PubMed Health⌕ Search

Biomedical subjects

C F van Bezooijen

Publications and source records attributed to C F van Bezooijen.

At least 19 recordsLinked to original sources
PubMed1995

The influence of dietary restriction on the metabolism of theophylline and antipyrine in the ageing female BN/BiRij rat.

The influence of ageing and dietary restriction (DR) on the in vivo activities of different P450 enzymes was studied longitudinally in female BN/BiRij rats. For this purpose, antipyrine (AP) and theophylline (TH) were used as substrates. The metabolic clearances of AP (CIm AP) and TH (CIm TH) were used as indicators for P450 enzyme activities in vivo. Therefore, we also included the assessment of the clearances of formation of three AP metabolites, i.e., 3-hydroxymethylantipyrine (CI-->HMA), 4-hydroxyantipyrine (CI-->OHA) and norantipyrine (CI-->NORA). Ninety, 50 and 10% survival times were prolonged significantly in DR rats. In control animals, the contribution to the metabolism of AP in the formation of HMA, OHA and NORA, expressed as percentage of the dose, decreased with ageing, indicating that other pathways compensate for this decrease. Only a significant decrease in the metabolism to OHA was observed in DR animals. CI-->HMA, CI-->OHA and CI-->NORA showed an age-related decrease in the control rats, whereas in the DR rats an age-related decrease was observed for CI-->HMA and CI-->OHA. The results of the present study suggest that the decrease in the activities of the P450 enzymes involved in the formation of HMA, OHA and NORA have a later onset in the DR rats. In conclusion, DR not only has a strong positive influence on the health and life span of the rats, but also results in a delayed onset of the decrease in activity of certain P450 enzymes.

Aging↗
PubMed1994

The influence of aging on the metabolism of simultaneously administered hexobarbital enantiomers and antipyrine before and after phenobarbital induction in male rats: a longitudinal study.

The influence of aging on the metabolism of antipyrine (AP) and hexobarbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12, 24 and 30 months. The metabolic clearances of AP (Clm AP), R-HB (Clm R-HB) and S-HB (Clm S-HB) were used as indicators for P450 enzyme activities in vivo. This also included the assessment of the clearances of formation of three AP metabolites, 3-hydroxymethylantipyrine (Cl-->HMA), 4-hydroxyantipyrine (Cl-->OHA) and norantipyrine (Cl-->NORA). Aging appeared to have little influence on the pharmacokinetics of the model compounds. By contrast, the influence of PB pretreatment on Clm AP changed dramatically with aging. The extent of induction decreased from 4.5-fold at 6 months to 1.7-fold at 30 months. Aging influenced the clearances of formation of the three metabolites differentially. Clm S-HB was about six times higher than Clm R-HB without induction. After PB induction, S-HB did not reach detectable levels in plasma at 6, 12 and 24 months. At 30 months, PB pretreatment resulted in a significantly decreased Clm S-HB when compared with the uninduced state. The extent of induction of R-HB metabolism had decreased strongly at 24 and 30 months. The present results clearly indicate that in the aged rat, the P450 enzyme system is much less sensitive to PB induction.

Aging↗
PubMed1993

Increased sensitivity to the anticonvulsant effect of valproate in aging BN/BiRij rats.

The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.5 mg/min/kg. The infusion was terminated when the anticonvulsant effect intensity had reached the maximum attainable level or at a total infusion time of three hours. A nonlinear relationship between valproate concentration and anticonvulsant effect intensity was observed with no maximal effect in the concentration range up to 1200 mg.L-1. With increasing age a parallel shift in the concentration versus anticonvulsant effect relationships toward lower concentrations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.

Aging↗
PubMed1993

Cortisol production rate and the urinary excretion of 17-hydroxycorticosteroids, free cortisol, and 6 beta-hydroxycortisol in healthy elderly men and women.

