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D D Breimer

Publications and source records attributed to D D Breimer.

At least 199 records · Page 11Linked to original sources
PubMed1986

Intra-arterial administration of hexobarbital enantiomers to the rat: disposition and estimation of apparent extraction ratio.

The enantiomers of hexobarbital, designated as S(+)-HB and R(-)-HB, were administered intra-arterially to rats in a dose of 25 mg X kg-1. Blood pharmacokinetics of the parent compound and two metabolites as well as urinary excretion of three major metabolites were studied. Using previously obtained data following oral administration of S(+)-HB and R(-)-HB two different methods for calculation of the hepatic extraction ratio (E) were compared. The metabolite profile in the urine after intra-arterial administration was not basically different from corresponding data on oral administration. The clearance of low-dose, intra-arterially administered S(+)-HB is useful as an indicator of hepatic blood flow in the rat.

Animals↗
PubMed1986

Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration.

The pharmacokinetics and hemodynamic effects of nifedipine were studied in patients with liver cirrhosis and in age-matched healthy control subjects. In a randomized order each subject received nifedipine by intravenous infusion (4.5 mg in 45 minutes) and as a tablet (20 mg). After intravenous nifedipine patients had a longer elimination t1/2 (420 +/- 254 vs. 111 +/- 22 minutes; P less than 0.01), a greater volume of distribution (1.29 +/- 0.60 vs. 0.97 +/- 0.42 L/kg), and a lower systemic clearance (233 +/- 109 vs. 588 +/- 140 ml/min; P less than 0.001). Plasma protein binding of nifedipine was lower in the patients (P less than 0.001). After oral nifedipine systemic availability was much higher in patients (90.5% +/- 26.2% vs. 51.1% +/- 17.1%; P less than 0.01) and maximal in patients with a portacaval shunt. Blood pressure decreased and heart rate increased after intravenous nifedipine and these effects could be fitted to plasma concentrations by a sigmoidal model. Maximal effects on heart rate and diastolic blood pressure were not different in liver cirrhosis. When free drug levels were considered, the concentrations corresponding to half the maximal effect were also not different. Blood pressure changes with oral nifedipine were comparable with those after intravenous infusion. We conclude that in patients with liver cirrhosis the pharmacokinetics of nifedipine are considerably altered; dose reduction is recommended when such patients need oral nifedipine.

Absorption↗
PubMed1986

Antipyrine clearance and metabolite formation: the influence of liver volume and smoking.

The influence of liver volume and cigarette smoking on antipyrine clearance and metabolite formation was studied in seventeen volunteers (eight smokers, nine non-smokers). Inter-test coefficient of variation of liver volume (as determined by ultrasound) was 6.3%. The mean antipyrine clearance was 49.3 +/- 18.3 ml min-1 and when normalized for liver volume 36.1 +/- 10.1 ml min-1 l-1. The antipyrine clearance per unit volume of liver was significantly higher in smokers (43.0 +/- 10.5 ml min-1 l-1), than in non-smokers (30.0 +/- 4.6 ml min-1 l-1) (P less than 0.01). No significant difference was found between the two groups as to the excreted amounts of 4-hydroxyantipyrine (OHA), norantipyrine (NORA), and 3-hydroxymethylantipyrine (HMA). Normalized for liver volume the mean clearances for production (Clm) of these metabolites were significantly higher in the group of smokers than in the group of non-smokers. The greatest change was observed for OHA formation. However, analysis of variance showed that the differences in the percentages of change of the mean Clm of these metabolites in the two groups are not significant.

Adult↗
PubMed1986

Pharmacokinetics of temazepam compared with other benzodiazepine hypnotics--some clinical consequences.

When the various benzodiazepine hypnotics are studied, large differences are seen with regard to their pharmacokinetic properties and metabolism in man. Some are eliminated from the body at a relatively slow rate (e.g. nitrazepam), others are metabolized rather rapidly (temazepam, triazolam). Some benzodiazepine hypnotics have major active metabolites that are slowly eliminated (flurazepam, quazepam), while others have non-active metabolites (temazepam, lormetazepam). In hypnotic treatment, the duration of drug action should be restricted to the duration of the night, hence a compound with a relatively short elimination half-life may represent a more rational choice. An overview is given of the pharmacokinetics of the currently available benzodiazepine hypnotics with emphasis on temazepam and other hydroxylated benzodiazepines.

Anti-Anxiety Agents↗
PubMed1986

Correlation between the metabolism of hexobarbital and aminopyrine in vivo in rats.

