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Biomedical subjects

M Danhof

Publications and source records attributed to M Danhof.

At least 199 records · Page 11Linked to original sources
PubMed1985

Nifedipine: influence of renal function on pharmacokinetic/hemodynamic relationship.

The hemodynamic effects and kinetics of nifedipine were examined in four groups of five subjects with different degrees of impaired renal function. In a randomized order, each subject received nifedipine by an intravenous infusion (4.5 mg in 45 minutes) and by mouth as a sustained-release tablet (20 mg). Plasma concentrations of nifedipine and urinary metabolite excretion were measured by liquid chromatography. Heart rate, blood pressure, forearm blood flow, and plasma norepinephrine levels were examined serially. After intravenous nifedipine infusion, the elimination t1/2 was 106 +/- 24 minutes in controls and increased gradually across the groups to 230 +/- 94 minutes in the group with severe renal impairment. In these same groups, the volume of distribution at steady state was 0.78 +/- 0.23 and 1.47 +/- 0.24 L/kg, but total systemic clearance did not differ. Plasma protein binding decreased from 96.0% +/- 0.5% in controls to 93.5% +/- 0.4% in severe renal insufficiency. Except for systemic clearance, kinetics were closely related to creatinine clearance, as was the urinary excretion of the main nifedipine metabolite. Except for systemic availability, which tended to decrease, the kinetics of nifedipine tablets were not influenced by the degree of renal failure. Hemodynamic effects after intravenous nifedipine could be fit to plasma concentrations under a sigmoidal model. When compared with control values, the maximal effect on diastolic blood pressure was more than doubled in severe renal failure. The inverse correlation between maximal effect on diastolic blood pressure and creatinine clearance (r = -0.68) was independent of pretreatment values. Neither free drug levels corresponding to 50% of the maximal effect on diastolic blood pressure nor the slope of the concentration-effect curve was influenced by the degree of renal impairment. The maximal effect on forearm blood flow tended to increase in renal failure, whereas the effect on heart rate was unchanged. Blood pressure changes after oral nifedipine were of the order of those after intravenous infusion. We conclude that, although nifedipine kinetics differ in patients with renal failure, these changes do not explain the greater blood pressure lowering effect.

Administration, Oral↗
PubMed1985

Kinetics of drug action in disease states. V. Acute effect of urea infusion on phenobarbital concentrations in rats at onset of loss of righting reflex.

It has been reported that patients suffering from azotemia attributable to urinary obstruction required significantly less thiopental for induction and maintenance of general anesthesia than did a comparable group of patients with normal blood urea concentrations. Moreover, the thiopental requirements of normal subjects could be reduced by urea administration. In rats, experimental renal dysfunction was associated with reduced concentrations of phenobarbital (PB) in serum, serum water, brain and cerebro-spinal fluid at onset of a defined hypnotic effect (loss of righting reflex) produced by a slow i.v. infusion of PB. To determine the mechanism of this effect, these studies have now been repeated in normal rats made azotemic (approximately 170 mg of urea nitrogen/100 ml of serum) by intra-arterial infusion of urea and in control animals infused with saline solution. The total dose of thiopental required to produce loss of righting reflex was significantly reduced in the rats infused with urea. confirming the clinical observations. Similar results were obtained with PB and heptabarbital, two barbiturates that (unlike thiopental) are not racemic mixtures and are therefore more suitable for this investigation. On the other hand, urea infusion had no apparent effect on the concentrations of PB and heptabarbital in serum, brain and cerebrospinal fluid at onset of loss of righting reflex. Urea apparently affects the distribution kinetics of barbiturates and this, rather than increased receptor sensitivity, appears to be responsible for the decreased barbiturate dose requirements in acute experimental azotemia produced by urea infusion.

Animals↗
PubMed1985

Kinetics of drug action in disease states. IV. Effect of pregnancy on phenobarbital concentrations at onset of loss of righting reflex in rats.

This investigation was designed to determine if the acute hypnotic activity of a barbiturate is altered by advanced pregnancy. Twenty-day-pregnant rats and nonpregnant rats of the same age received an i.v. infusion of phenobarbital, 0.824 mg/min/rat, until they lost their righting reflex. The concentrations of total and free phenobarbital in serum at that time were significantly lower in pregnant than in nonpregnant animals. However, pregnancy had no effect on the concentrations of phenobarbital in the brain and cerebrospinal fluid at onset of loss of righting reflex. The difference of the serum phenobarbital concentrations was due to the slower rate of phenobarbital infusion received by the pregnant rats when normalized for body weight. The lack of difference of phenobarbital concentrations in cerebrospinal fluid, a site that reflects the concentration of the free drug at the sites of action, indicates that advanced pregnancy has no apparent effect on the central nervous system response to phenobarbital.

