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Biomedical subjects

B M Frey

Publications and source records attributed to B M Frey.

At least 73 records · Page 4Linked to original sources
PubMed1990

Clinical pharmacokinetics of prednisone and prednisolone.

The growth of knowledge in the field of the pharmacokinetics of prednisolone/prednisone has been slow for several reasons. First, convenient and specific methods for measuring these steroids only became available with the development of high performance liquid chromatographic methods. Secondly, prednisolone is nonlinearly bound to transcortin and albumin: since the unbound concentrations of prednisolone are biologically relevant, it was necessary to determine the free fraction in each plasma sample. Thirdly, due to the short half-life of prednisolone no steady-state is achieved, and therefore area under the concentration-time curve needed to be determined in all studies. Fourthly, prednisolone and prednisone are interconvertible and prednisolone is given intravenously as an ester prodrug, features which created controversies about the correct interpretation of pharmacokinetic results. Finally, the total body clearances of total and (to a lesser degree) of unbound prednisolone increase with increasing concentrations of prednisolone. Therefore, in order to compare pharmacokinetic results between different subjects, standardised doses had to be administered. The investigations performed so far have revealed that: (1) the dose-dependent pharmacokinetics partly explain the clinical observation that an alternate-day regimen with prednisone yields fewer biological effects; (2) the interconversion of prednisone into prednisolone is not a limiting factor, even in patients with severely impaired liver function; (3) hypoproteinaemia per se does not cause increased unbound concentrations of prednisolone in vivo; (4) patients with liver failure, renal failure or a renal transplant, subjects older than 65 years, women on estrogen-containing oral contraceptive steroids or subjects taking ketoconazole have increased unbound concentrations of prednisolone-whereas hyperthyroid patients, some patients with Crohn's disease, subjects taking microsomal liver enzyme-inducing agents or patients on intravenous prednisolone phthalate (instead of prednisolone phosphate) or on some brands of enteric coated prednisolone tablets have decreased concentrations of prednisolone. The biological relevance of the altered pharmacokinetics is supported in part by altered clinical effects and altered effects on cellular immunofunctions.

Animals↗
PubMed1990

Increase of plasma nonesterified fatty acid concentration and decrease of albumin binding affinity after intravenous injection of glycocholate-lecithin mixed micelles.

Lipophilic drugs intended for intravenous use can be solubilized by mixed-micellar systems containing glycoholic acid and lecithin (MM). Our present studies determined the influence of such MM preparations on albumin binding of monoacetyldiaminodiphenyl sulfone (MADDS), a deputy ligand for bilirubin. After intravenous administration of MMs to healthy male and female adult volunteers, concentration-time profiles of bile acid and nonesterified (NEFA) and esterified fatty acids were obtained as well. In vitro experiments with blood from adults and from neonatal cords indicated a modest reduction in reserve albumin for binding of MADDS after addition of MMs, resulting from glycocholic acid in the micellar preparation. After injection of MM preparations with up to 530 mg glycocholic acid, a rapid decrease of the reserve albumin was observed. The effect was more pronounced in men than in women and resulted in different areas under the time curve for the decrease (p = 0.049). At their maximum (3 to 10 minutes after MM doses) the decreases averaged (+/- SD) 68% +/- 14% in men and 45% +/- 8.5% in women. Low reserve albumin concentrations were maintained over 20 minutes despite rapidly declining bile acid concentrations. Injection of MM caused a drastic increase of NEFA in the serum samples with a more pronounced effect in men (average +/- SD increase: 473% +/- 93%) than in women (148% +/- 91%) (p = 0.01). The changes in NEFA concentrations ran reciprocal to the changes of reserve albumin for binding MADDS. In all subjects the increase in NEFA was accompanied by a decrease in reserve albumin for palmitate. Fatty acid binding to albumin was well restored within 1 hour. Thus, before drugs incorporated in MM can be prescribed to neonates who are at risk for having kernicterus, the impact of intravenous MM on bilirubin binding and NEFA levels must be investigated in that patient population.

Adult↗
PubMed1989

Impaired liver function in stable renal allograft recipients.

Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.

Cyclosporins↗
PubMed1989

Study of acute renal ischemia in the rat using magnetic resonance imaging and spectroscopy.

