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Biomedical subjects

B M Frey

Publications and source records attributed to B M Frey.

At least 91 records · Page 5Linked to original sources
PubMed1984

[Transcortin concentrations in the plasma of normal persons and patients with kidney and liver diseases].

The purpose of the study was to assess the influence of chronic kidney and liver diseases on the transcortin concentrations in plasma. The mean (+/- SD) plasma concentration of transcortin was 45.0 +/- 6.7 mg/l in women not taking oral contraceptive steroids and 41.2 +/- 6.7 mg/l in healthy male volunteers. Patients with the nephrotic syndrome had low transcortin concentrations (females: 20.9 +/- 8.5 mg/l; males: 26.0 +/- 6.0 mg/l). Abnormally low concentrations were measured in females treated for endstage renal disease with chronic ambulant peritoneal dialysis (CAPD) (30.8 +/- 7.5 mg/l). Patients on hemodialysis or with a functioning renal allograft had normal transcortin concentrations in plasma. Females suffering from a primary biliary cirrhosis had normal transcortin concentrations and male patients with an alcoholic cirrhosis had abnormally low mean transcortin concentrations in plasma (32.6 +/- 7.4 mg/l). The transcortin concentrations in patients with a Gilbert syndrome were normal. Among patients with a kidney or liver disease, the large variability of the transcortin concentration in plasma indicates that the knowledge of the transcortin concentration or the unbound steroid concentration in plasma is mandatory for the interpretation of total glucocorticoid concentrations in plasma.

Adult↗
PubMed1984

Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone.

The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n = 10) had higher mean (+/- SD) area under the plasma concentration versus time curves of total (428 +/- 67 micrograms/ml/min vs 188 +/- 28 micrograms/ml/min, p less than 0.001) and unbound prednisolone (64 +/- 10 micrograms/ml/min vs 41 +/- 10 micrograms/ml/min, p less than 0.001) than women not taking oral contraceptive steroids (n = 10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p less than 0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.

Adult↗
PubMed1984

Altered plasma protein-binding of prednisolone in patients with the nephrotic syndrome.

Prednisolone binds in plasma to both albumin and transcortin. Since altered concentrations of plasma proteins change capacity and association constants of the drug-protein complex and thus influence the disposition of the drug, the kinetics of prednisolone following oral prednisone and intravenous (IV) prednisolone were studied in ten nephrotic patients and in 12 healthy volunteers. Compared to normal volunteers, nephrotic patients had significantly higher mean (+/- SD) association constants for the albumin-prednisolone complex (4.20 +/- 2.10 X 10(3) M-1 v 2.26 +/- 0.46 X 10(3) M-1, P less than 0.005) and tended to have higher association constants for the transcortin-prednisolone complex. Following the IV administration of prednisolone and the oral administration of prednisone, nephrotic patients exhibited lower total plasma concentrations of prednisolone than did normal volunteers. The difference was attributable to lower albumin-bound and/or transcortin-bound, but not unbound, concentrations of prednisolone in plasma. The mean prednisolone bioavailability from oral prednisone was not different between nephrotic patients and controls. When calculated with reference to total prednisolone concentrations in plasma, the mean nonrenal clearance rate, but not the mean renal clearance rate, was higher in the nephrotic patients than in the controls (2.63 +/- 0.61 mL/min/kg v 1.85 +/- 0.33 mL/min/kg, P less than 0.005). Compared to normal volunteers, patients with the nephrotic syndrome had lower renal clearance rates of unbound prednisolone when prednisolone was given intravenously (1.58 +/- 0.88 mL/min/kg v 2.89 +/- 0.89 mL/min/kg, P less than 0.005) or when prednisone was given orally (1.18 +/- 0.86 mL/min/kg v 2.80 +/- 1.13 mL/min/kg, P less than 0.005). Nephrotic patients had lower ratios of unbound prednisolone clearance/creatinine clearance (fractional excretion) after IV prednisolone (1.50 +/- 0.81 v 2.27 +/- 0.49, P less than 0.025) or after oral prednisone (1.07 +/- 0.60 v 2.12 +/- 0.77, P less than 0.005) than the controls. Since these fractional excretion values of unbound prednisolone exceeded one, there must be glomerular filtration of prednisolone bound to plasma proteins and/or tubular secretion of prednisolone. This study indicates that the nephrotic dysproteinemia changes the binding of prednisolone to plasma proteins not only in point of quantity, but also in point of quality, and alters the disposition of prednisolone.