Two model substrates for oxidative hepatic enzyme activity, namely hexobarbital and aminopyrine, were simultaneously orally administered to rats, and blood concentrations of the substrates measured by g.l.c. The apparent intrinsic clearances of hexobarbital (Cl*int.HB) and of aminopyrine (Cl*int,AM) were correlated in untreated rats, and in rats pretreated with phenobarbital, 3-methylcholanthrene, polychlorinated biphenyls or carbon tetrachloride. Cl*int,HB and Cl*int,AM were both increased by phenobarbital and polychlorinated biphenyl pretreatment. Pretreatment with 3-methylcholanthrene had hardly any effect, and carbon tetrachloride caused a strong diminution of Cl*int.HB and Cl*int.AM. When the dose of aminopyrine was decreased, both Cl*int,HB and Cl*int,AM increased. This indicated that the primary metabolite of aminopyrine, monomethylaminopyrine, inhibits cytochrome P-450. The correlation coefficient for all clearance data was 0.92 (N = 36). It was concluded that both hexobarbital and aminopyrine are metabolized in vivo by the same or closely related cytochrome P-450 isozymes, and both may be used as model substrates in vivo for metabolic conversions primarily mediated by the major phenobarbital-inducible cytochrome P-450 subspecies.

Administration, Oral↗
PubMed1986

An improved synthesis of 3-hydroxymethylantipyrine using antipyrine as starting material.

A partly new synthesis of 3-hydroxymethylantipyrine, an important metabolite of antipyrine in man and therefore frequently used as a reference substance, is described. The use of tri-n-butyltin hydride to reduce the vinyl bromide system in 3-hydroxymethyl-4-bromoantipyrine is the main improvement, since it enables the isolation of salt-free 3-hydroxymethylantipyrine in an almost quantitative yield.

Antipyrine↗
PubMed1986

Non-linear pharmacokinetics of sparteine in the rat.

In rats, blood concentrations of sparteine (SP) and relative concentrations of sodium borohydride-reducible metabolite following intra-arterial (i.a.) and portal venous administration of SP-sulphate were estimated up to 200 min. In 24 hr urine, unchanged SP was quantitated. Borohydride-reducible metabolite was measured as the difference in SP concentrations before and after reduction. Administration of SP in a dose of 50 mg/kg SP-sulphate i.a. revealed a blood concentration-time profile which did not allow characterization of the terminal half-life or systemic clearance. Therefore, the dose over the area under the curve up to 120 min after administration, CL0-120app, was defined as an apparent average clearance value over the time interval studied. After a dose of 50 mg/kg the CL0-120app was 34.8 +/- 5.9 ml/min/kg when administered i.a. and 80.4 +/- 7.5 ml/min/kg when administered via the portal vein, thus affording an estimate of 0.64 +/- 0.12 for the hepatic extraction ratio. A possible biliary excretion and enterohepatic circulation was studied in rats with a bile fistula. Although SP levels in blood were lower than in control rats, no SP was excreted in the bile and excretion of SP in urine was even slightly higher, which renders circulation of SP itself unlikely. About 25% of the dose was recovered in 180 min bile as borohydride-reducible metabolite, but the urinary excretion of borohydride-reducible metabolite was not changed. The gradual levelling-off of blood concentration versus time curves may partly be explained by the formation of reactive intermediates in the course of metabolism, which inactivate P-450. In support of this, the intrinsic clearance of orally administered hexobarbital (25 mg/kg) was determined 5 and 50 min after i.a. administered SP-sulphate (50 mg/kg), and decreased from 343 +/- 18 to 220 +/- 36 ml/min/kg (p less than 0.05).

Animals↗
PubMed1985

The Center for Bio-Pharmaceutical Sciences: scope and perspectives.

The Center for Bio-Pharmaceutical Sciences of the State University of Leiden was established in September 1984. Its main objective is to conduct multidisciplinary research on the production of drugs and their disposition and effects in man and animals. In addition, it will offer teaching programmes at M.Sc. and Ph.D. levels. Two integrated research themes may involve all disciplines present in the Center: stereoisomers and endogenous compounds. There will be close co-operation with the related disciplines medicine, chemistry, biology and biotechnology, and with pharmaceutical industry. Industry funding up to 35% of total funds will be pursued. An Industrial Liaison Body was established to take care of the management aspects of collaboration with industry.

Academies and Institutes↗
PubMed1985

Research in the Division of Pharmacology.

Within the Center for Bio-Pharmaceutical Sciences pharmacological research has its emphasis on kinetics of drug disposition, and its interrelationship with pharmacodynamics. The benzodiazepines present a class of related compounds where comparative studies have been performed. Both in humans and in animal models the relationship between plasma levels and central effects has been studied. Also the factors that influence individual responses to the same dose of a drug have been investigated. One of the approaches is the predictive value of antipyrine metabolite formation. Nifedipine shows polymorphism in oxidation, but it is possible to obtain the desired pharmacodynamic effect while minimizing side effects even in slow metabolizers.

Academies and Institutes↗
PubMed1985

Selected ion monitoring analysis of pseudoracemic hexobarbital and its major metabolites in blood and urine of rats.