BACKGROUND: Although many workers have tested adrenal function in the elderly, few have studied the effect of aging on cortisol production rate or urinary free cortisol or 6 beta-hydroxycortisol excretion, and none have published comparisons of these variables between old people of defined health status and young people. METHODS: We have measured cortisol production rate and the urinary excretion of free cortisol, 6 beta-hydroxycortisol, 17-hydroxycorticosteroids (Porter-Silber chromogens) and creatinine in elderly men and women screened by the SENIEUR protocol and in young men; 17-hydroxycorticosteroid and 6 beta-hydroxycortisol excretion were also measured in young women. The period of measurement was 24 h or, usually, 48 h. RESULTS: Only 6 beta-hydroxycortisol excretion was affected by aging; it was lower in the elderly men and women than in their younger counterparts. Urinary free cortisol excretion was lower in the elderly women than in the elderly men. There were no significant differences between groups in cortisol production rate or 17-hydroxycorticosteroid excretion. Excretion and (over the first 24 h) clearance of creatinine were lower in the old women than in the old men. The cortisol-related variables tended to be positively correlated with each other and with the relevant creatinine-related variables in the elderly subjects; over the first but not the second 24 h, most of the correlations were significant in the men and women combined. CONCLUSIONS: With the exception of 6 beta-hydroxycortisol, the data agree with measurements of plasma cortisol and the results of adrenal function tests in showing little change in hypothalamic-pituitary-adrenal function with aging in healthy people.

17-Hydroxycorticosteroids↗
PubMed1993

The relationship between phenazone (antipyrine) metabolite formation and theophylline metabolism in healthy and frail elderly women.

The influence of aging on the metabolism of phenazone (antipyrine), and the relationship between the formation of 3 phenazone metabolites and the metabolic clearance of theophylline in healthy and frail elderly women, were examined. Whereas the elimination half-life did not change, clearance of phenazone decreased by about 50% with age in healthy women receiving phenazone without theophylline. However, the summation of the urinary recovery of phenazone and the measured metabolites, expressed as percentage of the phenazone dose, was lower in the healthy elderly (37 +/- 9% vs 74 +/- 15%). In both healthy and frail females the clearance of formation of 4-hydroxy-phenazone and the metabolic clearance of theophylline correlated strongly (r = 0.93 and 0.90, respectively). In non-healthy elderly females, strong correlations were also observed between the other metabolic pathways of phenazone and the metabolic clearance of theophylline. Coadministration of theophylline in the elderly increased the percentage of the phenazone dose excreted as the measured metabolites. A considerably higher interindividual variability in the disposition of phenazone and theophylline was observed in the frail elderly women. This high degree of variability in drug metabolism may be one of the explanations for the problems often occurring after drug prescription in the elderly.

Adult↗
PubMed1992

Age and the pharmacokinetic-pharmacodynamic relationship of phenobarbital in rats: "pseudo"-longitudinal vs cross-sectional study design.

In a previous study, an apparent age-related increase in brain sensitivity to the anesthetic effect of phenobarbital was observed in BN/BiRij rats. However, since this study was conducted according to a cross-sectional design, the observed change could, in principle, also have been the result of a cohort effect. The purpose of the present investigation was to exclude the role of such a cohort effect by adopting a "pseudo"-longitudinal study design. In this design 45 animals out of one cohort were reserved, and one subgroup was investigated at five ages (7, 14, 21, 29, and 34 months). A decrease in the anesthetic threshold dose of phenobarbital was found during aging, which appeared to be due mainly to an increase in the brain sensitivity. It is concluded that the previously observed increase in brain sensitivity is indeed the result of the aging process rather than a cohort effect.

Aging↗
PubMed1992

Pharmacodynamics of the anticonvulsant effect of oxazepam in aging BN/BiRij rats.

