Biomedical subjects

C Friis

Publications and source records attributed to C Friis.

At least 37 records · Page 2Linked to original sources

PubMed1998

Glucose uptake in Oesophagostomum dentatum and the effect of oxfendazole.

The uptake of 14C-glucose by adult Oesophagostomum dentatum was characterised. The uptake was a non-linear function of external glucose concentration. The maximum velocity of uptake (Vmax) was 0.964 nmol/100 mg dry weight (dw)/5 min, and the transport constant (Kt) was 10.02 microM. When phlorizin, phloretin and 3-O-methylglucose were tested for their effects on the uptake of 14C-glucose, phloretin and 3-O-methylglucose produced significant inhibitions, indicating that the uptake was mediated and occurred by facilitated diffusion. Exposure of the worms to oxfendazole prior to incubation with 14C-glucose did not affect the uptake of glucose. In another experiment worms were incubated with unlabelled glucose and the external glucose concentration was measured enzymatically. During a 7 h incubation period, the quantity of glucose remaining in the incubation medium of oxfendazole exposed worms was significantly greater than in the control group. It was concluded that oxfendazole did not influence the process of 14C-glucose uptake, but might induce changes in the parasite leading to a reduced ability to deplete the incubation medium of glucose.

3-O-Methylglucose↗

PubMed1998

Bioavailability of amoxycillin in pigs.

Amoxycillin was administered to pigs intravenously (i.v.), intramuscularly (i.m.) and orally (p.o.), in a cross-over design to examine the bioavailability (F) of various drug formulations. These included: a sodium salt for reconstitution in water and administration i.v.; trihydrate salt in an oil base for intramuscular administration producing 'conventional' duration of plasma concentrations; a trihydrate salt in oil base giving prolonged (LA) duration, and a trihydrate powder for oral administration in solution. The concentration of amoxycillin in plasma was measured by high-performance liquid chromatography, and its pharmacokinetic variables were assessed for the individual pigs by use of noncompartmental methods. Following i.v. administration (8.6 mg/kg), amoxycillin was eliminated rapidly with a mean residence time (MRT) of 1.4 h. After i.m. administration of the conventional formulation (14.7 mg/kg), the plasma amoxycillin concentration peaked at 2 h at 5.1 micrograms/mL. The bioavailability was 0.83. Intramuscular administration (14.1 mg/kg) of the long acting formulation (i.m. LA), lead to two peaks in plasma at 1.3 and 6.6 h. The bioavailability was calculated to be 1.11. After p.o. administration to fasted pigs, peak concentration was reached after 1.9 h, and the bioavailability was 0.33. In fed pigs, the corresponding values were 3.6 h and 0.28. Data showed that treatment of respiratory tract diseases in pigs by p.o. dosing alone, may not be optimal, because of the relatively low bioavailability and the fact that infections often result in reduced feed and water consumption. A rational treatment regime for susceptible respiratory pathogens includes an initial i.m. injection, followed by p.o. dosing every 12 h. Alternatively, the long acting formulation may be administered i.m. in a dose of 15 mg/kg, which would lead to active plasma concentrations for approximately 48 h.

Amoxicillin↗

PubMed1998

Water medication of a swine herd with amoxycillin.

A swine herd, consisting of 201 swine, was treated with amoxycillin. Amoxycillin was administered in the water system for 5 days, at a mean dose of 23 mg/kg body weight per day. Twice a day the water consumption was monitored, and blood samples collected from 10 randomly selected pigs. The plasma concentration of amoxycillin was measured by use of high performance liquid chromatography (HPLC). Three days after initiating amoxycillin treatment, the plasma concentration reached a constant level, at which it varied between a maximum of 1.3 micrograms/mL and a minimum of 0.5 microgram/mL. The plasma concentration was compared with a predicted curve based on pharmacokinetic variables obtained previously. The plasma concentrations were at the same level as the simulated ones. The minimum inhibitory concentration (MIC) values of the common respiratory pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida are about 0.1 microgram/mL. In pigs the distribution between bronchial mucosa and plasma (AUCmucosa/AUCplasma) is 0.3, which indicates a therapeutic plasma concentration of 0.3 microgram/mL. Data from the present study indicates that water medication with amoxycillin is effective as follow-up treatment.

