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Biomedical subjects

M Bonati

Publications and source records attributed to M Bonati.

At least 91 records · Page 5Linked to original sources
PubMed1990

In vivo and perfused liver caffeine kinetics in the rat.

The kinetics of caffeine (1,3,7-TMX) was investigated in male rats given four different doses (1, 2.5, 10 and 25 mg/kg), comparing the patterns found in vivo and after liver perfusion. The same animals were used in both experimental conditions in order to reduce the variability of the caffeine profile. For doses less than 10 mg/kg or mg/L, caffeine blood or perfusate concentrations/time profiles followed first-order kinetics and the elimination rate constant (average 0.013 min-1) and half-life (55 min) were similar for the in vivo and ex vivo conditions. After larger doses (10 and 25 mg/kg or mg/L), kinetics were nonlinear. The area under the blood or medium concentration-time curve increased, but not in proportion to the dose, and modifications of pharmacokinetic parameters were observed, with significant differences for t 1/2 and CL after 10 and 25 mg/kg or mg/L, due to dose-dependent elimination of caffeine at these doses (Km of 8.3 and 7.8 micrograms/ml in vivo and in vitro, respectively). The two different approaches gave close kinetic estimates in vivo and in vitro. Thus, under standardized conditions, the isolated perfused liver technique is a useful tool for studying the kinetics of drugs eliminated by hepatic metabolism.

Animals↗
PubMed1989

Placental transfer and tissue distribution of thiopental in the pregnant rat.

The pharmacokinetic profile of thiopental was studied in pregnant rats after an iv bolus dose of 15 mg/kg. The unbound concentration-time profile of the drug in maternal plasma, placenta, fetal brain, fetal carcass, and amniotic fluid was described, developing an adequate pharmacokinetic model. Maternal plasma levels of thiopental fell rapidly after injection, distributing into tissues (half-life of distribution phase averaged 3 min). Thiopental crossed the placenta and entered the fetal body (brain included) and amniotic fluid. Peak levels were seen within 10 min of injection and declined in all tissues parallel to maternal plasma (rate constant range 0.012-0.017 min-1). The concentrations of drug in the fetal unit were smaller than in the central compartment and maternal plasma. However, the absolute transfer ratios (calculated using the pharmacokinetic parameters obtained from the model) and the relative exposure ratios (as the ratio of the area under the unbound concentration-time curve in tissue to that in maternal plasma) suggested that fetuses were exposed to a potentially efficacious level of the drug. The model formulated to describe the tissue distribution of thiopental may offer a useful approach for analysis of the kinetic profile of other compounds administered during pregnancy or at delivery in rats and other species.

Amniotic Fluid↗
PubMed1989

Bioavailability of intramuscular vitamin E acetate in rabbits.

The bioavailability of alpha-tocopherol acetate and alpha-tocopherol (vitamin E) was assessed in male rabbits given 50 mg kg-1 doses according to a randomized design. After intramuscular injection of alpha-tocopherol acetate in colloidal aqueous solution, a mean absolute bioavailability of 65% was calculated for the acetate and 35% for the physiologically active compound, alpha-tocopherol. Comparison of the kinetic profiles after intravenous and intramuscular administration of the acetate and intravenous injection of alpha-tocopherol, revealed absorption of alpha-tocopherol acetate from the site of injection and hydrolysis of the acetate to be potential limiting steps in the bioavailability of alpha-tocopherol. Intramuscularly injected alpha-tocopherol acetate in olive oil (the only formulation available in a few European countries) proved completely bio-unavailable. It thus appears necessary to re-assess the utility of current vitamin E supplementation, since the only formulations available offer poor bioavailability.

Animals↗
PubMed1989

In-vitro plasma protein binding of propafenone and protein profile in eight mammalian species.