1. The purpose of this investigation was to examine the influence of increasing age on the pharmacokinetics and the time course of the anticonvulsant response of oxazepam in BN/BiRij rats as an animal model of aging. 2. Oxazepam was administered intravenously in a dose of 12 mg kg-1 body weight and the anticonvulsant effect intensity was measured as elevation above baseline of a threshold for induction of localized seizure activity (TLS). Direct cortical stimulation with ramp shaped electrical pulse trains of increasing intensity was used to determine this threshold. 3. The pharmacological effect vs. time profile showed in young rats an anticonvulsant component followed by proconvulsant component which is suggestive for the occurrence of acute tolerance and/or withdrawal syndrome. With increasing age the proconvulsant component disappeared, resulting in a monophasic effect profile (anticonvulsant effect only) at the age of 35 months with significantly higher anticonvulsant effect intensity immediately following drug administration. No age-related changes in the pharmacokinetic parameters of oxazepam were observed. 4. In five animals of each age group, benzodiazepine receptor binding characteristics were determined in vitro with [3H]-flunitrazepam as a ligand. Both receptor density and affinity did not show age-related changes. Available literature data on post-receptor events do not indicate conclusive age-related changes. 5. It is concluded, that the observed change in the pharmacodynamics of anticonvulsant effect of oxazepam can be explained by the disappearance of the tolerance/withdrawal phenomenon. This is compatible with a decreased efficiency of homeostatic control mechanisms in the elderly.

Aging↗
PubMed1992

Pharmacokinetic-EEG effect relationship of midazolam in aging BN/BiRij rats.

1. The purpose of the present investigations was to determine the influence of increasing age on the pharmacokinetics and pharmacodynamics of midazolam in male BN/BiRij rats as an animal model of aging. 2. Midazolam was administered intravenously at a dose of 2.5 mg kg-1 and its pharmacokinetics were determined on the basis of plasma concentrations as measured by high performance liquid chromatography (h.p.l.c.). Pharmacodynamics were studied using the midazolam-induced changes in the electro-encephalogram (EEG) as a measure of the pharmacological effect. Results were evaluated on the basis of simultaneous pharmacokinetic-pharmacodynamic modelling. In an attempt to differentiate between the effects of aging and of concurrent disease, an extensive clinical biochemical/pathological examination was conducted in individual rats by an independent pathologist. 3. The pharmacokinetics of midazolam were best characterized on the basis of a two exponential model. In the 4-month-old rats the values of the clearance, volume of distribution and elimination half-life were 104 +/- 13 ml min-1 kg-1 (mean +/- s.e. mean), 3.4 +/- 0.7 l kg-1 and 30 +/- 3 min, respectively. With increasing age, no changes in the pharmacokinetics of midazolam were observed. 4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/- 6 micrograms l-1 and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed.4. The pharmacodynamics of midazolam were determined on the basis of the sigmoidal Emax model. In the 4-month-old rats the values of the parameters relative maximum effect, midazolam concentration at half maximum effect and Hill factor were 106 +/- 10%, 50 +/-6 lg 1' and 1.6 +/- 0.3, respectively. In the group as a whole no significant changes in the pharmacodynamic parameters of midazolam were observed. However, when diseased animals were excluded from the evaluation, a tendency towards a decrease in the midazolam concentration at half maximum effect to 25 +/- 14 pg 1-1 was observed in the 36-month-old rats.5. These findings suggest, that increasing age is associated with a tendency towards an increased brain sensitivity to midazolam, which is reflected in a parallel shift of the concentration vs. EEG effect relationship towards lower concentrations. However, it appears that factors other than age also contribute to interindividual variability in pharmacodynamics, considering the substantial interindividual variability within certain age groups.

Aging↗
PubMed1990

The influence of ageing on the induction of the mRNAs of rat liver cytochromes P450IIB1 and P450IIB2.

To investigate the influence of age on the regulation of the cytochromes P450IIB1 and P450IIB2 the levels of the messenger RNAs for these two cytochromes were determined in liver cytoplasmic RNA of rats of various ages after maximal induction with either phenobarbital or isosafrole and in untreated rats. The levels of these mRNAs were determined by solution hybridization with a RNA-probe (riboprobe system) complementary to both mRNAs. This study showed a marked decrease in the maximal induction levels of these mRNAs between the ages of 12 and 36 months irrespective of the type of inducer used. To assess whether this age-related decrease could be found for both individual mRNAs also solution hybridization experiments were performed with deoxyoligonucleotide probes of a defined sequence. The data presented in this paper show that ageing influences the levels of both the cytochrome P450IIB1 and P450IIB2 mRNA in a similar way. After induction the amount of mRNA for P450IIB1 was in all age groups measured four- to five-fold higher than that of P450IIB2. These data indicate that previously observed age-related changes in the cytochrome P450 system could be related to a lower accumulation of its mRNAs.