Actinobacillus pleuropneumoniae↗

PubMed1998

Transport of paraquat by isolated renal proximal tubular segments from rabbits.

Paraquat is a non-selective herbicide, which induces lung, liver and kidney damage in mammalian species. Because paraquat is mainly eliminated by the kidneys, the induced kidney damage may suppress excretion and enhance toxicity of paraquat in other organs. Since proximal tubules appear to be the target segment of the nephron, this study focuses on transport of paraquat by isolated proximal tubular segments from rabbits. Proximal tubules were isolated using a combined magnetic iron perfusion and collagenase method. Incubations were carried out at 25 degrees under 100% oxygen or nitrogen for varying times at different concentrations of paraquat. Proximal tubules accumulated paraquat by a slow process, which was non-saturable in the concentration range (0.1-5 microM) examined. Tubular excretion of cations involves transport across both basolateral and luminal membranes of the cell. The basolateral uptake of paraquat was inhibited by low temperature, low medium pH and quinine. In contrast to quinine, tetraethylammonium enhanced paraquat accumulation probably by trans-stimulating the basolateral uptake. Incubation under nitrogen enhanced paraquat accumulation possibly by reducing the transport out of the cell at the luminal membrane. Thus, this study shows that proximal tubules accumulate paraquat by an active process related to the cation transport mechanism.

Animals↗

PubMed1997

Pig hepatocytes as an in vitro model to study the regulation of human CYP3A4: prediction of drug-drug interactions with 17 alpha-ethynylestradiol.

The objective of this study was to provide evidence of the validity of pig hepatocytes as a model to study the regulation of human CYP3A4 with special emphasis on drug-drug interactions. Thirteen different drugs were incubated with primary monolayer cultures of pig hepatocytes (n = 4). The study included both drugs reported to cause drug interactions in the clinic with 17 alpha-ethynylestradiol (EE2), other drugs metabolized by CYP3A4, and drugs not reported to cause any problems. Effect of the drug exposure to pig hepatocytes was determined by immunodetection using a monoclonal human CYP3A4 antibody and measurement of 6 beta-hydroxylation of testosterone and 2-hydroxylation of 17 alpha-ethynylestradiol (EE2), both reactions known to be catalyzed by CYP3A4 in humans. Data were compared to data from human hepatocytes and to reported observations of drug-drug interactions in the clinic. The drugs known to be inducers of CYP3A4 in humans significantly increased a CYP isoform in pigs catalyzing 6 beta-hydroxylation of testosterone and 2-hydroxylation of EE2, whereas drugs not reported to have clinical interactions with EE2 had no or only marginal effect. Induction by the drugs known to be inducers of CYP3A4 increased with drug exposure time and the CYP3A4 activity, represented by testosterone 6 beta-hydroxylation, was highest at 72 h for the investigated induction periods (24, 48 and 72 h), except for dexamethasone where the effect peaked after 24 h. Induction of the 2-hydroxylation of EE2 correlated well with the increase in 6 beta-hydroxylation of testosterone (except for sulphinpyranzone) and the increase in the protein level of CYP3A detected by a monoclonal human CYP3A4 antibody, thus confirming the 2-hydroxylation of EE2 in pigs as being biotransformed by a CYP isoform presumably belonging to the CYP3A subfamily as in humans. In conclusion, these results indicate that pig hepatocytes may be a valuable model to mimic the regulation of human CYP3A4.

Animals↗

PubMed1997

The cytotoxic effect of paraquat to isolated renal proximal tubular segments from rabbits.