Administration, Oral↗
PubMed1984

Phenytoin modulates the pharmacokinetics of prednisolone and the pharmacodynamics of prednisolone as assessed by the inhibition of the mixed lymphocyte reaction in humans.

Following induction of the microsomal liver enzymes, lower total prednisolone concentrations in plasma and an altered pattern of the prednisolone metabolites generated were observed. The purpose of the present study was to establish whether--as a consequence of an enhanced clearance--lower unbound concentrations of prednisolone in plasma are detectable after enzyme induction and to determine if the altered prednisolone metabolism modulates the biological effect. Before and during phenytoin dosage in ten volunteers, the mean (+/-SD) total body clearance (ml min-1 kg-1) of both total and unbound prednisolone increased from 2.74 +/- 0.47 to 3.94 +/- 0.66 (P less than 0.001) and from 10.76 +/- 2.68 to 16.00 +/- 3.17 (P less than 0.001), respectively. These increments were due to increased non-renal clearances. The immunosuppressive activity as a function of time in plasma determined as the percent inhibition of the mixed lymphocyte reaction decreased by one third after phenytoin dosing, while the EC50 values of unbound prednisolone were unaffected. Thus enzyme induction decreases both the unbound prednisolone concentration and the steroid efficacy.

Adult↗
PubMed1984

Pharmacokinetics and pharmacodynamics of three different prednisolone prodrugs: effect on circulating lymphocyte subsets and function.

To be pharmacologically active, i.v. prednisolone disodium phosphate (prednisolone phosphate), prednisolone sodium tetrahydrophthalate (prednisolone phthalate), and oral prednisone have to be converted in vivo into prednisolone. The purpose of the present study was to establish whether these agents are functionally equivalent when given in equimolar doses. The peak concentrations of total and unbound prednisolone assessed by HPLC and equilibrium dialysis in five normal volunteers were five to 12 times higher after i.v. prednisolone phosphate than after i.v. prednisolone phthalate or oral prednisone (p less than 0.001). The area under the plasma concentration vs time curves (AUC) of total and unbound prednisolone was higher after i.v. prednisolone phosphate than after oral prednisone or i.v. prednisolone phthalate (p less than 0.001). The immunosuppressive activity of the plasma samples was determined as the percentage inhibition of the mixed lymphocyte reaction, and the area under the inhibition vs time curve of the MLR (AUIC), a measure of immunosuppressive capacity over time, was calculated. After i.v. prednisolone phthalate or oral prednisone, the mean AUC of unbound prednisolone were 45 and 61% of that obtained after i.v. prednisolone phosphate, and the corresponding AUIC were 76 and 68%, respectively, indicating lower systemic availability of prednisolone and less of an immunosuppressive effect in plasma after i.v. prednisolone phthalate or oral prednisone than after i.v. prednisolone phosphate. These differences in biologic activity of the plasma were corroborated by determining ex vivo the cell cycle progression within the G1 phase, and the interleukin 2 (IL 2) release after the activation of peripheral lymphocytes obtained at various time points after administration of the three steroids. After steroid doses corresponding to 1 mg/kg of prednisolone, a transient inhibition of 80% of IL 2 production was observed with all three glucocorticoids given, whereas the maximal inhibition of the IL 2 production was 60, 30, and 22% after a low dose (0.1 mg/kg) of prednisolone phosphate, prednisone, or prednisolone phthalate, respectively. After the low dose, only minimal changes in the percentages of the OKT4+ and OKT8+ cells were detectable, whereas after the high dose of all three steroids the ratio of OKT4+ to the OKT8+ cells dropped, the decline being more pronounced after prednisolone phosphate than after prednisolone phthalate or prednisone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1983

Urinary 6 beta-hydroxyprednisolone excretion indicates enhanced prednisolone catabolism.

