Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone

Summary 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 µg/ml/min vs 188±28 µg/ml/min, p<0.001) and unbound prednisolone (64±10 µg/ml/min vs 41±10 µg/ml/min, p<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<0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.     

Plasma protein binding of prednisolone in normal volunteers and arthritic patients

Summary The plasma binding of prednisolone was studied in twenty normal volunteers and twenty rheumatoid arthritis patients. An in vitro assessment of the binding following the addition of prednisolone, prednisone, and hydrocortisone to the plasmas obtained from the subjects showed significant differences in the percentage of prednisolone bound. However, the differences observed were regarded as clinically insignificant. The plasma protein binding was determined by an in vitro equilibrium dialysis of the individual plasma samples at 37° C. Prednisolone levels on both sides of the dialysis membrane were determined using radioactivity and HPLC analytical methodologies. The percentages of prednisolone bound calculated from the analytical results of either the radiochemical or HPLC method were not significantly different. The change in the percentage of prednisolone bound to plasma proteins was studied as a function of the total prednisolone plasma concentration in a normal volunteer and in a systemic lupus erythematosis patient. As a result of prednisolone binding to both transcortin and albumin, the binding of prednisolone changes as a function of prednisolone concentration. The binding data were fitted using nonlinear least squares regression, and the affinity constants for the binding of prednisolone to transcortin and albumin were estimated.     

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m ² for the 5mg dose to 2271 ml/min/1.73 m ² for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m ² over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.This work was supported in part by Grant 24211 from the National Institutes of General Medical Sciences, National Institutes of Health.     

Effects of oral contraceptive combinations containing levonorgestrel or desogestrel on serum proteins and androgen binding

The effects of the oral contraceptive combinations 0.125 mg Org 2969 (desogestrel) (13-ethyl-11-methylene-18, 19-dinor-17α-pregn-4-en-20-yn-17—01) + 0.05 mg ethinyloestradiol (EE) and 0.125 mg levonorgestrel + 0.05 mg EE on serum sex-hormone-binding globulin (SHBG), ceruloplasmin, transcortin and ratio free testosterone over total testosterone (percentage free testosterone) and ratio free 5α-dihydrotestosterone over total 5α-dihydrotestosterone (percentage free 5α-dihydrotestosterone) were compared in healthy female volunteers.

Treatment was randomly distributed over the volunteers; 11 women received Org 2969 + EE and 11 women received levonorgestrel + EE. These combinations induced similar increases in transcortin levels (115 and 140%) and ceruloplasmin levels (115 and 123 %) after 3 months of treatment. However, the combination Org 2969 + EE induced a substantial increase (213%) in SHBG capacity after 3 months of treatment, whereas a smaller increase (80%) was observed with levonorgestrel + EE. A return to pretreatment values was observed 2 months after termination of treatment for all parameters. The difference in the effects of both preparations on SHBG was statistically significant and can be best explained by a difference in the androgenicity of the progestogens. A good correlation was observed between SHBG capacity and the reciprocal value of the percentage free testosterone and the reciprocal value of the percentage free 5α-dihydro-testosterone. These results confirm that SHBG is the major regulator of the biologically active free androgen fraction in women before, during and after combined oral contraceptive treatment.     

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.     

The macromolecular binding of prednisone in plasma of healthy volunteers including pregnant women and oral contraceptive users

The macromolecular binding of prednisone has been studied in the plasma of eight healthy human volunteers. The subjects included two control males, two control females, two females taking estrogen-containing oral contraceptives, and two females in the third trimester of pregnancy. All volunteers exhibited the expected nonlinear plasma binding of prednisolone with free fraction increasing as the total prednisolone concentration was increased. Both the oral contraceptive and pregnant subjects had increased transcortin binding capacity over the control volunteers as evidenced by their increased binding of prednisolone. Prednisone macromolecular binding, however, was not altered by either changing total prednisone concentration or transcortin binding capacity. The mean prednisone free fraction was 0.250 ± 0.027 in the eight subjects over the concentration range 0–2500 ng/ml. The addition of prednisolone in up to a 25- fold excess did not alter prednisone's free fraction. Prednisone apparently does not bind to transcortin with the same strong affinity that characterizes prednisolone's binding, and due to albumin's extensive binding capacity, prednisone macromolecular binding is not saturable over the pharmacological drug concentration range.Supported in part by NIH grant GM 26691. During the course of this work Linda E. Gustavson received support as the American Foundation for Pharmaceutical Education Edwin L. Newcomb Memorial Fellow.     

The effect of prednisone and hydrocortisone on the plasma protein binding of prednisolone in man

Summary The protein binding of prednisolone was studied in plasma obtained from healthy volunteers in the presence of added amounts of prednisone and hydrocortisone. The plasma protein binding was determined using in vitro equilibrium dialysis for 16 h at 37°C against isotonic Krebs-Ringer buffer using radioactive prednisolone. Prednisone appeared to have no effect on prednisolone binding. This surprising result was observed even when prednisone concentrations were more than 35 fold greater than prednisolone concentrations. In contrast, a marked competition between hydrocortisone and prednisolone was observed. These binding data were fit using a nonlinear least squares regression computer program and the capacity and affinity constants for the binding of prednisolone to transcortin and albumin were estimated including the competition for binding sites between prednisolone and hydrocortisone. The results from these studies compare favorably with recent parameter calculations, and our previous work where differences in binding were noted between cushingoid and noncushingoid patients.     

Effects of oral contraceptive therapy on the circadian patterns of cortisol and thyrotropin (TSH).

The daily variation of serum cortisol and thyrotropin (TSH) has been simultaneously recorded every 30-min. in 4 women taking the same oral contraceptive containing oestrogens and progestogens and in 4 control women. The circadian rhythm of cortisol persisted under contraceptive therapy with about a 2.5 fold elevation of the mean level and amplitude of the basal rhythm. Theoretical equilibrium calculations of the circadian variations of the free, transcortin-bound and albumin-bound cortisol fractions showed that these elevations are explained qualitatively and quantitatively by an oestrogen-induced increase of the same order of the transcortin cortisol-binding sites. As a consequence of the already high saturation of transcortin in normal conditions, the magnitude of the variation of free cortisol level resulting from a burst in cortisol secretion varies with the time of day. The role of albumin as a buffer is thereby emphasized. The early morning maximum, characterizing the normal TSH daily pattern, appeared to be considerably enhanced in women under contraceptive therapy. If the circadian variations of TSH are driven by thyrotropin releasing hormone (TRH), these higher morning peaks probably reflect a higher burst of TRH secretion rather than an increased responsiveness of the pituitary to TRH secretion induced by contraceptive therapy. Finally these results do not support the hypothesis of a regulation of TSH circadian variations by an inhibiotry action of cortisol. Contraceptive therapy does not appear to play a role at the level of the central clock or on the resetting mechanism.