Magnetic resonance (MR) imaging and spectroscopy, chemical lactate measurements, and microscopic examinations were performed to investigate acute renal ischemia in rats. MR images (1H) and spectra (31P and 1H) were acquired on a 2.0-T superconducting small-bore magnet by using implanted coils. Occlusion of the renal artery induced a significant decrease in signal intensity of the renal parenchyma on T2-weighted images, which was most obvious in the outer medulla (-50 +/- 15%, n = 8, P less than 0.001) and was the result of venous congestion, as verified histologically, 31P spectroscopy demonstrated a drop in pH from 7.3 +/- 0.2 to 6.6 +/- 0.2 (n = 18, P less than 0.001), characterized by a time constant (Tc) in the same range as that of the depletion of ATP (2.3 +/- 1.3 min versus 1.9 +/- 1.2 min, n = 10, P = ns). By means of 1H spectroscopy, a lactate peak was detected within 1.5 to 4 min of ischemia, still increasing in intensity after 1 h of ischemia. The Tc of the lactate buildup (15.9 +/- 7.5 min, n = 8) was significantly longer than that of the drop in pH (P less than 0.005). The chemically measured intrarenal concentration of lactate was 1.3 +/- 0.5 mumol/g in control kidneys and 8.7 +/- 3.2 mumol/g (P less than 0.005) in kidneys made ischemic for 1 h. The present study demonstrated important features of acute renal ischemia: (a) acute ischemia induces venous congestion in the medulla; (b) accumulation of lactate is not the main cause of the intracellular acidification observed during ischemia.

Animals↗
PubMed1989

Impact of ketoconazole on the metabolism of prednisolone.

The impact of ketoconazole (200 mg for 7 days) on the kinetics of oral prednisone and intravenous prednisolone and on the apparent activity of the 6 beta-hydroxylase was investigated in 10 healthy volunteers. The ratio of urinary 6 beta-OH-cortisol/17-OH-corticosteroids declined by greater than 50% and the urinary excretion of 6 beta-OH-prednisolone decreased more than twofold in all subjects. The decline of the activity of the 6 beta-hydroxylase was associated with impaired metabolic and renal clearances of total and unbound prednisolone. The ratios of the AUCs of prednisolone/prednisone after oral prednisone and intravenous prednisolone were independent of the administration of ketoconazole, suggesting that the enzymes responsible for the interconversion of prednisolone in equilibrium prednisone were not affected by ketoconazole. Thus ketoconazole inhibits 6 beta-hydroxylase and increases the exposure of the body to the biologically active unbound prednisolone after oral prednisone or intravenous prednisolone.

Adult↗
PubMed1989

Cyclosporine kinetics in renal transplant patients as assessed by high-performance liquid chromatography and radioimmunoassay using monoclonal and polyclonal antibodies.

The area under the blood concentration vs. time curves of cyclosporine (24 hr) were determined nonspecifically by the polyclonal RIA, specifically by a monoclonal RIA and by HPLC after an oral and an i.v. dose of CsA in 10 renal transplant patients. The mean blood concentrations determined by monoclonal RIA were 10-20% higher than those measured by HPLC, whereas the concentrations assessed by polyclonal RIA were greater than 100% higher than those determined by HPLC. As a corollary, the pharmacokinetic parameters (clearance, volume of distribution, and systemic availability) differed when the results from the 3 methods were compared. The RIA/HPLC concentration ratio of CsA was higher after oral than after i.v. dosing when RIA measurements were performed by the polyclonal but not by the monoclonal RIA. These ratios changed continuously during the first 12 hr after the administration when the polyclonal but not when the monoclonal RIA was used. In conclusion, blood concentrations assessed by the 3 methods are not identical, and when compared with the polyclonal RIA the monoclonal RIA exhibits 3 advantages: (1) much less crossreactivity with metabolites; (2) a constant RIA/HPLC concentration ratio after the third hr after administration of CsA; and (3) a RIA/HPLC concentration ratio that is independent of the route of administration.

Adult↗
PubMed1989

Clinical career ladders: Thomas Jefferson University Hospital.