Paraquat (PQ) induces lung, liver and kidney damage. Since PQ mainly is eliminated by the kidney, the kidney damage is of particular importance to the outcome of PQ poisoning. The exact toxic mechanism of PQ is still unclear but it is assumed to involve redox cycling and formation of reactive oxygen species. In this study, further investigations on the toxic mechanism and metabolic effects of PQ were performed using isolated renal proximal tubules from rabbits. Proximal tubules were isolated using a combined iron perfusion and collagenase method. Suspended tubules were incubated for varying periods and concentrations of PQ at 25 or 37 degrees C in Krebs-Ringer phosphate buffer or HCO3-/CO2 buffer. The cytotoxic effect of PQ was evaluated by (1) markers of oxidative stress: status of glutathione (GSH/GSSG) and formation of malondialdehyde (MDA); and (2) markers of tubular metabolism: oxygen consumption (QO2), transport of 14C-p-aminohippuric acid (PAH) and 14C-tetraethylammonium (TEA). Using 0.5 and 5 mM PQ, the GSH/GSSG ratio decreased whereas formation of MDA increased indicating oxidative stress. PQ reduced the accumulation of PAH and TEA, the basal QO2 and the ouabain sensitive QO2 indicating inhibition of the Na/K-ATPase. Nystatin-stimulated QO2 was reduced by PQ, excluding inhibition of Na+ entry as a possible cytotoxic mechanism and suggesting mitochondrial injury. This was confirmed by measuring FCCP-uncoupled QO2. Thus high concentrations of PQ appear to disrupt mitochondrial electron chain transfer resulting in reduction of metabolic functions.

Aminohippuric Acids↗

PubMed1997

A new in vitro assay of benzimidazole activity against adult Oesophagostomum dentatum.

A new in vitro assay of benzimidazole activity against adult Oesophagostomum dentatum is described. The method is based on the ability of O. dentatum to migrate through polyamide nets after exposure to various concentrations of benzimidazole. To determine an appropriate mesh size, control worms and worms exposed to 10 microM oxfendazole for 24 h were allowed to migrate through nets with various mesh sizes (300-500 microns) for up to 1 h. A mesh size of 350 microns and migration periods of 10, 20 and 30 min were selected. Exposure to oxfendazole at 10 microM for 24, 48 and 72 h inhibited the migration in a time-dependent manner. After 72 h of exposure and with a 20-min migration period, the EC50 of oxfendazole for O. dentatum was 0.564 microM. In further studies the activities of albendazole sulphoxide, albendazole, cambendazole, fenbendazole, flubendazole, luxabendazole, mebendazole, oxfendazole, oxibendazole, parbendazole and thiabendazole were compared. The worms were exposed to each drug at two concentrations (0.1 and 3.16 microM) for 72 h. At 3.16 microM there were no significant differences in the activity of the drugs. At 0.1 microM significant differences in activity were found. Albendazole sulphoxide and oxfendazole were poor inhibitors of migration compared with their parent compounds, albendazole and fenbendazole.

Animals↗

PubMed1997

Characterization of the P450 system in Göttingen minipigs.

It is essential to establish the activity and regulation of the cytochrome P450 system of species selected for toxicological and pharmacological studies. The minipig has become a popular substitute for the traditional non-rodent species although little information is available on its P450 system. The total P450 and the enzyme activity of the most important drug-metabolizing isoenzymes: CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 were measured in liver microsomes from 4 minipigs and 8 conventional pigs of both sexes. Immunochemical levels were determined for 4 of teh isoenzymes. The total P450 activity was slightly higher in minipigs compared to conventional pigs but no sex difference was detected. CYP1A2 activity (7-ethoxyresorufin) was 4 times higher in female minipigs than in male minipigs. The activity in male minipigs was almost identical to the activity in conventional pigs. The activity of CYP2E1 (chlorzoxazone) was 4 times higher in female than in male minipigs and 2 times higher in female than in male conventional pigs. No activity of CYP2D6 (debrisoquine) and CYP2C19 (mephenytoin) could be detected. The CYP3A4 activity (testosterone) detected in minipigs was higher than the activity in conventional pigs. A weak sex difference was seen in both strains. Western blotting using anti-human CYP2E1 and CYP3A4 confirmed the results obtained in the enzyme activity assays, while only CYP1A2 correlated with the activity in the conventional strain. The total P450 enzyme activity was close to the levels reported for human beings, as were the activities of CYP2E1 and CYP3A4.

Animals↗

PubMed1996

The kinetic disposition of pyrantel citrate and pamoate and their efficacy against pyrantel-resistant Oesophagostomum dentatum in pigs.