Animals↗
PubMed1985

Kinetics of drug action in disease states. VI. Effect of experimental diabetes on phenobarbital concentrations in rats at onset of loss of righting reflex.

To investigate the effect of diabetes on the sensitivity of the central nervous system to the hypnotic action of a barbiturate, studies were conducted on adult female Lewis rats made diabetic by injection of either streptozotocin or alloxan. The animals then received a slow i.v. infusion of phenobarbital (PB) until the onset of a defined pharmacologic effect [loss of righting reflex (LRR)] and the PB concentrations at that time in serum (total and unbound drug), brain and cerebrospinal fluid (CSF) were determined. In the experiments on rats with streptozotocin-induced diabetes, animals not treated with insulin had significantly lower serum concentrations of total PB at onset of LRR than did animals treated with insulin and nondiabetic control rats. Otherwise, there were no significant differences in PB concentrations between untreated diabetic and control animals. Additional experiments on untreated diabetic rats showed that, as in normal rats, the PB concentrations in CSF (but not in serum and brain) at onset of LRR were independent of PB infusion rate over a 10-fold range, indicating that PB equilibrates very rapidly between CSF and receptor sites. Experiments in rats with alloxan-induced diabetes showed no significant differences between untreated diabetic, insulin-treated diabetic, alloxan-nonresponding and nondiabetic control rats with respect to PB concentrations at onset of LRR in serum (total and unbound drug), brain and CSF and in serum protein binding. These results show that the central nervous system response to the hypnotic effect of PB is not significantly affected in two different experimental models of diabetes.

Animals↗
PubMed1985

Kinetics of drug action in disease states. VII. Effect of experimental renal dysfunction on the pharmacodynamics of ethanol in rats.

This investigation was designed to determine if renal dysfunction is associated with an increased sensitivity to the CNS depressant effect of ethanol. Adult female Lewis rats were given injections of either 2 or 5 mg/kg of uranyl nitrate (saline for controls) or had both ureters ligated (sham operation for controls) to provide different experimental models of renal dysfunction. Normal and renal dysfunction (ureter-ligated) rats were infused i.v. with ethanol at rates of 8.1, 16.3 or 32.6 mg/min; concentrations of ethanol in cerebrospinal fluid, serum and brain at onset of loss of righting reflex were independent of infusion rate in both groups, indicating rapid equilibration of ethanol between the sampling sites and the biophase. Ethanol concentrations in cerebrospinal fluid at onset and offset (after approximately 110 min of sleep) of loss of righting reflex were not significantly different, reflecting negligible acute tolerance development under the experimental conditions. Ethanol concentrations at onset of loss of righting reflex in cerebrospinal fluid, serum and brain of rats with severe renal dysfunction (5 mg/kg of uranyl nitrate-treated and ureterligated groups) were slightly but statistically significantly lower than in normal controls. This difference was relatively much smaller than the difference in phenobarbital concentrations observed in a similar preceding study, which is consistent with the different mechanisms of action of alcohols and barbiturates.

Animals↗
PubMed1984

Kinetics of drug action in disease states. II. Effect of experimental renal dysfunction on phenobarbital concentrations in rats at onset of loss of righting reflect.

The purpose of this investigation was to determine if renal dysfunction is associated with an alteration in the concentration-pharmacologic activity relationship of phenobarbital (PB). Adult female rats (congruent to 200 g) were pretreated with uranyl nitate or subjected to bilateral ureteral ligation to produce renal dysfunction. Saline-injected and sham-operated rats, respectively, served as controls. PB (0.824 mg/min) was infused i.v. until the animals lost their righting reflex (LRR). Renal dysfunction reduced the total dose of PB required to produce LRR, the concentrations of total and free (unbound) PB in serum and the concentrations of PB in brain and cerebrospinal fluid at onset of LRR. Results were quantitatively similar in both experimental models of impaired renal function. Concomitant infusion of p-hydroxyphenobarbital (the major metabolite of PB) and PB in rats with uranyl nitrate-induced renal dysfunction had no effect on the PB concentrations at onset of LRR. When PB was infused at different rates (either 0.412, 0.824, 2.04 or 4.12 mg/min), rats with renal dysfunction had increasing concentrations of PB at onset of LRR with increasing infusion rate, not only in serum and brain but also (unlike normal rats) in cerebrospinal fluid. Thus, renal dysfunction is associated with increased sensitivity to PB and with a change in the kinetic relationship between PB in cerebrospinal fluid and in the biophase.

Acute Kidney Injury↗
PubMed1984

Kinetics of drug action in disease states. I. Effect of infusion rate on phenobarbital concentrations in serum, brain and cerebrospinal fluid of normal rats at onset of loss of righting reflex.