Patients with enhanced catabolism of prednisolone exhibit a reduction in steroid efficacy. Since prednisolone never reaches steady state at the usual dosage, the clearance rate can only be estimated by determining the area under the plasma concentration-time curve after an i.v. dose of prednisolone. To obviate that time-consuming procedure for screening of patients with enhanced prednisolone metabolism, we developed a quantitative assay for 6 beta-hydroxyprednisolone in urine to determine whether the urinary excretion of 6 beta-hydroxyprednisolone increases concomitantly with the clearance rate of total and of unbound prednisolone in subjects with an enhanced catabolism of prednisolone. The results are given separately for males and females because there is some debate as to whether females compared to males exhibit a higher capacity of the liver to hydroxylate steroids at the sixth position. Before and during the administration of phenytoin the total body clearance of total and of unbound prednisolone and the urinary excretion of prednisolone and of 6 beta-hydroxyprednisolone were determined in six female and eight male volunteers. The fraction of the i.v. dose of prednisolone excreted in urine as 6 beta-hydroxyprednisolone was higher in females than in males (p less than 0.001) and increased during phenytoin dosing from 6.4%-10.4% (range) to 15.6%-20.4% in females and from 2.4%-7.2% to 12.2%-18.3% in males. The ratio of 6 beta-hydroxyprednisolone to prednisolone in urine increased linearly with the nonrenal clearance of both total and unbound prednisolone. This is the first demonstration that the fractional excretion of 6 beta-hydroxyprednisolone increased after the induction of the microsomal liver enzymes. Thus measurements of urinary 6 beta-hydroxyprednisolone excretion may be of potential value to detect patients with enhanced catabolism of prednisolone.

Adult↗
PubMed1982

Simultaneous measurement of prednisone, prednisolone and 6 beta-hydroxyprednisolone in urine by high-performance liquid chromatography coupled with a radioactivity detector.

We describe the first method of routine measurement of prednisone, prednisolone and 6 beta-hydroxyprednisolone concomitantly in urine. Urine (3 ml) is extracted with ethyl acetate, washed with base and separated by high-performance liquid chromatography on a silica column with a solvent system of hexane--diethyl ether--ethanol--tetrahydrofuran--glacial acetic acid (59.9:31:2.3:6.5:0.3, v/v). The steroids are detected at 254 nm. Because no conventional internal standard was found, 6 beta-[3H]hydroxycortisol and [3H]prednisolone are added to urine prior to extraction; 3H is monitored by a radioactivity detector coupled with the chromatograph. The assay exhibits linearity from 200 to 7500 ng and an inter-day variability of less than 11.4% (C.V.).

Adult↗
PubMed1982

Nonlinear plasma protein binding and haemodialysis clearance of prednisolone.

The impact of nonlinear plasma protein binding of a drug on its removal by haemodialysis has been quantified. Prednisolone 10-100 mg was given i.v. to 10 renal transplant patients on haemodialysis for acute tubular necrosis. Dialysate and afferent and efferent blood samples were collected simultaneously in 67 instances. Total and unbound prednisolone in plasma and its total concentration in blood and dialysate were assessed by high performance liquid chromatography and equilibrium dialysis. The amount of prednisolone lost, as measured directly in the dialysate (21.8 +/- 4.4 micrograms/min, mean +/- SE), was predictable from the afferent-efferent blood concentration differences (20.1 +/- 4.8 micrograms/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1 +/- 3.0 micrograms/min). The amount of prednisolone lost in the dialysate increased linearly with unbound (r2 = 0.96) and hyperbolically with the total prednisolone concentration in plasma. The latter hyperbolic relationship is adequately described by the equation for nonlinear plasma protein binding, using the affinity and capacity constants of albumin and transcortin for prednisolone (r2 = 0.98). Thus, the haemodialysis clearance of total prednisolone is concentration-dependent, while the clearance of unbound prednisolone is constant (76 ml/min). Free clearance values or measurements of afferent-efferent blood concentrations are mandatory for a drug showing nonlinear plasma protein binding in order to predict the amount lost in the dialysate.

Blood Proteins↗
PubMed1982

Prednisolone pharmacodynamics assessed by inhibition of the mixed lymphocyte reaction.

Eight to 14 plasma samples were obtained from 12 patients on chronic prednisone treatment following their usual dose of prednisone (0.262 to 1.053 mg/kg . day) and following an equivalent amount of prednisolone given i.v. Total and unbound prednisolone were assessed by high performance liquid chromatography and by equilibrium dialysis. The immunosuppressive activity of the plasma was determined as the inhibition of the mixed lymphocyte reaction. The area under the plasma concentration time curve (AUC) for total and unbound prednisolone and the area under the inhibition time curve (AUIC) of the mixed lymphocyte reaction were determined by the trapezoidal rule. A hyperbolic concentration response curve was found when inhibition of the mixed lymphocyte reaction was plotted versus concentrations of total and free prednisolone. The mean EC50 (+/- SD) for total prednisolone concentration following the oral and the i.v. dosing was 66.3 +/- 26.7 and 86.5 +/- 30.9 ng/ml, respectively; for free prednisolone concentration the corresponding values were 10.0 +/- 5.0 and 12.4 +/- 12.6 ng/ml. A similar hyperbolic relationship is observed when the AUIC is plotted versus the AUC of free or total prednisolone, but not when AUIC is plotted versus the oral dose. Over the range of drug concentrations observed, no difference is found between total and free concentrations in the ability to predict inhibition of the mixed lymphocyte reaction.