The clinical career ladder program developed for pharmacists at Thomas Jefferson University Hospital, a 700-bed teaching hospital, is described. A task force was assembled to develop a clinical career ladder that would parallel the managerial advancement track in terms of rewards and recognition. The task force created separate lists of competencies for staff and clinical pharmacists and ranked the competencies according to their complexity and the number of years most pharmacists would need to achieve them. Separate pathways were established for staff and clinical pharmacists: staff pharmacist I, II, and III and clinical pharmacist I, II, and III. A salary scale designed to provide meaningful salary increases between levels was established. Nearly all pharmacists who are hired begin at level I and are allowed to apply for promotion to level II within six months. Opportunities for promotion occur twice annually. Pharmacists who have received an overall rating of effective or outstanding at the most recent performance appraisal may submit documented evidence that they have gained the knowledge and skills required at the higher level. A promotions review board evaluates each application and informs the director of pharmacy as to whether the applicant meets the criteria for promotion. Response to the program has been favorable, as indicated by the number of pharmacists who have applied for promotion and the quality of their applications. A carefully planned clinical career ladder program was well received by pharmacists, who responded by acquiring the knowledge and skills necessary for promotion.

Career Mobility↗
PubMed1988

Trough levels and concentration time curves of cyclosporine in patients undergoing renal transplantation.

We determined the AUC of cyclosporine (24 hours) nonspecifically by RIA and specifically by HPLC after an oral and an intravenous dose of cyclosporine in 58 patients undergoing renal transplantation. The RIA/HPLC concentration ratio of cyclosporine changed continuously during the first 12 hours after administration. The ratio was higher after oral than after intravenous administration and varied from patient to patient. The predictive value of trough levels for the corresponding AUCs was better when trough levels were assessed 24 than 12 hours after administration. Trough levels assessed by RIA poorly predicted AUCs measured specifically by HPLC. Therefore if, in the future, therapeutic cyclosporine monitoring has to be improved, trough levels should be assessed 24 hours after the last dose by means of a specific HPLC method.

Adult↗
PubMed1988

Altered metabolism and decreased efficacy of prednisolone and prednisone in patients with hyperthyroidism.

To evaluate the effect of hyperthyroidism on the protein binding and metabolism of prednisolone, eight subjects with hyperthyroidism were investigated before and after thyroid status returned to normal. Hyperthyroidism was associated with a reduced volume of distribution of prednisolone, a decreased systemic availability of prednisolone after oral prednisone, a displacement of the prednisolone in equilibrium with prednisone equilibrium toward prednisone, and an increased nonrenal clearance of unbound prednisolone in the presence of an impaired 6 beta-hydroxyprednisolone formation. After oral prednisone or intravenous prednisolone, patients with hyperthyroidism had lower albumin-bound, transcortin-bound, and unbound concentrations of prednisolone but normal affinities of albumin and transcortin for prednisolone binding. These differences in prednisolone plasma concentrations were biologically relevant, because the capacity of these plasma samples to inhibit allogeneically stimulated lymphocytes was lower by 70% in the hyperthyroid than in the euthyroid state. Thus hyperthyroidism reduces the biologic effect of prednisolone and exhibits a differential effect on various enzymes involved in the catabolism of prednisolone.

Administration, Oral↗
PubMed1988

Kinetics of prednisolone and endogenous cortisol suppression in the elderly.

The kinetics of prednisolone after intravenous prednisolone and oral prednisone were investigated in 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. The systemic availability of unbound prednisolone after oral prednisone and the apparent interconversion of prednisolone into prednisone and vice versa (reflecting the activity of the 11 beta-hydroxydehydrogenase) were independent of age. The total exposure of the elderly subjects to prednisolone was increased because the nonrenal (5.7 +/- 1.0 vs. 7.7 +/- 1.6 ml/min/kg, mean +/- SD; P less than 0.001) and renal (0.9 +/- 0.3 vs. 2.9 +/- 0.7 ml/min/kg; P less than 0.001) clearances of unbound prednisolone were lower in the elderly. The fractional clearance of 6 beta-hydroxyprednisolone (reflecting the activity of the 6 beta-hydroxylase) decreased linearly with the metabolic clearance of prednisolone. Despite increased prednisolone exposure, elderly subjects had higher endogenous cortisol concentrations. It was concluded that elderly subjects exhibit higher concentrations of both total and unbound prednisolone. Despite this greater exposure of target tissues, there appears to be less suppression of endogenous cortisol concentrations in plasma compared with younger subjects.

Administration, Oral↗
PubMed1987

Evidence that cyclosporine does not affect the metabolism of prednisolone after renal transplantation.