The protein binding of propafenone in vitro was assessed in plasma of mouse, rat, rabbit, dog, sheep, man, cow, and horse at two concentration levels. In all species and at both concentrations propafenone was found highly bound (86-99%) to plasma proteins. No significant relationship was found between free propafenone and the plasma protein fractions. A concentration-dependency was seen in plasma of mouse, sheep, man, and horse, in which the free fraction of propafenone became larger on raising the concentration. Qualitative and quantitative differences were observed in the protein plasma profile of studied species. The protein plasma profile and propafenone concentration may affect the free fraction of the drug to different extents in different species. Thus the pharmacological activity of propafenone may be different in different species even at the same propafenone plasma concentration.

Animals↗
PubMed1989

Hematology and serum chemistry values of adult, pregnant and newborn New Zealand rabbits (Oryctolagus cuniculus).

Hematological and serum chemistry values were determined in adult female and pregnant New Zealand rabbits (Oryctolagus cuniculus) and their newborn at delivery. No significant difference was found between adult and pregnant hematological profiles. In the newborn, RBC were significantly lower and WBC, MCV and MCH higher than in their mother and adults. A characteristic protein profile was observed for the serum of each animal group, as well as for amniotic fluid. Lipoprotein pattern of the newborn was close to that of the dam, which differed from the adult female rabbit profile. The serum biochemical patterns are close to those of humans, suggesting that the New Zealand rabbit could be a reliable animal model for studies in the perinatal field involving monitoring of selected variables.

Animals↗
PubMed1988

Pharmacokinetic profile and metabolism of N-nitrosobutyl-(4-hydroxybutyl)amine in rats.

N-Nitrosodibutylamine and its omega-hydroxylated metabolite N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) induce tumors in the urine bladder of different animal species through their common urinary metabolite N-nitrosobutyl(3-carboxypropyl)amine (NB3CPA), resulting from the oxidation of the alcoholic group of NB4HBA to a carboxylic group. NB4HBA disappearance from blood, the formation of its main metabolites, NB3CPA and NB4HBA-glucuronide (NB4HBA-G), and their urinary excretion, were investigated in rats after an i.v. dose of 1 mg/kg (5.7 mumol/kg). NB3CPA and NB4HBA-G formation was readily detectable 2 min after treatment and levels were still measurable at 120 and 30 min, respectively. The parent compound disappeared from blood 90 min after injection. The NB4HBA blood concentration-time profile was adequately described by a one-compartmental linear model. NB4HBA half-life was 8 min, total body clearance and renal clearance were 86.1 and 0.22 ml/min/kg, respectively. The 0-96-h urinary excretion of NB4HBA was 0.3% of the administered dose. NB3CPA half-life was 15 min; NB3CPA and NB4HBA-G urinary excretion were 36 and 11.7%, respectively, urinary excretion of known compounds accounting for less than 50%. After i.v. injection of NB3CPA equimolar to the NB4HBA dose, only 50% of unchanged compound was recovered in the urine and after NB4HBA-G, 41% of the administered dose was excreted unchanged, NB3CPA accounting for 10%. Thus NB3CPA and NB4HBA-G might undergo further biotransformation, suggesting that NB3CPA may not be the ultimate carcinogen responsible for urinary bladder tumor induction.

Animals↗
PubMed1988

Information on drug use in pregnancy from the Viewpoint Regional Drug Information Centre.

The need for information on drug use during pregnancy was assessed by reviewing the requests for information arriving at a drug information centre in the past nine years. Of all the queries received 24% concerned this aspect, of which the majority were focused on drug use during pregnancy. Mothers received an average of 2.6 prescriptions, most frequently for antiinfectives, psychotropics, hormones and non-narcotic analgesics. Questions were answered personally after a literature search. A profile of questions and a summary of model cases registered in the archives of the centre are reported. The evaluation confirmed the need for and value of a drug information service in relation to pregnancy, so as to avoid alarmist and falsely reassuring attitudes in a field where knowledge is often based on scanty information.

Drug Information Services↗
PubMed1988

Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia.