The purpose of this investigation was to develop a method to determine the effect of various diseases on the concentration-pharmacologic activity relationship of phenobarbital (PB) in a manner that excludes or accounts for pharmacokinetic variables affecting drug disposition. Adult female rats (congruent to 180 g) received an i.v. infusion of PB at one of five different rates (0.412-4.12 mg/min) until the animals lost their righting reflex (after 8.0 +/- 0.4 to 62 +/- 10 min of infusion). The total dose, the serum concentration (both total and unbound drug) and the brain concentration of PB at onset of loss of righting reflex (LRR) increased with increasing infusion rate. The PB concentration in cerebrospinal fluid at onset of LRR (mean +/- S.D.: 108 +/- 19 micrograms/ml, n = 29) was not affected by the infusion rate. Concomitant infusion of PB and its p-hydroxy metabolite had no apparent effect on the concentrations of PB at onset of LRR even though the serum concentration of p-hydroxy PB was higher than upon infusion of PB only. The results of this investigation indicate that cerebrospinal fluid, unlike some regions of the brain, equilibrates very rapidly with the biophase of the receptors for PB-induced LRR. Determination of PB concentrations in the cerebrospinal fluid at the onset (rather than offset) of action facilitates assessment of the effect of diseases on the PB concentration-pharmacologic activity relationship by avoiding development of acute tolerance and excluding or minimizing effects due to disease-associated pharmacokinetic variables such as altered plasma protein binding and body distribution of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Disposition of hexobarbital in the rat. Estimation of "first-pass" elimination and influence of ether anesthesia.

The disposition of hexobarbital was studied in rats after i.v. and i.a. administration. In addition to sleeping times, plasma concentration profiles were measured. No significant differences were found in sleeping times, volumes of distribution, elimination half-lives or systemic clearances between these different routes. The average elimination half-lives were 13.5 +/- 0.8 (n = 17) and 11.6 +/- 1.9 min (n = 21) (means +/- S.E.M.), respectively, whereas the systemic whole blood clearance values were 75.4 +/- 3.4 (n = 17) and 85.8 +/- 3.5 ml/min/kg (n = 21) (means +/- S.E.M.). The values of the latter parameter approach hepatic blood flow in the rat (i.e., 100 ml/min/kg) and therefore the oral availability of hexobarbital was established by comparing areas under plasma concentration time curves, after i.v. and oral administration to the same rat. Oral availability was found to be only 36%, which corresponds to an extraction ratio of 64%. The consequences of such a "first-pass" effect are discussed in view of the use of hexobarbital as a model substrate for measuring drug-metabolizing enzyme activity. Furthermore, it was found that anesthesia as induced by diethylether during the experiments resulted in a very significant inhibition of the rate of hepatic metabolism of hexobarbital; the elimination half-life increased by about 50% due to a similar decrease in the systemic clearance. The protein binding of hexobarbital in rat plasma amounted to 51.4 +/- 1.2% (mean +/- S.E.M., n = 15) and it was found not to be dependent on the plasma concentration of hexobarbital in the range encountered in vivo.

Absorption↗
PubMed1982

Studies of the different metabolic pathways of antipyrine in man. Oral versus i.v. administration and the influence of urinary collection time.

The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8 +/- 1.9% of the dose was excreted in urine as unchanged antipyrine in 48 h, 24.9 +/- 6.3% as 4-hydroxyantipyrine, 16.5 +/- 3.2% as norantipyrine, 13.0 +/- 2.2% as 3-hydroxymethyl-antipyrine and 5.8 +/- 1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36 h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.

Administration, Oral↗
PubMed1982

Differential effects of enzyme induction on antipyrine metabolite formation.

1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethyl-antipyrine + 3-carboxy-antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4-hydroxyantipyrine and 3-hydroxymethyl-antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.

Adult↗
PubMed1982

3-Hydroxymethyl antipyrine excretion in urine after an oral dose of antipyrine. A reconsideration of previously published data and synthesis of a pure reference substance.

Previously published data from this laboratory on the urinary excretion of 3-hydroxymethyl antipyrine (one of the major metabolites of antipyrine in man) have to be reconsidered, because of use of an impure reference substance in the high-pressure liquid chromatographic assay method. Comparison with newly synthesized, pure 3-hydroxymethyl antipyrine has shown that a correction factor of 0.45 needs to be applied to previously published data. Details of the synthesis of the pure reference 3-hydroxymethyl antipyrine are given.

Administration, Oral↗
PubMed1981

Influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation.