Binding, Competitive↗
PubMed1982

Inequality of clearance values obtained by intravenous bolus and by steady-state infusion. Prednisolone studies in dogs.

In order to compare total and free prednisolone clearance values following an intravenous bolus dose with those following zero-order infusions to steady state, 6 dogs were given an intravenous bolus and four different zero-order infusions of prednisolone. Prednisolone clearance for the infusion studies were calculated by dividing the infusion rate by the steady-state concentration. Time-averaged clearances for the intravenous bolus doses were calculated as dose divided by area under the concentration curve. The total and unbound prednisolone clearance values calculated using the steady-state levels averaged 24 and 39% higher, respectively, than the corresponding clearance values obtained following intravenous bolus dosing.

Animals↗
PubMed1982

Altered prednisolone kinetics in patients with the nephrotic syndrome.

The impact of low plasma protein levels on the kinetics of prednisolone was investigated in patients with the nephrotic syndrome. Nephrotics exhibited higher unbound fractions of prednisolone, lower total plasma concentrations than normal volunteers, but normal unbound plasma concentrations and normal mean residence times. Thus altered prednisolone kinetics in patients with low plasma protein levels do not explain the higher frequency of prednisolone-related side-effects in these patients, compared to patients with normal plasma protein levels.

Adult↗
PubMed1982

Endogenous and exogenous glucocorticoids in cushingoid patients.

The pharmacokinetics of prednisone/prednisolone and the time-course of endogenous hydrocortisone were investigated in 15 stable renal transplant patients and 12 patients with oral mucocutaneous vesiculoerosive diseases. All 27 patients were given their usual prednisone dose orally on one occasion, and 24 were given an equivalent amount of prednisolone intravenously on another occasion. After dosing, 8-14 plasma samples were obtained for the determination of total prednisolone, prednisone, and hydrocortisone concentrations by high performance liquid chromatography and unbound prednisolone concentrations by equilibrium dialysis. The bioavailability of prednisone, the interconversion of prednisone into prednisolone, the total and unbound prednisolone clearances, the prednisolone binding capacity of albumin and transcortin, and the affinity of albumin for prednisolone were not different when the 14 patients without cushingoid side effects were compared with the 13 cushingoid patients. Patients with cushingoid side effects had a higher affinity constant for prednisolone binding to transcortin, more frequently exhibited peak hydrocortisone levels within the normal range, and more often had measurable (greater than 10 ng/ml) hydrocortisone in the plasma samples collected during the kinetic studies, as compared with those not showing side effects. The data suggest that endogenous hydrocortisone production is not as suppressed in patients with visible cushingoid signs as in noncushingoid patients and that no significant difference in the pharmacokinetics of exogenous glucocorticoids exists between patients with and without cushingoid side effects.

Blood Proteins↗
PubMed1982

Three radioactivity detectors for liquid-chromatographic systems compared.

Three radioactivity detectors coupled to a "high-performance" liquid-chromatography system are compared with regard to static efficiency, dynamic efficiency, background measurements, and within- and between-day variabilities. Their advantages and disadvantages are discussed.

Chromatography, High Pressure Liquid↗
PubMed1981

A single dose of azathioprine does not affect the pharmacokinetics of prednisolone following oral prednisone.

Clinical and pharmacokinetic observations suggest that azathioprine may diminish the plasma level of prednisolone. To study the extent of this possible interaction, and to define the underlying mechanism, total and unbound prednisolone and total prednisolone concentrations were assessed in 11 subjects following an oral dose of prednisone once with and once without concomitant oral administration of azathioprine. Azathioprine did not affect the area under the plasma concentration-time curve of total and unbound prednisolone; furthermore, the interconversion of prednisone into prednisolone was not influenced by azathioprine.

Administration, Oral↗