The pharmacokinetic disposition of pyrantel after intravenous (i.v.) and oral (p.o.) administration as the citrate and p.o. administration as the pamoate salt was determined in pigs. Following i.v. administration pyrantel was quickly cleared from the bloodstream, exhibiting a terminal half-life of 1.75 +/- 0.19 h and a residence time (MRT) of 2.54 +/- 0.27 h. After p.o. administration as the citrate salt, the absorption time (MAT) of pyrantel was 2.38 +/- 0.25 h and although significant quantities of pyrantel were absorbed (mean bioavailability of 41%) the rapid clearance resulted in a MRT of only 4.92 +/- 0.36 h. By comparison, the significantly extended MAT of the less soluble pamoate salt resulted in reduced circulating concentrations and a significantly lower mean bioavailability of 16%. The poor efficacy of pyrantel citrate against nematodes inhabiting the large intestine of pigs is therefore suggested to result from insufficient quantities of drug passaging to the site of infection. When tested against pyrantel-resistant adult Oesophagostomum dentatum the mean efficacy of pyrantel citrate was only 23%, whereas the efficacy of the lesser absorbed pyrantel pamoate was 75%. These results indicate that for maximum activity pyrantel should be administered to pigs as the pamoate salt.

Administration, Oral↗

PubMed1993

Disposition of 4-methylimidazole in goats and heifers.

4-Methylimidazole (MeI) is formed when hay is ammoniated and it has been suspected of being the compound causing the 'crazy cow' syndrome. The aim of the present study was to describe the disposition of MeI in goats and heifers. The mean residence time was about five hours and the volume of distribution 0.9 litre kg-1 bodyweight in both goats and heifers. Goats metabolised MeI to a much higher extent than heifers which excreted the major part as the unchanged compound. MeI and its metabolites were excreted mainly in urine, but also in milk and faeces. In spite of administration of a dose (20 mg kg-1 bodyweight) which is much higher than the one intoxicated animals may have received through contaminated fodder none of the typical signs of intoxication were observed and it is concluded that MeI may not alone be the cause of the 'crazy cow' syndrome.

Animals↗

PubMed1993

Penetration of danofloxacin into the respiratory tract tissues and secretions in calves.

Pharmacokinetic determinants of danofloxacin (1.25 mg/kg of body weight, IV) and its penetration into the respiratory tract tissues were studied in sixteen 4- to 6-week-old calves. The disposition curve was best described by an open 3-compartment model. Mean elimination half-life was 7.4 hours and the steady-state volume of distribution was 4.3 L/kg. The large volume of distribution was confirmed by a rapid and high penetration of the drug into respiratory tract tissues and secretions. In all structures (lung tissue, bronchial mucosa, bronchial secretions, and nasal secretions), danofloxacin concentration peaked 1 hour after drug administration. The area under the curve ratio for concentrations in tissue or secretions to concentrations in plasma was approximately 5 for lung tissue, 3 for bronchial mucosa, 0.85 for bronchial secretions, and 0.42 for nasal secretions. Protein binding of danofloxacin was 49% in plasma, 31% in bronchial secretions, and 14% in nasal secretions, resulting in consistently higher free danoflaxacin concentrations in bronchial secretions than in plasma. Accumulation of danofloxacin within bronchial mucosa and the high concentration of free drug in bronchial secretions suggested that an active process may be involved in the transport of danofloxacin across the airway epithelium. The dose of danofloxacin administered provided drug concentrations above the minimal inhibitory concentration of common respiratory pathogens for up to 12 hours in bronchial mucosa, up to 8 hours in bronchial secretions, and up to 4 hours in nasal secretions.

Aging↗

PubMed1991

Disposition of parathion in neonatal and young pigs.