The following investigation was performed to establish whether renal transplant patients treated with cyclosporine and prednisone have a decreased prednisolone catabolism and/or an increased systemic availability of oral prednisone when compared with patients treated with azathioprine and prednisone. Therefore we assessed, by HPLC and equilibrium dialysis, the total concentrations of prednisolone and prednisone and the unbound concentrations of prednisolone in plasma samples collected over 24 hr, and the 24-hr urinary excretion of prednisolone, prednisone, and 6 beta-hydroxyprednisolone after an i.v. dose of prednisolone and an equal oral dose of prednisone in 25 renal transplant patients on cyclosporine and in 25 patients on azathioprine and prednisone one month after transplantation. The metabolic clearance, the renal clearance, the volume of distribution, and the systemic availability of total and unbound prednisolone were identical in patients with and without cyclosporine. The apparent activities of the oxidoreductases involved in the biotransformation of prednisone into prednisolone and vice-versa were not affected by cyclosporine therapy. The fractional urinary excretions of 6 beta-hydroxyprednisolone increased with increasing metabolic clearance rate of prednisolone (r = 0.50, P less than 0.001). This relationship was not modulated by cyclosporine, indicating that cyclosporine does not affect the activity of the microsomal P-450-dependent 6 beta-hydroxylase. Thus, early after transplantation, patients on cyclosporine have a normal metabolism of prednisolone.

Azathioprine↗
PubMed1987

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug-drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1-acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1-acid glycoprotein were increased between 50-85% even at 'therapeutic' doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1-acid glycoprotein.

Glycocholic Acid↗
PubMed1987

Stereochemistry of aromatic phenytoin hydroxylation in various drug hydroxylation phenotypes in humans.

Phenytoin pharmacokinetics exhibit large intersubject differences and coinheritance of phenytoin metabolism with known drug hydroxylation polymorphisms was therefore suspected. To study the inherited enzymatic mechanisms underlying phenytoin disposition in humans, we have investigated the rate and the stereochemical course of aromatic phenytoin hydroxylation in subjects with and without genetic drug hydroxylation deficiencies for mephenytoin or debrisoquine. For the separate analysis of S- and R-enantiomers of 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH; the major phenytoin metabolite), a chiral ligand exchange chromatography system was used. The S-enantiomer of HPPH was the major urinary phenytoin metabolite irrespective of the various drug hydroxylation phenotypes studied. By contrast, the formation of the HPPH R-enantiomer was significantly decreased in poor metabolizer phenotypes of mephenytoin leading to a bimodal distribution of the urinary HPPH S/R-ratio in humans which was correlated closely with the mephenytoin hydroxylation index. Thus, HPPH S/R-values greater than 40 are likely to occur in S-mephenytoin hydroxylation-deficient phenotypes. Analysis of HPPH S/R-ratios in urine samples in a population of 122 randomly selected epileptic patients under chronic phenytoin treatment showed that product-stereoselective aromatic phenytoin hydroxylation is preserved after chronic drug administration. In subjects with and without genetic S-mephenytoin hydroxylation deficiency, extensive HPPH formation was confirmed by a pronounced NIH-shift of the tritium isotope during the product-stereoselective hydroxylation of the pro-S phenyl ring of phenytoin. Substrate-stereoselective glucuronidation of R- and S-HPPH (and related enantiomeric hydantoin metabolites) could be excluded based on identical urinary excretion of p.o. administered pure metabolite enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Effect of liver function on the metabolism of prednisone and prednisolone in humans.

The systemic availability of total prednisone and unbound prednisolone, and the urinary excretion of 6 beta-hydroxyprednisolone, were measured after an oral dose of prednisone and an i.v. dose of prednisolone in 22 patients covering a wide range of liver function (galactose elimination capacity ranging from 3.3 mg/min X kg body wt to 9.2 mg/min X kg body wt). The area under the plasma concentration versus time curves of prednisolone and of prednisone decreased with increasing galactose elimination capacity. This dependency of the steroid concentrations on liver function was attributed to a decreased metabolic clearance and not to an increased systemic availability of the steroid given p.o. in patients with impaired liver function. The fractional excretion and the fractional clearance of 6 beta-hydroxyprednisolone declined with decreasing metabolic clearance rate of prednisolone or with decreasing galactose elimination capacity. Thus, the enzymes involved in the 6 beta-hydroxylation are not spared as liver function declines, and the exposure to the biologically active unbound prednisolone is increased in patients with impaired liver function in relation to the amount of prednisone or prednisolone administered.

