sex hormones.5. In contrast to rats, a sex difference in the duration of action of hexobarbitone was not found in mice. Thyroxine prolonged sleeping time equally in each sex.6. Analgesia induced by morphine in mice was unaffected by hyperthyroidism. No increase in sedative or ;Straub tail' activity could be detected, but toxicity was increased when higher doses of morphine were used.7. The mechanism by which thyroid hormones produce these changes in sensitivity to centrally acting drugs is discussed. It is suggested that the effects of thyroxine vary according to whether the mode of action of the drug or its metabolism is modified.

Analgesia↗