Pharmacokinetics, metabolism (in vivo and in vitro), elimination and tissue distribution of 14C-parathion was studied after intravenous administration of 0.5 mg/kg to newborn, 1 week and 8 weeks old piglets. Body clearance increased from 7 ml/min./kg in newborn to 35 and 121 ml/min./kg in 1 and 8 weeks old piglets, respectively. Urinary excretion during the first 3 hr rose from 18 to 48 and 82% of the dose in newborn, 1 and 8 week old piglets. The main metabolite of parathion was p-nitrophenyl-glucuronide making up 85% of the urinary 14C excretion. About 6% was excreted as p-nitrophenyl-sulfate and only 1% as free (non-conjugated) p-nitrophenol. Unchanged parathion or paraoxon was not detectable in urine from any of the age groups. The in vitro experiments showed that biotransformation of parathion took place only when cofactors for oxidative reactions were present, indicating that oxidation is the first and necessary metabolic step and that hydrolysis does not contribute significantly to the elimination of parathion. The highest concentration of 14C 3 hr after administration was found in kidney and liver. In newborn piglets the 14C-concentration in tissues was higher than or equal to the plasma concentration. The 14C tissue/plasma ratio decreased with age for all tissues except kidney. Parathion was present in high concentrations in plasma, liver and kidney from newborn piglets, whereas the level just exceeded the detection limit in the 8 week old ones. Paraoxon was clearly detectable in plasma and liver from newborn piglets, while only traces were found in the older groups.

Animals↗

PubMed1991

Purification and characterization of hepatic microsomal cytochrome P-450 in phenobarbital- and beta-naphthoflavone-treated pigs.

Different cytochrome P-450 isoenzymes from hepatic microsomes of phenobarbital (PB) and beta-naphthoflavone (beta-NF) treated pigs and rats were isolated, purified, and characterized. The physico-chemical properties of the porcine isoenzymes were similar to properties of forms isolated from other species. The molecular sizes ranged from 52.5 to 59.5 kD and, in the ferrous-carbonyl state, the isoenzymes had absorbance maxima between 447 and 451 nm. Antigenic similarities were found between the isoenzymes present in PB-induced pigs, and between the isoenzymes present in beta-NF-induced pigs. Cross-reactivity was not observed between PB- and beta-NF-inducible isoenzymes, but beta-NF-inducible isoenzymes in pigs and rats possessed antigenic similarities.

Animals↗

PubMed1991

Respiratory tract distribution and bioavailability of spiramycin in calves.

Pharmacokinetic determinants of spiramycin and its distribution into the respiratory tract were studied in 2 groups of calves, 4 to 10 weeks old. Group-A calves (n = 4) were used to determine pharmacokinetic variables of spiramycin after IV (15 and 30 mg/kg of body weight) and oral administrations of the drug (30 mg/kg) and to measure distribution of spiramycin into nasal and bronchial secretions. Group-B calves (n = 4) were used to determine distribution of spiramycin into lung tissue and bronchial mucosa. Spiramycin disposition was best described by use of an open 3-compartment model. Mean (+/- SD) elimination half-life was 28.7 +/- 12.3 hours, and steady-state volume of distribution was 23.5 +/- 6.0 L/kg. Bio-availability after oral administration was 4 +/- 3%. High and persistent concentrations of spiramycin were achieved in the respiratory tract tissues and fluids. Tissue-to-plasma concentration ratio was 58 for lung tissue and 18 for bronchial mucosa at 3 hours after spiramycin administration and 137 and 49, respectively at 24 hours. Secretion-to-plasma concentration ratio was 4 for nasal secretions and 7 for bronchial secretions, and remained almost constant with time. Thus, spiramycin penetrates well into the respiratory tract, although the value in bronchial secretions is lower than that in lung tissues and bronchial mucosa. Calculations indicate that a loading dose of 45 mg/kg, administered IV, followed by a maintenance dose of 20 mg/kg, IV, once daily is required to maintain active concentrations of spiramycin against bovine pathogens in bronchial secretions.

Animals↗

PubMed1988

Uptake of ochratoxin A by slices of pig kidney cortex.

Ochratoxin A (OCT A) is a nephrotoxin causing selective necrosis of the proximal tubule. Being an organic anion OCT A might be expected to enter the tubule cells by the organic anion transport system. Pig renal cortical slices were used to characterize the OCT A transport. OCT A (5 X 10(-3) mM) was accumulated against a concentration gradient with a slice to medium ratio of 8.9 +/- 2.9 in the presence of oxygen. This accumulation was markedly reduced in a nitrogen atmosphere (S/M ratio = 2.9 +/- 0.5). OCT A accumulation was dependent on medium concentration. With increasing concentration (5 X 10(-4)-5 X 10(-1) mM), slice to medium ratio initially rose from 6.9 +/- 2.0 to 11.7 +/- 1.2 whereupon it declined to 5.4 +/- 1.1. This pattern indicates that both carrier mediated transport and intracellular metabolism may contribute to the net accumulation of the toxin. OCT A (10(-4) to 1 mM) inhibited p-aminohippurate (PAH) and phenolsulphophthalein (PSP) uptake in a dose-dependent manner. Up to 10(-1) mM, OCT A did not inhibit acetylation of PAH suggesting that aerobic metabolism and the energy supply for the transport process were unaffected. Kinetic studies revealed a competitive inhibition of the PSP transport. It is concluded that OCT A enters the proximal tubule cells by the common organic anion transport system.