Aging↗
PubMed1990

Effect of different doses of 3-methylcholanthrene on the localization of the 3-methylcholanthrene-inducible isoenzymes of cytochrome P450 within the centrilobular and periportal zones of the rat liver.

Immunohistochemical staining techniques were used to investigate the localization of the 3-methylcholanthrene inducible isoenzymes (P450 IA1 and IA2) in the rat liver. The rats were induced with different doses of 3-methylcholanthrene, ranging from 2.5 to 25 mg/kg body weight. A heterogeneous induction pattern was observed with induction doses of 2.5; 5; 7.5 and 10 mg/kg body weight with the highest concentration of the isoenzymes around the central vein. With a dose of 25 mg/kg body weight, a homogeneous pattern was found. Induction with a dose of 15 mg/kg body weight resulted in an intermediate situation.

Animals↗
PubMed1989

The effect of age on antipyrine metabolism by liver microsomes isolated from phenobarbital-treated rats.

A study was performed to test the hypothesis that ageing influences the activities of diverse forms or populations of cytochrome P-450 isoenzymes in different ways. The formation of antipyrine metabolites in induced rats is mediated by such different forms or populations of cytochrome P-450 isoenzymes. To test the hypothesis, the formation rates of antipyrine metabolites by liver microsomes isolated from phenobarbital-treated rats of different ages was determined. After phenobarbital induction in vitro, the maximal velocity for norantipyrine formation decreased from 12 to 24 months and then showed a tendency to increase with age. Hydroxymethylantipyrine formation did not change with age. 4-Hydroxyantipyrine increased between 3 and 12 months and remained constant afterwards. This is in agreement with data obtained in vivo in uninduced male BN/BiRij rats. It can be concluded that age does indeed influence the activities of different forms or populations of the cytochrome P-450 isoenzymes in different ways. Consequently, determining the overall clearance of antipyrine, which is metabolized by several isoenzymes, especially in the induced situation, is not to be recommended for measuring the activity of cytochrome P-450 isoenzymes as a function of age.

Aging↗
PubMed1989

Pharmacokinetics of hexobarbital in young and old rats.

Hexobarbital is a drug widely used to study the capacity of the liver to metabolize drugs. The pharmacokinetics of hexobarbital in 3- and 30-month-old male BN/BiRij rats were studied. The half-life of hexobarbital in 30-month-old rats (39.9 +/- 4.1 min) was significantly higher than that of 3-month-old ones (21.3 +/- 3.8 min). The volume of distribution (ml.kg-1 body weight) did not change with age. The intrinsic clearance, expressed as ml.min-1.kg-1 body weight, of hexobarbital in 30-month-old rats (20.2 +/- 6.6) was half that of the 3-month-old ones (39.5 +/- 7.6). Further studies will be performed to investigate the effect of age on the intrinsic clearance of S(+)- and R(-)- hexobarbital.

Age Factors↗
PubMed1989

The effect of age on antipyrine pharmacokinetics and metabolite formation in rats.

The great interindividual variation in drug handling, especially in the elderly, causes a problem in determining the correct individual dose for the administration of a drug. A solution would be the determination of the capacity to metabolize lipophilic drugs in vivo on an individual basis. One approach, as reported in the literature, may be to determine the clearance rates of the antipyrine metabolites, which are formed by different isoenzymes of cytochrome P-450. Pharmacokinetics of antipyrine were determined in 3-, 12-, 24-, 30- and 36-month-old male BN/BiRij rats. The elimination T1/2 did not change with age, or were changes found in apparent volume of distribution. The systemic clearance of 24-month-old rats, when expressed as milliliters per minute-1 was higher than that of 3- and 12-month-old ones. When expressed as milliliters per minute-1 per kilogram-1, the systemic clearance decreased between 3 and 12 months. Thereafter, no change occurred. The partial clearance, expressed as milliliters per minute-1, did not change with age. Expressed as milliliters per minute-1 per kilogram-1, the partial clearance of the metabolites also did not change for hydroxymethylantipyrine (HMA) and 4-hydroxyantipyrine (4-OHA) but for norantipyrine (NORA) a decrease was found between 3 and 24 months, followed by a tendency to increase between 24 and 36 months. When the data were expressed per rat (milliliters per minute-1), the increase in liver weight with age influenced the data markedly.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1988