Adult↗
PubMed1986

The dose-dependent systemic availability of prednisone: one reason for the reduced biological effect of alternate-day prednisone.

An analysis of the literature was performed, revealing that in many studies both the desired and the undesired effects are decreased in alternate-day prednisone regimens as compared with the daily regimens. In the present report evidence is given that part of the diminished biological effect of dose-spacing regimens is attributable to a decreased total exposure to prednisolone. Following a high dose of 0.8 mg kg-1 of oral prednisone or prednisolone the plasma concentration vs time curves of total prednisolone, unbound prednisolone and prednisolone bound to albumin or transcortin were always less than four times higher than following a low dose of 0.2 mg kg-1 of prednisone or prednisolone. This dose-dependent systemic availability of prednisolone explains partly the diminished biological effect when the same total amount of prednisone or prednisolone is divided into several small doses as opposed to a single oral dose.

Administration, Oral↗
PubMed1985

The effect of altered prednisolone kinetics in patients with the nephrotic syndrome and in women taking oral contraceptive steroids on human mixed lymphocyte cultures.

The purpose of this study was to examine the influence of altered prednisolone kinetics in patients with the nephrotic syndrome and women taking oral contraceptive steroids on mixed lymphocyte cultures (MLC). After oral and iv prednisolone treatment, blood samples were collected over 24 h. The area under the plasma concentration vs. time curve (AUC) of unbound, transcortin- bound, and albumin-bound prednisolone was determined. All plasma samples were incubated with MLCs, and the area under the inhibition vs. time curve of the MLC (AUIC), a measure of the effect over time, was calculated. The steroid concentrations required to produce half-maximal inhibition (EC50) were calculated. The 10 women taking oral contraceptives had higher AUCs of unbound and transcortin-bound prednisolone than the 10 normal subjects. The mean biological effect (AUIC value) was more pronounced in women taking contraceptive steroids. An analysis of the concentration-response curves revealed that the EC50 values of total, but not unbound, prednisolone were higher in women taking contraceptives. Compared with the normal subjects, the 9 nephrotic patients had lower total and comparable unbound AUCs of prednisolone. The AUIC values were higher whereas the EC50 values of unbound and total prednisolone were lower in the nephrotic patients. These findings indicate that the increased steroid effect in women taking oral contraceptives is explained by higher concentrations of prednisolone, while the increased effect in nephrotic patients is not attributable to the abnormal kinetics or protein binding of prednisolone.

Adult↗
PubMed1985

Pharmacokinetics of 3 prednisolone prodrugs. Evidence of therapeutic inequivalence in renal transplant patients with rejection.

Renal allograft rejections are often treated with high doses of prednisone or prednisolone. The solubility of the biologically active prednisolone is poor. Therefore prednisolone is given i.v. as prednisolone disodium phosphate (prednisolone phosphate) or as prednisolone sodium tetrahydrophthalate (prednisolone phthalate). The time course of hydrolysis of high doses of these prodrugs and the reduction of high doses of oral prednisone into prednisolone has not been investigated. Therefore 10 patients treated for acute rejection were given, on 3 occasions, oral prednisone, i.v. prednisolone phosphate, or i.v. prednisolone phthalate in equimolar doses corresponding to 7 mg/kg of prednisolone. Blood samples were collected over a 24-hr period. Measurements were performed by high-performance liquid chromatography and equilibrium dialysis. The time to peak, the peak concentrations, and the area under the plasma-concentration-vs.-time curve (AUC) of prednisone and of unbound prednisolone were calculated. In all patients the hydrolysis of the prednisolone phosphate ester was faster than that of the prednisolone phthalate ester. The mean (+/- SD) peak concentrations of unbound prednisolone were higher after i.v. prednisolone phosphate (18.5 +/- 3.4 micrograms/ml) than after i.v. prednisolone phthalate (2.9 +/- 0.5 micrograms/ml) or after oral prednisone (3.1 +/- 0.8 micrograms/ml), (P less than 0.001). The mean AUCs of unbound prednisolone were 2324 +/- 683 micrograms/ml/min from prednisolone phosphate, 1209 +/- 324 micrograms/ml/min from prednisolone phthalate, and 1584 +/- 556 micrograms/ml/min from oral prednisone. The AUCs of prednisolone from i.v. prednisolone phosphate (P less than 0.001) or from oral prednisone (P less than 0.005) were higher than from i.v. prednisolone phthalate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