A stereospecific synthesis of N1-(2H3)-labelled R(-)-hexobarbital is described. A sensitive and rapid selected ion monitoring assay procedure for pseudoracemic hexobarbital, consisting of equal amounts of S(+)-hexobarbital (1a) and (2H3)-R(-)-hexobarbital (1b) in 100 microliters blood samples of rats was developed. Both the parent enantiomers in blood and three major metabolites excreted in urine were quantified. An application of the method in rats is described, and the results are compared to previously obtained data of separately administered enantiomers.

Animals↗
PubMed1985

Antipyrine metabolite formation and excretion in patients with chronic renal failure.

In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides the parent drug, 3-hydroxymethylantipyrine (HMA) was present in plasma in the free and conjugated forms, whereas 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) were found only in the conjugated form. The same was true for urine. The plasma concentrations of these metabolites are too low to be measured in subjects with normal renal function. Plasma antipyrine clearance in the patients was in the same range as in healthy subjects. Investigation of metabolite kinetics, however, revealed that the rate of formation of NORA was preferentially decreased, whereas that of OHA and HMA were unaltered. Renal clearance of the metabolites of antipyrine was severely impaired in patients with renal insufficiency, and the resulting accumulation made it possible for the first-time to measure the antipyrine metabolites in plasma. Mean residence times of metabolites were longer than that of the parent compound. Renal clearances of the conjugates were correlated with the creatinine clearance, but were somewhat higher. Renal clearance of free HMA was lower and was also correlated with creatinine clearance. The mean clearance for glucuronidation of HMA was 93.1 ml/min. The results suggest that in healthy subjects Phase I metabolism is the rate-limiting step in the elimination of antipyrine, which is essential for its application as a model drug in metabolism studies.

Adult↗
PubMed1985

Influence of cimetidine on steady state concentration and metabolite formation from antipyrine infused with a rectal osmotic mini pump.

The utility of an osmotic rectal drug delivery system as a tool in steady-state pharmacokinetic interaction studies has been investigated using the cimetidine-antipyrine interaction. Antipyrine was administered to six healthy male volunteers at the rate of 15 mg/h until steady-state was reached. Cimetidine 400 mg was then given followed by 200 mg cimetidine after 2, 4 and 6 h. Antipyrine kinetics in plasma and saliva were assessed, and metabolite excretion was determined in urine. Antipyrine levels in plasma and saliva increased shortly after cimetidine administration, indicating inhibition of antipyrine metabolizing enzymes. From the metabolite data it was concluded that all major metabolic pathways of antipyrine were affected to the same extent. The effect lasted somewhat longer than anticipated on the basis of the plasma cimetidine concentrations, but it had disappeared within 48 hours after cessation of treatment. It is concluded that the osmotic rectal drug delivery system is a useful tool in pharmacokinetic interaction studies, because it provides very constant steady-state concentrations, thus permitting investigation of the time course of drug interactions.

Adult↗
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

Interaction between digoxin and nifedipine at steady state in patients with atrial fibrillation.

The possible kinetic and hemodynamic interactions between digoxin and nifedipine were evaluated in nine patients with atrial fibrillation who were receiving chronic digoxin. After 2 control weeks, nifedipine (20 mg b.i.d.), in a new formulation with sustained release characteristics, was added to the therapeutic regimen for 2 weeks. Trough serum digoxin concentrations and peak nifedipine concentrations were determined repeatedly. On the same days, resting blood pressure and heart rate were measured. During nifedipine administration, serum digoxin levels increased by 15% from 0.87 +/- 0.38 to 1.04 +/- 0.37 ng/ml (mean +/- SD, p less than 0.05). This was accompanied by a reduction in systolic and diastolic blood pressure of 16 +/- 6 (p less than 0.01) and 12 +/- 5 mm Hg (p less than 0.001), respectively. In two patients, noncardiac side effects were reported. In two other patients, nifedipine was discontinued because of skin rash and severe headache, respectively. In conclusion, plasma digoxin levels were elevated slightly in the presence of nifedipine, but this probably has little clinical relevance.

Adult↗
PubMed1985

Pharmacokinetics and nephrotoxicity of cyclosporine in renal transplant recipients.

Pharmacokinetics of Cyclosporine (CsA) were studied in 14 renal transplant patients during a three-month period of treatment. At 3 and 15 days after transplantation 12-hr blood level studies of the drug were performed to calculate the elimination half-life, area under the curve (AUC), and total blood clearance; trough levels were measured twice weekly. In 9 patients terminal half-lives could be calculated after discontinuation of CsA treatment. In the course of CsA treatment, prolongation of half-life was found in most cases, with a significant decrease in clearance (46 +/- 17 L/hr on day 3 versus 28 +/- 10 L/hr on day 15). This resulted in a continuous increase in the CsA blood level. The terminal half-life varied considerably among the patients (24-93 hr) and did not correlate with other pharmacokinetic parameters. A good correlation (r = 0.9589) was observed between CsA trough levels before discontinuation of CsA and the increment in renal function two weeks after conversion to azathioprine. This indicates that short-term CsA treatment induces a dose-dependent reversible nephrotoxic effect in renal transplant recipients.

Adult↗