Animals↗

PubMed1986

Metabolism of sulfadiazine in neonatal and young pigs. Comparative in vivo and in vitro studies.

Metabolism of sulfadiazine (SDZ) was studied in vivo and in vitro during postnatal development of piglets in order to examine whether in vitro metabolism approaches the in vivo situation. Experiments were performed in 1-day-, 8-day- and 60-day-old piglets. In vivo: 14C-SDZ was injected intravenously and urine and tissue samples collected after 3 hr. Urinary excretion data as well as data from liver and kidney tissue indicated a relatively high capacity for acetylation at birth, while the capacity for oxidation is low during the first week of life. At 60 days of age the acetylation and oxidation of SDZ is equal each accounting for about 20% of the amount excreted in urine. In vitro: Incubation of subcellular fractions of liver and kidney showed that acetylation of SDZ in liver reached maximum within 1 week. Oxidative activity was absent at 1 day, present at a low level at day 8, and at a high level at day 60. Neither acetylation nor oxidation of SDZ took place in kidney. The results show a close correlation between in vivo and in vitro results with respect to the developmental pattern seen in piglets during the postnatal period of life.

Acetylation↗

PubMed1984

Pharmacokinetics and metabolism of sulphadiazine in neonatal and young pigs.

The pharmacokinetics of sulphadiazine was studied in newborn, 1 week, and 8 weeks old piglets after intravenous administration of 60 mg/kg. Kinetic parameters were calculated using a two compartment open model. Steady state volume of distribution averaged 0.62, 0.56, and 0.48 1/kg at birth, 1 week, and 8 weeks, respectively. Elimination half-life decreased from 455 min. at birth to 322 min. at 1 week and 157 min. at 8 weeks leading to a rise in body clearance from 0.99 to 2.20 ml/min./kg during the same age period. Urinary excretion data indicated that the increase in body clearance reflects maturational changes in both renal function and metabolic capacity. Although renal clearance increased several times more than metabolic clearance, metabolism remained the main contributor to elimination of SDZ at all ages. Metabolism of SDZ involves two important pathways - acetylation and aromatic hydroxylation; the former being well developed at birth, while the latter increased markedly during the age period studied.

Acetylation↗

PubMed1984

Metabolism of trimethoprim in neonatal and young pigs: comparative in vivo and in vitro studies.

Metabolism of trimethoprim (TMP) was investigated in in vivo and in vitro experiments on 1 day (group A), 8 days (group B), and 60 days (group C) old piglets. In the in vivo studies piglets received an intravenous injection of 14C-trimethoprim. Urine was then collected for 3 hours after which the animals were killed. During the collection period 13, 24, and 40% of the dose was excreted in the urine in group A, B, and C, respectively. Trimethoprim and the following metabolites: Metabolite 1 and 4, minor metabolites, and conjugates were determined in plasma, liver, kidney, urine, and bile. The results show that newborn piglets have little capacity for oxidation of TMP while the ability to conjugate with glucuronic acid and sulfate seems somewhat higher. During the following 8 weeks a marked increase in the oxidative as well as conjugative potential took place. The microsomal fractions of liver and kidney were used for the in vitro metabolism studies of TMP. No metabolic activity could be demonstrated in the kidney preparations. Oxidative demethylation was just detectable in livers from the newborn piglets but increased considerably with age. Glucuronidation of metabolite 4 took place in the liver preparations from all three groups but at the highest rate in group C. The development in metabolic capacity was found to be qualitatively similar in vivo and in vitro.

Aging↗