Conjugated estrogens have a significant and long-lasting effect in shortening bleeding time in patients with end-stage renal disease. The studies so far available indicate that repeated estrogen administrations are necessary to short bleeding time in uremia in a dose range of 95 to 325 mg. With the present study we wanted to establish whether single or repeated doses are required to induce a significant shortening of bleeding time in uremia, and the minimum cumulative dose of conjugated estrogens necessary to control bleeding time for a prolonged period of time, and to check whether the prolonged effect of estrogens on bleeding time in uremia is due to an accumulation of the drug or its metabolites in the blood. Fifteen uremics on chronic hemodialysis were studied. A pilot study carried out in five uremic patients indicated that single or repeated estrogen infusions of 0.3 mg/kg did not significantly influence bleeding time values. Therefore the subsequent studies have been carried out using daily infusion of 0.6 mg/kg. A single estrogen infusion of 0.6 mg/kg shortened bleeding time in all patients. The effect was transient and bleeding time returned to pre-infusion values within 72 hours. A 50% decrease of bleeding time or a shortening of bleeding time more than 30 to 15 minutes or less was obtained in all patients with four or five infusions (0.6 mg/kg) spaced 24 hours apart. The effect lasted for 14 days. At day 25 from the last infusion all the patients had bleeding time values comparable with the pre-infusion ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Pharmacokinetics of a single intravenous dose of teicoplanin in subjects with various degrees of renal impairment.

The pharmacokinetic profile of teicoplanin after single 3 mg/kg doses in adults with different degrees of renal failure was reviewed. The disposition of teicoplanin was adequately described by a three-compartment open pharmacokinetic model and it appears to be primarily related to the degree of renal function. Teicoplanin total body clearance was less and the terminal elimination half-life progressively prolonged in association with renal failure, but the volume of distribution at steady-state did not change. Highly significant relationships between teicoplanin total body and renal clearance and creatinine clearance have been reported and serve as a basis for adjusting dosage in patients with renal failure. In patients on continuous ambulatory peritoneal dialysis teicoplanin, administered either intravenously or intraperitoneally, showed bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid was consistently low. Haemodialysis made no significant contribution to total body clearance of teicoplanin. Guidelines for administration of teicoplanin in patients with renal failure are discussed.

Adult↗
PubMed1988

Pharmacokinetics of intraperitoneal teicoplanin in patients with chronic renal failure on continuous ambulatory peritoneal dialysis.

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, is described in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). A single 3 mg kg-1 dose was given intraperitoneally in the dialysate during a 6 h dwell time. The drug appeared in the plasma within 15 min at 1.00-0.28 mg l-1 (mean +/- s.d. = 0.70 +/- 0.45) in all five subjects, and peak serum concentrations ranged from 5.53 to 2.80 mg l-1 (4.84 +/- 1.43) at 6 h. Approximately 70% (71 +/- 12) of teicoplanin was absorbed from the peritoneal dialysis fluid during a single 6 h dwell time. The rate constant for peritoneal transfer (lambda d) averaged 0.318 h-1 and the half-life (t1/2 lambda d) was 2.18 h. Further values were serum elimination half-life 114-173 h; total body clearance 263-532 ml h-1; steady-state volume of distribution 68-93 l. This drug profile closely agrees with data reported after intravenous injection in patients on CAPD and suggests that teicoplanin has bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid is consistently low. Instillation of teicoplanin in CAPD fluid may be a useful route of administration for treatment of peritonitis and exit site infections in CAPD patients.

Aged↗
PubMed1987

Metabolism of caffeine to 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil in the isolated, perfused liver from control or phenobarbital-, beta-naphthoflavone- and 3-methylcholanthrene-pretreated rats.