The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation was studied by giving 500 mg antipyrine to 14 extensive and 10 poor metabolizers of debrisoquine. The pharmacokinetics of antipyrine were determined on the basis of the saliva concentration time curve and the cumulative urinary excretion of 4-hydroxyantipyrine, norantipyrine, 3-hydroxymethyl-antipyrine, and 3-carboxyantipyrine was measured for 32 h following drug administration. Antipyrine elimination half-life, volume of distribution, and total clearance were almost equal for the two groups. Significant differences in the excretion of antipyrine metabolites were not observed, except for 3-hydroxymethyl-antipyrine which was excreted in poor metabolizers about 30% less than in extensive metabolizers (p less than 0.01). However, this difference only reached borderline significance (p less than 0.1) when clearance values for production of this metabolite were calculated. It is concluded that different species of the drug-oxidizing enzymes (cytochrome P-450 system) are involved in the metabolism of debrisoquine and antipyrine. Possibly the enzyme responsible for hydroxylating debrisoquine is partly involved in the formation of 3-hydroxymethyl-antipyrine.

Aging↗
PubMed1980

Antipyrine metabolite formation in children in the acute phase of malnutrition and after recovery.

1. The plasma elimination rate of antipyrine and the urinary excretion of antipyrine and its primary metabolites 4-hydroxy-antipyrine, norantipyrine, 3-hydroxymethyl-antipyrine and 3-carboxyantipyrine were measured in five children in the acute phase of malnutrition and after recovery. The results were compared with those obtained in 3 normal children. 2. Upon nutritional rehabilitation antipyrine clearance increased from 0.65 +/- 0.14 ml min-1 kg-1 to 1.07 +/- 0.20 ml min-1 kg-1. 3. The urinary excretion of 4-hydroxy-antipyrine increased from 6.1 +/- 4.5 to 14.7 +/- 5.9%, norantipyrine from 8.8 +/- 5.7 to 14.3 +/- 5.4 and 3-hydroxy-methyl-antipyrine from 11.8 +/- 8.3 to 20.5 +/- 5.6% (% of dose/24h urine). Excretion of unchanged antipyrine decreased from 5.2 +/- 3.7 to 2.7 +/- 0.9% dose. The metabolite profile (ratio between the amounts of the various metabolites excreted) was not significantly different. 4. It is concluded that malnutrition decreases the rate of antipyrine metabolism, but it does not affect the three oxidative pathways differently.

Acute Disease↗
PubMed1979

Influence of bile salts on hepatic transport of dibromosulphthalein.

The influence of bile salts on hepatic transport of the organic anion dibromosulphthalein (DBSP) was investigated in rats. Bile salts influence the hepatic uptake, intracellular binding, and biliary excretion of DBSP. The overall effect depends on the administered dose of bile salts and DBSP. High doses of bile salts inhibited hepatic uptake of DBSP, whereas low doses of bile salts stimulated bile flow and simultaneously increased maximal biliary excretion of DBSP. The uncharged nonbile salt choleretic ouabain also stimulated biliary DBSP excretion. In contrast, the anionic nonbile salt choleretics, ethacrynic acid and theophylline, did not stimulate biliary excretion of DBSP. Because DBSP inhibited biliary excretion of ethacrynic acid and its metabolites, the lack of a stimulatory effect of ethacrynic acid choleresis might be explained by concomitant inhibition of biliary excretion of DBSP, masking the stimulatory effect of ethacrynic acid. Biliary transport maximum of DBSP was highly correlated with bile flow. The biliary clearance (Vmax/Km) was only moderately changed by bile salt administration, whereas the increase in the maximal biliary excretion rate was more pronounced, implying that the apparent Km for biliary excretion of DBSP was also increased by the bile salts. It is inferred that the stimulation of net biliary excretion of DBSP by bile salts may be due to a diminished transport from bile into the hepatocytes as the consequence of the decreased biliary concentration caused by the choleresis.

Animals↗
PubMed1979

Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high-performance liquid chromatography and some preliminary results in man.

A reversed phase system for the HPLC separation of antipyrine and its primary metabolites is described. Based on this system an assay procedure for antipyrine in plasma and saliva was developed with a lowest measurable concentration of 25 ng/ml and precision of +/- 3.6 and +/- 4.5%, respectively. Furthermore, assays for the parent compound, 3-hydroxymethyl-antipyrine, norantipyrine and 4-hydroxy-antipyrine in urine were developed. The lowest measurable concentration for these compounds is about 100 ng/ml except for 3-hydroxymethyl-antipyrine with a lowest measurable concentration of about 200 ng/ml. The precision was established at +/- 3.6 and +/- 5.0% for 3-hydroxymethyl-antipyrine, and antipyrine, respectively, and +/- 7.0 and +/- 3.6% for norantipyrine and 4-hydroxy-antipyrine, respectively. The method was applied to studies on antipyrine metabolism in humans. Following administration of a single dose of 500 mg antipyrine to 5 healthy volunteers, 3.3 +/- 1.2% of the dose was recovered from 48-hour hydrolyzed urine as unchanged drug, 39.7+/- 8.7% as 3-hydroxymethyl-antipyrine, 14.5 +/- 6.8% as norantipyrine and 28.5 +/- 2.2% as 4-hydroxy-antipyrine.

Animals↗