Molecular aspects of age-related changes in albumin synthesis in female WAG/Rij rats.

The rate of albumin gene transcription and the level of albumin RNA sequences in liver nuclei of rats of various ages were determined to investigate the regulation of age-related changes in levels of cytoplasmic albumin mRNA in rat liver. No change was observed with age in both the rate of albumin gene transcription and the amount of nuclear albumin RNA sequences, which suggests that the increase in cytoplasmic albumin mRNA content in the rat liver with age is caused by a decreased turnover of this messenger. The length of poly(A)-tails of rat liver cytoplasmic RNA with age was also examined. Although no change with age was observed in the poly(A)-tail length sedimenting at the peak fraction, a shift towards shorter poly(A)-tails was found with age in the overall poly(A)-tail length distribution.

Aging↗
PubMed1988

Albumin elimination in female WAG/Rij rats with age: a longitudinal study.

A longitudinal study was performed to examine total albumin elimination and urinary albumin excretion in the female WAG/Rij rat. Complete necropsies were performed following the spontaneous death of the animals. The survival characteristics of this group was similar to that of survival cohorts. An increase in total albumin elimination, urinary protein excretion and urinary albumin excretion was observed with age. A proportional increase in the contribution of albumin to the urinary protein excretion was also observed. However, the observed increase in urinary albumin excretion could not totally account for the increase in total albumin elimination. The predominant kidney lesion was chronic progressive nephrosis. The histological severity of the renal lesions were closely correlated with the increase in urinary albumin and total protein loss. It is concluded that the increase in total albumin elimination in rats in this study was due to age-related changes and not to cohort effects.

Aging↗
PubMed1988

[Interindividual variability in drug metabolism, especially in the elderly. Underlying mechanisms and a possible solution].

The metabolism of a drug reveals a large interindividual variability, which might be attributed to large interindividual differences in the activity of cytochrome P-450 isoenzymes. However, it is difficult to determine this activity in the intact animal or man. With the help of antipyrine, a measure for this activity in man might be possible. Antipyrine is metabolized via 3 metabolic pathways, which are regulated by different isoenzymes of cyt.P-450. In addition, the ratio 6 beta-hydroxycortisol(6 beta-OHF)/17-hydroxycorticosteroids(17-OHCS) in the urine is a measure for the activity of another cyt.P-450 isoenzyme, namely NIF. A correlation between the formation rates of the antipyrine metabolites, hydroxymethylantipyrine and hydroxyantipyrine (OHA) and the clearance of hexobarbital and theophylline, respectively, has been observed. In young volunteers, a good correlation between the formation rate of OHA and the clearance of theophylline have also been found. It must be investigated whether these correlations can also be observed if one smokes, consumes alcohol, keeps diet, takes several drugs, is young or old or is a male or female. If this is the case, the metabolism is predictable, the dose can be adapted and adverse reactions can be prevented, especially in the aged.

Aged↗
PubMed1987

Anatomy, function and aging in the mouse liver.

A brief overview is given of the embryology, gross and microscopic anatomy and sinusoidal lining cells of the mouse liver. The handling of xenobiotics is also considered. So called phase I and II reactions are of major importance. Furthermore, heterogeneity of metabolism occurs in the different zones of the hepatic acinus. Finally, some of the manifest pathological changes are discussed. Despite the occurrence of these changes there is still no clearcut evidence that liver function declines with age.

Aging↗