Caffeine metabolism to 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil was studied in the isolated, perfused rat liver. The [2-14C]-labelled drug and metabolites were separated by thin-layer chromatography or high-pressure liquid chromatography. The chemical structure of 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil was confirmed by mass spectrometry and it was quantitatively determined by liquid scintillation counting. 6-Amino-5-[N-methylformylamino]-1,3-dimethyluracil is one of the major metabolites of caffeine found in the perfusion medium. The kinetics of caffeine elimination and of the uracil metabolite formation were studied up to 2 h perfusion time using livers from control rats and rats pretreated with phenobarbital, beta-naphthoflavone or 3-methylcholanthrene. Phenobarbital pretreatment did not modify the rate of caffeine elimination or the extent of 6-amino-5-[N-methylformylamino]-1,3-dimethyluracil formation. In contrast, there was a highly significant inducing effect on both drug elimination and formation of the uracil metabolite in perfusions of livers from beta-naphthoflavone- and 3-methylcholanthrene-pretreated animals.

Animals↗
PubMed1987

Reversed-phase high-performance liquid chromatography determination of cyclosporin in human blood.

A high-performance liquid chromatographic (HPLC) method for determination of cyclosporin A (CyA) in blood, using cyclosporin D (CyD) as internal standard, is described. The method is specific, precise, reproducible, accurate, and isocratic, and it requires no derivatization. It is more rapid than previously described methods. Its detection limit is 25 ng/ml, suitable for quantitation of the drug at clinically observed concentrations. No interference was found by any of the other commonly coadministered drugs tested. Comparison of measurements in patients' blood with radioimmunoassay (RIA) results showed lower estimates by the chromatographic technique. Because measurements of the drug in blood banks spiked with pure CyA were similar with the two techniques, the nonspecificity of RIA, probably related to cyclosporin metabolites, was demonstrated. Because the chromatographic technique is simple, it should be preferred to RIA in therapeutic drug monitoring.

Chromatography, High Pressure Liquid↗
PubMed1987

Correlation between n-octanol/water partition coefficient and liquid chromatographic retention for caffeine and its metabolites, and some structure-pharmacokinetic considerations.

A method to establish the correlation between the reverse phase high performance liquid chromatographic retention of caffeine and its metabolites and their n-octanol/water partition coefficients is described. The log (P) values were always below zero, ranging from -0.02 to -2.03. The capacity factor quadratically back-extrapolated to 100% water eluent (k'w) was used as the index of lipophilicity. The compounds examined gave a good correlation (r greater than 0.99) with log (k'w) if considered in separate series, depending on the substituent position. For a structure-pharmacokinetic relationship study, correlations were found between the partition coefficient and some pharmacokinetic parameters, suggesting that for drugs that are widely metabolized, any predictions of their disposition from physicochemical characteristics are hazardous.

1-Octanol↗
PubMed1987

Aspirin prolongs bleeding time in uremia by a mechanism distinct from platelet cyclooxygenase inhibition.

We reported that aspirin (ASA) abnormally prolongs bleeding time (BT) in uremia. The present study was designed to investigate whether the abnormally prolonged post-ASA BT in uremia is due to different ASA pharmacokinetics and bioavailability that might be a consequence of uremic condition, platelet cyclooxygenase is peculiarly sensitive to ASA in uremia, and ASA affects primary hemostasis in uremia by a mechanism independent of cyclooxygenase inhibition. Our results showed that in patients with uremia, but not in normal subjects, ASA markedly prolongs the BT. This effect is transient and depends on the presence of ASA in the blood. The observed differences in ASA kinetic parameters are not an explanation of the exaggerated effect of ASA on primary hemostasis in uremia. The sensitivity of platelet cyclooxygenase to ASA inhibition is comparable in uremics and in normal subjects. The temporal dissociation between ASA-induced prolongation of BT and the effect on platelet thromboxane A2 generation suggests that ASA inhibits platelet function in uremia by a mechanism distinct from cyclooxygenase blocking. This possibility is strengthened by the observation that ibuprofen at a dose that fully inhibits platelet cyclooxygenase activity does not significantly prolong BT.

Acetylation↗